Orgenesis Acquiring Tamir, And Other News: The Good, Bad And Ugly Of Biopharma – Seeking Alpha

Orgenesis to Acquire Tamir Biotechnology's Assets for $19 Million

Orgenesis Inc. (ORGS) reported that it has signed a deal with Tamir Biotechnology Inc., under which the former will acquire the assets of the latter, including its broad spectrum antiviral platform ranpirnase. The deal is cash- and stock-based and is expected to be worth nearly $19 million. Orgenesis plans to merge ranpirnase with its co-developed Bioxome technology for improving payload delivery direct to the cells.

Combined with ranpirnase, Bioxomes have showed the ability to fuse with cell membranes and delivering an intracellular cargo, mimicking the working of natural exosomes. Bioxomes, when loaded with predesignated genetic material, proteins, signaling molecules and drugs, copy the natural membrane fusion capacities of exosomes. This feature may help in providing more efficient antiviral results.

TamirBio is a clinical-stage company focusing on developing treatments for viruses and other pathological conditions. Its lead asset, ranpirnase, is a ribonuclease and belongs to a superfamily of enzymes which may catalyze the degradation of RNA. It may also mediate in different essential biological activities, such as the regulation of cell proliferation, differentiation, maturation and death. According to Orgenesis, this feature makes it suitable for treating viral and autoimmune diseases which require therapies with anti-proliferative and apoptotic properties.

TamirBio has used these properties for developing topical ranpirnase for treating human papillomavirus, a leading cause of genital warts. The drug candidate has been evaluated in Phase I/II clinical trial for genital warts, and the results demonstrated clear clinical effects. The company plans to hold additional clinical trials. Orgenesis CEO Vered Caplan said, In independent third-party testing, ranpirnase has shown anti-viral activity in multiple viruses. Additionally, over 1,000 patients have been dosed with ranpirnase in previous cancer/mesothelioma clinical trials. Ranpirnase demonstrated a strong safety and tolerability profile that should help accelerate the approval pathway. TamirBio claims that the drug candidate has shown preclinical antiviral activity in such viral diseases as HPV, HIV, Ebola, and SARS.

Orgenesis also provided updates about its operating activities and reported that its research & development labs are still working. In February, the company sold its subsidiary Masthercell Global Inc. to Catalent Pharma Solutions for nearly $127 million. Masthercell was a contract development manufacturing organization. Orgenesiss CGT Biotech Platform mainly consists of three core components, which are POCare Therapeutics, POCare Technologies, and POCare Network. The CGT Biotech Platform aims to decentralize the CGT supply chain.

The company also recently entered into a new joint venture with Revatis. The partnership will work towards providing autologous cell therapies with exosomes and other cellular products obtained from muscle-derived mesenchymal stem cells. The task of making the stem cells will be entrusted to Revatis, which will use its minimally invasive muscle biopsy technique and isolator technology for this purpose. Orgenesis will be responsible for providing clinical and regulatory expertise and access to its point-of-care (PoC) technology. This POCare platform provides access to a global network of hospitals and research institutes which may be used for carrying out clinical trials for developing life-saving therapies.

Teladoc Health Inc. (TDOC) stock showed solid gains as the ongoing pandemic has put a spotlight on telemedicines. The company has seen a surge in the download of its app BetterHelp, which has a virtual behavioral health offering. According to a research note released by Bank of America Global Research, the app had the download volume of nearly 1000 per day in March, which has now surged to over 1800 per day.

While telemedicine has been around for quite some time, the current scenario has led to mass acceptance of this virtual practice. Due to strict restrictions on movement and the unprecedented burden on healthcare services, telemedicine has proved to be a boon for people with non-critical ailments. Under the 1135 waiver authority and the Coronavirus Preparedness and Response Supplemental Appropriations Act, 2020, the scope of telehealth facilities has been widened to include coverage for office, hospital and other visits equipped with telehealth facilities in the United States and at patients residences.

The Teladoc platform was recently deployed by Tower Health for offering virtual health care for patients suffering from different ailments. Each visit was provided at $45 and is available 24 hours a day, 7 days a week. Apart from COVID 19, some of the other prominent health issues addressed by the platform are flu symptoms, respiratory infection and rashes. Dr. Lewis Levy, chief medical officer of Teladoc, said, There is no doubt that we are seeing positive momentum and that awareness has increased. Telemedicine is now a household term.

It is estimated that the global telehealth market is expected to register 16.9 percent CAGR during the 2020-2025 forecast period. It will likely be worth $55.6 billion by 2025, up from current valuation of $25.4 billion in 2020. The low-risk and high-efficiency nature of these services are making them very popular now.

Pluristem Therapeutics Inc. (PSTI) reported that it has treated its first patient suffering from complications arising from the novel coronavirus. The patient was treated under the FDA Single Patient Expanded Access Program, and PLX cell therapy was used for this purpose. The company is now looking to initiate a multinational clinical trial at the earliest possible.

Pluristem further said that the patient was in critical condition with respiratory failure due to acute respiratory distress syndrome. The patient was in an intensive care unit with mechanical ventilation for three weeks. Single Patient Expanded Access Program is also known as a compassionate use program and is a part of the US Coronavirus Treatment Acceleration Program. The program is mainly aimed at accelerating the development of new therapies for dealing with this disease.

Pluristem focuses on using PLX cell treatment regimen. These cells are available off the shelf and may be manufactured in bulk quantities. Pluristem CEO and President Yaky Yanay said, We are receiving many inquiries and requests for treatment from healthcare providers and families worldwide. In parallel with our planned clinical trial, we expect to continue treating patients under compassionate use through the appropriate regulatory clearances in the United States and Israel, as well as expanding treatment under compassionate use in other countries. PLX cells are allogeneic mesenchymal-like cells and demonstrate immunomodulatory properties.

Pluristem Therapeutics is mainly invested in developing regenerative medicines and placenta-based cell therapy products. The company has solid development pipeline and has several products in late-stage clinical trials. PLX cell drug candidates are expected to work by releasing different therapeutic proteins in response to radiation damage, inflammation, muscle trauma and ischemia. Pluristem also owns and manages a GMP certified research and manufacturing facility.

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Orgenesis Acquiring Tamir, And Other News: The Good, Bad And Ugly Of Biopharma - Seeking Alpha

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Human mesenchymal stem cells – current trends and future …

Abstract

Stem cells are cells specialized cell, capable of renewing themselves through cell division and can differentiate into multi-lineage cells. These cells are categorized as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult stem cells. Mesenchymal stem cells (MSCs) are adult stem cells which can be isolated from human and animal sources. Human MSCs (hMSCs) are the non-haematopoietic, multipotent stem cells with the capacity to differentiate into mesodermal lineage such as osteocytes, adipocytes and chondrocytes as well ectodermal (neurocytes) and endodermal lineages (hepatocytes). MSCs express cell surface markers like cluster of differentiation (CD)29, CD44, CD73, CD90, CD105 and lack the expression of CD14, CD34, CD45 and HLA (human leucocyte antigen)-DR. hMSCs for the first time were reported in the bone marrow and till now they have been isolated from various tissues, including adipose tissue, amniotic fluid, endometrium, dental tissues, umbilical cord and Wharton's jelly which harbours potential MSCs. hMSCs have been cultured long-term in specific media without any severe abnormalities. Furthermore, MSCs have immunomodulatory features, secrete cytokines and immune-receptors which regulate the microenvironment in the host tissue. Multilineage potential, immunomodulation and secretion of anti-inflammatory molecules makes MSCs an effective tool in the treatment of chronic diseases. In the present review, we have highlighted recent research findings in the area of hMSCs sources, expression of cell surface markers, long-term invitro culturing, invitro differentiation potential, immunomodulatory features, its homing capacity, banking and cryopreservation, its application in the treatment of chronic diseases and its use in clinical trials.

Keywords: chronic diseases, homing, immunomodulatory features, in vitro differentiation, mesenchymal stem cells

Abbreviations: AD, Alzheimer disease; AD-MSC, adipose-derived mesenchymal stem cell; ALS, amylotrophic lateral sclerosis; BDNF, brain-derived neurotrophic factor; BME, -mercaptoethanol; BM-MSC, bone marrow-derived mesenchymal stem cell; BMP, bone morphogenic protein; CD, cluster of differentiation; CPA, cryoprotective agent; CRF, controlled rate freezer; DA, dopamine; DMEM, Dulbecco's modified Eagle's media; EGF, epidermal growth factor; ESC, embryonic stem cell; FCS, fetal calf serum; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; HLA, human leucocyte antigen; hMSC, human mesenchymal stem cell; ICM, inner cell mass; IFN, interferon; IL, interleukin; IMDM, Iscove's modified Dulbecco's medium; iPSC, induced pluripotent stem cell; LMX1a, LIM homoeobox transcription factor 1 ; MHC, major histocompatibility complex; MMP, matrix metallo-protease; MSC, mesenchymal stem cell; NBCS, new-born calf serum; NK, natural killer; PD, Parkinson's disease; PD, population doubling; PPAR, peroxisome proliferator-activated receptor ; RA, rheumatoid arthritis; Runx2, runt-related transcription factor 2; SSEA, stage-specific embryonic antigen; TGF-, transforming growth factor-; Th, T helper cell; TLR, toll-like receptor; Treg, regulatory T-cell; UCB-MSC, umbilical cord blood-derived mesenchymal stem cell

In this review, we highlighted recent research findings in the area of human mesenchymal stem cells, its application in the treatment of chronic diseases and its use in human clinical trials.

Stem cells are the cells with a specific function with the ability of self-renewal, possess varied potency and differentiate into multilineages [1]. Because of clinical applications and biological importance, stem cells become a prominent subject in modern research era. On the basis of origin, stem cells are divided into different categories.

Embryonic stem cells (ESCs) are pluripotent stem cells, isolated originally from the inner cell mass (ICM) of mouse early pre-implantation blastocyst, having the capacity to generate into any mature cell of the three germ lines [2]. Later on, Thomson et al. [3] also isolated ESCs from ICM of human blastocyst, but until now as compared with humans, only mouse ESCs have been investigated in depth. ESCs possess distinctive self-renewal capacity, pluripotency and genomic stability [4] and can give rise to almost all lineages and are promising cells for cellular therapy [1]. From the very first derivation of human ESCs, scientists are keenly interested in the use of ESCs for drug discovery, immunotherapy and regenerative medicine, but their use has been restricted due to ethical issues and also because of difficulty in obtaining quality human oocytes.

Induced pluripotent stem cells (iPSCs) are generated from adult cells by the overexpression of four transcription factors Oct4/3 (octamer-binding transcription factor 4/3), Sox2 (sex determining region Y), Klf4 (kruppel-like factor 4) and c-Myc (Avian Myelocytomatosis virus oncogene cellular homologue) [5]. The iPSCs at cellular level are almost similar to ESCs as they are having the capacity of self-renewal, differentiation potential and the ability to produce germ line competent-chimeras. After these findings, two groups Takahashi et al. [6] and Nakagawa et al. [7] have generated the iPSCs from adult human fibroblasts. Though iPSCs possess great potential for cell therapy, but their genomic stability is still questionable.

Around the world, scientists are researching for stable, safe and highly accessible stem cells source with great potential for regenerative medicine. The cells isolated from mouse bone marrow upon culture exhibited the plastic adherence properties and formed spindle-shaped colonies were referred as colony forming unit fibroblasts [8]. Due to their ability to differentiate into specialized cells developing from mesoderm, they were named as mesenchymal stem cells (MSCs). MSCs, also known as multipotent cells, exist in adult tissues of different sources, ranging from murine to humans. They are self-renewable, multipotent, easily accessible and culturally expandable invitro with exceptional genomic stability and few ethical issues, marking its importance in cell therapy, regenerative medicine and tissue repairment [9].

The current review highlights recent findings in the areas of hMSCs (human MSCs) sources, its ex vivo differentiation ability, immunogenicity, homing ability, banking and cryopreservation, its role in the treatment of chronic diseases and its use in human clinical trials.

Since the first description of hMSCs derived from bone marrow [10], they have been isolated from almost all tissues including perivascular area [11]. Still there is neither a single definition nor a quantitative assay to help in the identification of MSCs in mixed population of cells [9]. However, the International Society for Cellular Therapy has proposed minimum criteria to define MSCs. These cells (a) should exhibits plastic adherence (b) possess specific set of cell surface markers, i.e. cluster of differentiation (CD)73, D90, CD105 and lack expression of CD14, CD34, CD45 and human leucocyte antigen-DR (HLA-DR) and (c) have the ability to differentiate invitro into adipocyte, chondrocyte and osteoblast [12]. These characteristics are valid for all MSCs, although few differences exist in MSCs isolated from various tissue origins.

MSCs are present not only in fetal tissues but also in many adult tissues with few exceptions. Efficient population of MSCs has been reported from bone marrow [10]. Cells which exhibits characteristics of MSCs were isolated from adipose tissue [13,14], amniotic fluid [15,16], amniotic membrane [17], dental tissues [18,19], endometrium [20], limb bud [21], menstrual blood [22], peripheral blood [23], placenta and fetal membrane [24], salivary gland [25], skin and foreskin [26,27], sub-amniotic umbilical cord lining membrane [28], synovial fluid [29] and Wharton's jelly [30,31] ().

Summary of hMSCs sources, cell surface markers and expansion media with serum supplements

There are different protocols reported previously in terms of isolation, characterization and expansion of MSCs, but all MSCs (despite of protocol) exhibits the minimum criteria proposed by International Society for Cellular Therapy.

hMSCs were isolated based on their ability to adhere to plastic surface, but this method resulted in the formation of heterogeneous cells (stem cells along with their progenitor cells) [32]. Bone marrow-derived MSCs (BM-MSCs) are considered the best cell source and taken as a standard for the comparison of MSCs from other sources.

Establishment of a comprehensive procedure for the isolation, characterization and expansion of MSCs is the key to success for the use of these cells as a good source for regenerative medicine [33]. Unlike bone marrow, MSCs from other tissues can be easily obtained by non-invasive methods and its proliferation can be maintained up to many passages [34,35]. MSCs from bone marrow, peripheral blood and synovial fluid were isolated by using Ficoll density gradient method with small modifications [24,30,36] and seeded into culture plates. While isolating MSCs from bone marrow, some haematopoietic cells also adhere to the plastic plate but during sub-culturing these cells are washed away, leaving only adherent fibroblast like cells [37]. MSCs from various tissue sources (adipose, dental, endometrium, foreskin, placenta, Wharton's Jelly) were isolated after digestion with collagenase and then cultured at varying densities [20,25,33]. Recently an efficient method to isolate BM-MSCs using novel marrow filter device is explored [38], which is less time consuming and avoids the risk of external contamination. MSCs isolated from different sources were cultured using condition media such as Dulbecco's modified Eagle's media (DMEM) [25,33], DMEM-F12 [17,20,26], MEM [19,23,29], DMEM-LG [21,24], DMED-HG [27,28] and RPMI (Roswell Park Memorial Institute medium) [39]. The primary culture media was supplemented with 10% FBS [25,33], new-born calf serum (NBCS) [23] or fetal calf serum (FCS) [25] (). Besides the culture media and supplementation, the oxygen concentration also affects the expansion and proliferation of MSCs [40]. MSCs expansion is also documented when cultured in DMEM with low glucose supplemented with growth factors like fibroblast growth factor (FGF), epidermal growth factor (EGF) and B27 [27]. But most commonly DMEM with 10% FBS is vastly employed in culturing and expanding MSCs invitro; however, the use of exogenous FBS is highly debated.

According to the International Society for Cellular Therapy standard criteria, expression of specific set of cell surface markers is one of the essential characteristics of hMSCs. Those cells which are positive for CD73, D90, CD105 whereas negative expression of CD14, CD34, CD45 and HLA-DR are considered as MSCs. However, the most characterized and promising markers with highest specificities for MSCs are describe in the present study (). MSCs have been reported from various human tissues, which exhibit the expression of above mentioned cell surface markers along with positive expression of CD29, CD44, CD146, CD140b specific to tissue origin. The expression of CD34, which is a negative marker, is still controversial [41]. A number of studies have also reported that stage-specific embryonic antigen (SSEA)-4 [13,42], CD146 [43,44] and stromal precursor antigen-1 (Stro-1) [45] are the stemnes markers for MSCs. The human amniotic fluid-derived MSCs exhibits the expression of CD29, CD44, CD90, CD105, HLA-ABC [major histocompatibility complex class I (MHC I)] along with SH2 (Src homology 2), SH3 (Src homology 3), SH4 (Src homology 4) but lack the expression of HLA-DR (MHC II) [16]. Stro-1, which is consider as stemnes marker for MSCs, is reported positive in dental [46] and bone marrow [47,48] whereas negative in human adipose-derived MSCs (AD-MSCs) [49].

Although MSCs have great advantages over other stem cells, their clinical applications are hindered by many research barriers. One of the major challenges is to obtain adequate number of cells as these cells were found to lose their potency during sub-culturing and at higher passages. One of the reasons behind the senescence and aging of MSCs during invitro expansion is the decrease in telomerase activity [50]. It has been reported that human BM-MSCs become senescent during long-term culture, manifested by decline in differentiation potential, shortening of the telomere length and morphological alterations [51]. Similar results are also reported when MSCs derived from bone marrow and adipose tissues were progressively cultured at higher passages. The actual age of the cells in culture is usually determined by population doublings (PDs) time and MSCs colonies derived from a single cell has shown up to 50 PDs in 10weeks [52], whereas others have reported 30 PDs in approximately 18weeks [51]. However, culturing MSCs for a long time resulted in an increase in the probability of malignant transformation [53] and also showed decline in their multipotency. Early MSCs have proved higher differentiation ability to chondrocytes, adipocytes and osteocytes; however, at higher passages and on long-term culture, this differentiation property declines [54]. There are two vital compounds which influence MSCs properties during invitro culturing, serum and growth factors, which are associated with malignant transformation of MSCs at higher passages [54]. In minimal media condition, MSCs culturing requires 10% heat-inactivated FCS, but in such culture conditions the MSCs retain some FCS proteins, which may evoke immunologic response invivo [55]. Expanding MSCs in serum-free culture media showed a gradual decrease in differentiation potential and telomerase activity, but cells were resistant to spontaneous transformation and could be expanded at higher passages without any chromosomal alteration [54]. However, due to variation in culture media and growth factors used, the comparison of data is difficult.

hMSCs have the capacity to differentiate into all the three lineages, i.e. ectoderm, mesoderm and endoderm, with various potency by employing suitable media and growth supplements which initiate lineage differentiation ().

Invitro differentiation potential of hMSCs

In addition to multipotency and expressions of cell surface markers, one of the determining properties of MSCs is to differentiate into mesodermal lineages. The invitro differentiation into adipocytes, osteocytes and chondrocytes, confirmed by production of oil droplet, formation of mineralized matrices and expression of typeII collagen respectively, has been evaluated by immunocytochemical, histochemical and PCR analysis [10,5658]. Differentiation of MSCs into adipocytes is induced by proper media supplementations, which activate transcription factors (genes) responsible for adipogenesis. For adipogenesis, MSCs were cultured in growth medium supplemented with dexamethasone, indomethacine, insulin and isobutyl methyl xanthine for 3weeks and the cells were analysed by accumulation of lipid droplets and expression of adipocytes-specific genes peroxisome proliferator-activated receptor (PPAR), adipocyte protein 2 (ap2) and lipoprotein lipase (LPL) genes [10,59]. Induction of adipogenesis is characterized by two phases: determination phase and terminal differentiation phase [60]. During determination phase, the cells committed towards pre-adipocytes show similar morphology to fibroblasts and cannot be distinguished from their MSCs precursors; however, at terminal phase the pre-adipocytes become mature adipocytes and formed lipid droplets and express adipocytes-specific proteins [59]. Overall, adipogenesis is an ordered process, involving multiple signalling cascades which are further discussed later in the present review.

The classical method to differentiate MSCs into osteocytes is by culturing the cells with ascorbic acid, -glyceralphosphate and dexamethasone for 3weeks in growth conditioned media. The osteogenic induction of MSCs initiated mineral aggregation and showed increase in alkaline phosphatase activity at final week of differentiation [10]. These mineralized nodules were found positive for Alizarin Red and von Kossa staining. The process of osteogenesis starts with assurance of osteoprogenitor which first differentiate into pre-osteocytes and then finally differentiate into mature osteoblasts [61]. One of the most important indicating factors for osteogenesis is the expression of runt-related transcription factor 2 (Runx2) [61]; however, other transcription factors like osteonectin, bone morphogenic protein 2 (BMP2) and extracellular signal molecules along with Runx2 expression, are involved in this process. In the whole process of bone formation, first osteoblasts synthesize the bone matrix and then help in bone remodelling and mineral deposition.

The differentiation of MSCs into mesenchymal lineage is known to be controlled by diverse transcription factors and signalling cascades. Many investigators have reported that a correlation exists between adipogenesis and osteogenesis [62,63]. It was reported that a converse relationship exists between adipogenesis and osteogenesis during culturing with different media supplements. [64]. Several signalling pathways such as Hedgehog [65,66], NEL-like protein 1 (NELL-1) [63] and catenin-dependent Wnt [67,68] are well manifested for pro-osteogenic and anti-adipogenic stimulations in MSCs, although there are various signalling cascades which demonstrate positive regulation of both adipo- and osteogenesis. Among them, one of the most familiar clinically-relevant molecule is BMP, which promotes MSCs differentiation and its osteogenic commitment [69,70] and also induce pro-adipogenic effects [71]. PPAR and Runx2 are the key transcription factors which control the adipogenic and osteogenic signalling cascades and the expression of one transcription factor counteracts expression of other transcription factor [14,72].

Like the adipogenesis and osteogenesis, hMSCs have the potential to differentiate into mature chondrocytes. The first standard protocol for chondrocytes differentiation was established for MSCs derived from human bone marrow [73]. According to the standard protocol for chondrogenesis, cells were cultured in DMEM media supplemented with insulin transferrin selenium, linoleic acid, selenious acid, pyruvate, ascorbate 2-phosphate, dexamethasone and transforming growth factor- III (TGF-III). The pre-induction stage of chondrogenic differentiation of MSCs resulted in the formation of pre-chondrocytes and expresses typeI and typeII collagens [74]. The expression of these genes and other adhesion molecules depends on the presence of soluble factors, i.e. TGF- family (TGF-1, TGF-2 and TGF-3) [75]. In the final step, pre-chondrocytes differentiate into mature chondrocytes and express chondrogenic transcription factors like Sox9, L-Sox5 and Sox6 [76,77]. In association with TGF-1, other growth factors such as, insulin like growth factor-I (IGF-I) and BMP-2 were known to induce the differentiation of MSCs into chondrocytes [78]. In hMSCs, TGF-1 interacts with Wnt/-catenin pathways inhibits osteoblast differentiation and induce chondrogenesis [79]. When human AD-MSCs were treated with BMP-2, they differentiated into chondrocytes and expressed mature cartilage markers (type II collagen/GAG) [80]. Besides these growth factors, other hormones such as parathyroid hormone-related peptide (PTHrp) [81,82] and triiodothyronine (T3) also influenced chondrogenesis.

Like cardiomyocytes, MSCs can differentiate into other mesodermal lineages. Twenty years ago, the rat BM-MSCs were cultured with 5-azacytidine which resulted in the differentiation of these cells into multinucleated myotubes [83]. Later Xu et al. [84] treated human BM-MSCs with the same chemical and demonstrated that the cells differentiate into myocytes and were expressing myocyte-related genes, -myocin heavy chain, -cardiac actin and desmin with additional calciumpotassium-induced calcium fluxes. Human BM-MSCs also differentiate into skeletal muscles and smooth muscles when transfected with notch intracellular domain (NICD) [85] followed by treatment with TGF- [86]. Yet the exact invivo signalling mechanism which initiates the differentiation of hMSCs into myocytes is not completely understood and under investigation.

Despite the mesodermal origin, hMSCs have displayed the capacity of trans-differentiation into ectodermal lineages. The hMSCs isolated from different sources have demonstrated trans-differentiation into neuronal cells upon exposure to neural induction media supplemented with cocktails of growth factors. Several growth factors like hepatocyte growth factor (HGF), FGF and EGF were used in neuronal induction media cocktail and successfully obtained neuronal specific phenotypes, i.e. oligodendrocytes, cholinergic and dopaminergic neurons [8791]. Barzilay et al. [89] reported that a transcription factor neurogenin-1 was found effective in the trans-differentiation of MSCs into neuronal protein expressing cells. In another study, a LIM homoeobox transcription factor 1 (LMX1a) expression into human BM-MSCs resulted in differentiation to dopaminergic neurons [89]. When BM-MSCs were cultured in serum-free media with forskolin and cAMP, cells attained neuronal morphology and elevated the expression of neuronal-specific markers [92]. -Mercaptoethanol (BME)- and nerve growth factor (NGF)-treated MSCs also differentiated into cholinergic neuronal cells [87]. Many studies have shown that factors like insulin, retinoic acid, bFGF, EGF, valproic acid, BME and hydrocortisone support neuronal differentiation of AD-MSCs [93,94]. Glial cell line-derived neurotrophic growth factors (GNDF), brain-derived neurotrophic factors (BDNF), retinoic acid, 5-azacytidine, isobutylmethylxanthine (IBMX) and indomethacin enhanced the MSCs differentiation into mature neuronal cells [95]. Gangliosides are glycosphingolipids which interact with EGF receptor (EGFR) and enhance osteoblast formation. However, reduction in gangliosides biosynthesis leads to inhibition of neuronal differentiation [96]. Human umbilical cord blood-derived MSCs (UCB-MSCs) co-transfected with telomerase reverse transcriptase (TERT) and BDNF revealed a longer life span and maintained neuronal differentiation which was effective in recovery of hypoxic ischaemic brain damage (HIBD) [97]. The dental derived MSCs, which originate from neural crest, successfully differentiated into mature neuronal cells [98,99]. hMSCs originate from mesoderm but have the potential to transdifferentiate into neural cells which can revolutionize the regenerative cell therapy in treating many neurological disorders.

It was believed that hepatocytes could only be derived from the cells originating from endoderm and their progenitor cells. However, MSCs have revealed the capacity of trans-differentiation into hepatocytes and pancreocytes upon induction with their corresponding conditioned media. Human BM-MSCs were trans-differentiated into hepatocyte by using two steps protocol: differentiation step followed by maturation step. In differentiation step, cells were cultured in Iscove's modified Dulbecco's medium (IMDM) supplemented with EGF, bFGF and nicotinamide for a week. Finally during maturation step, differentiated human BM-MSCs were cultured with IMDM supplemented oncostatin M, dexamethasone and ITS+ (insulin, transferrin, selenium) premix which resulted in mature hepatocytes [100,101]. The hepatocyte-differentiated cells expressed liver-specific transcription markers, i.e. albumin, -fetoprotein, nuclear factor 4 (HNF-4); however, the differentiation capacity remains inadequate for clinical application. Among these transcription factors, HNF-4 is an essential transcription factor for the morphological and functional differentiation towards hepatocytes [102,103]. When human UCB-MSCs were transduced with HNF-4, it enhanced the differentiation capacity of the cells and increased expression of liver-specific markers [104]. In other studies, it was shown that valproic acid, which is histone deacetylase inhibitor, up-regulate the expression of hepatic marker through activation of protein kinase B (AKT) and extracellular signal-regulated kinases (ERK) [105].

Human BM-MSCs have been successfully differentiated into insulin producing -cells invitro and transplanted to streptozotocin-induced diabetic mice which corrected the hyperglycaemic condition [106,107]. The paracrine factors increase the differentiation and maturation of human BM-MSCs into pancreatic lineage without any genetic manipulation [108]. Human dental pulp stem cells also differentiated into insulin producing cells by induction with growth factors, i.e. acitvin A, sodium butyrate, taurine and nicotinamide [109]. Till now hMSCs derived from adipose, dental, umbilical cord, amnion, Wharton jelly and placental tissues have successfully differentiated into insulin producing -cells [110112]. These studies have revealed that hMSCs can differentiate into endodermal lineages which can transform the current traditional drug therapies to a future promising cell based therapies.

Regarding clinical research on cellular therapy, it is very important to know about the immunomodulatory capabilities of MSCs. In the current era of cell therapy and transplantation, the infusion of MSCs and host compatibility is the main subject of interest. Due to low expression of MHC I and lack expression of MHC class II along with co-stimulatory molecules, like CD80, CD40 and CD86, MSCs are unable to bring substantial alloreactivity and these features protects MSCs from natural killer (NK) cells lysis [113]. The MSCs therapy might alleviate disease response by increasing the conversion from Th2 (T helper cells) response to Th1 cellular immune response through modulation of interleukin (IL)-4 and interferon (IFN)- levels in effector T-cells [114]. MSCs have the ability to inhibit the NK cells and cytotoxic T-cells by means of different pathways. The secretion of human leucocytes antigen G5 was also found helpful in the suppression of T lymphocytes and NK cells [115]. By the secretion of suppressors of T-cells development [116], inhibitory factors i.e. leukaemia inhibitory factor (LIF) [117] and IFN- [118] enhance immunomodulatory properties of MSCs. Moreover, it is observed that human BM-MSCs were not recognized by NK cells, as they expressed HLA-DR molecules [119]. When allogenic hMSCs were transplanted into patients, there was no production of anti-allogeneic antibody nor T-cell priming [120], but the cytotoxic immune factors were found to be involved in the lysis of MSCs [114,121]. In this situation, the IFN- act as antagonist of NK cells, i.e. IL-2-treated NKs are recognized to destroy MSCs whereas IFN- helps the MSCs to keep it safe from NKs [122]. In the same report, Jewett et al. [122] mentioned that along with the protection of MSCs from cytotoxic factors, IFN- also enhances the differentiation of these cells by nuclear factor kappa (NFB)-dependent and -independent pathway. Toll-like receptors (TLRs) are the key components of innate immune system, which is critically involved in the initiation of adaptive immune system responses. MSCs have the expression of TLRs that elevate their cytokines secretions as well as proliferation [123]. MHC class I chain-like gene A (MICA) together with TLR3 ligand and other immunoregulatory proteins kept the MSCs safe from NKs invasion [123]. Together with other properties, these immunomodulatory features makes MSCs one of the feasible stem-cells source for performing cell transplantation experiments.

Considering the homing ability, multilineage potential, secretion of anti-inflammatory molecules and immunoregulatory effects, MSCs are considered as promising cell source for treatment of autoimmune, inflammatory and degenerative diseases. Efforts have been made to discuss the role of MSCs in treating chronic diseases in animal disease model ().

hMSCs and chronic diseases

We previously discussed that MSCs have the ability to differentiate into neurons [8799]. The first MSCs transplantation for neurodegenerative disorder was conducted in acid sphingomyelinase mouse model. After the injection of MSCs, there was a decrease in disease abnormalities and improvement in the overall survivability of the mouse [124]. Based on this experiment, a new study was designed to ascertain the potency of MSC transplantation into amylotrophic lateral sclerosis (ALS), a neurodegenerative disease that particularly degenerate the motor neurons and disturb muscle functionality [124]. The MSCs were isolated from the bone marrow of patients and then injected into the spinal cord of the same patients, followed by tracking of MSCs using MRI at 3 and 6 months. As a result, neither structural changes in the spinal cord nor abnormal cells proliferation was observed. However, the patients were suffering from mild adverse effects, i.e. intercostal pain irradiation and leg sensory dysesthesia which were reversed in few weeks duration. In another study, the AD-MSCs were genetically modified to express GDNF and then transplanted in rat model of ALS which improved the pathological phenotype and increased the number of neuromuscular connections [125].

Parkinson's disease (PD) is a neurodegenerative disorder, characterized by substantial loss of dopaminergic neurons. The MSCs enhanced tyrosine hydroxylase level after transplantation in PD mice model [126]. MSCs by secretion of trophic factors like vascular endothelial growth factor (VEGF), FGF-2, EGF, neurotrophin-3 (NT3), HGF and BDNF contribute to neuroprotection without differentiating into neurocytes [127,128]. Now new strategies are being adopted like genetic modifications of hMSCs, which induce the secretions of specific factors or increase the dopamine (DA) cell differentiation. BM-MSCs were transduced with lentivirus carrying LMX1a gene and the resulted cells were similar to mesodiencephalic neurons with high DA cell differentiation [89]. Research group from the university hospital of Tubingen in Germany first time delivered MSCs through nose to treat neurodegenerative patients. The experiments were performed on Parkinson diseased rat with nasal administration of BM-MSCs [129]. After 4.5 months of administration, MSCs were found in different brain regions like hippocampus, cerebral, brain stem, olfactory lobe and cortex, suggesting that MSCs could survive and proliferate invivo successfully [129]. Additionally, it was observed that this typeof administration increased the level of tyrosine hydroxylase and decreased the toxin 6-hydroxydopamine in the lesions of ipsilateral striatum and substantia nigra. This novel delivery method of MSCs administration could change the face of MSCs transplantation in future.

Alzheimer disease (AD) is one of the most common neurodegenerative disease. Its common symptoms are dementia, memory loss and intellectual disabilities. Till now no treatment has been established to stop or slow down the progression of AD [130]. Recently, researchers are in the search to reduce the neuropathological deficits by using stem cell therapy in AD animal model. It was demonstrated that human AD-MSCs modulate the inflammatory environment, particularly by activating the alternate microglia which increases the expression of A-degradation enzymes and decreases the expression of pro-inflammatory cytokines [131]. Furthermore, it was observed that MSCs modulate the inflammatory environment of AD and inadequacy of regulatory T-cells (Tregs) [132] and later on it was reported that they could modulate microglia activation [133]. It was previously demonstrated that human UCB-MSCs activate Tregs which in turn regulated microglia activation and increased the neuronal survival in AD mice model [134]. Most recently, it was evidenced that MSCs enhanced the cell autophagy pathway, causing to clear the amyloid plaque and increased the neuronal survivability both invitro and invivo [135].

MSCs are also used to assuage immune disorders because MSCs have the capacity of regulating immune responses [1]. After revealing the facts that human BM-MSCs could protect the haematopoietic precursor from inflammatory damage [136], other hMSCs can be used for the treatment of autoimmune diseases.

Rheumatoid arthritis (RA) is a joint inflammatory disease which is caused due to loss of immunological self-tolerance. In preclinical studies on animal models, MSCs were found helpful in the disease recovery and decreasing the disease progression. The injections of human AD-MSCs into DBA/1 mice model resulted in the elevation of inflammatory response in the animal [137]. They further demonstrated that following the injections of AD-MSCs, the Th1/Th17 antigen-specific cells expansion took place due to which the levels of inflammatory chemokines and cytokines reduced, whereas this treatment increased the secretion of IL-10 [138]. Along with its anti-inflammatory function, IL-10 is an important factor in the activation of Tregs that controls self-reactive T-cells and motivates peripheral tolerance invivo [138]. Similar to this, human BM-MSCs demonstrated the same results in the collagen-induced arthritis model in DBA/1 mice [139]. These studies suggest that MSCs can improve the RA pathogenesis in DBA/1 mice model by activating Treg cells and suppressing the production of inflammatory cytokines. However, some contradictions were reported in adjuvant-induced and spontaneous arthritis model, showing that MSCs were only effective if administered at the onset of disease, which suggests that on exposing to inflammatory microenvironment MSCs lost their immunoregulatory properties [140].

Type 1 diabetes is an autoimmune disease caused by the destruction of -cells due the production of auto antibody directed against these cells. As a result, the quantity of insulin production reduces to a level which is not sufficient to control the blood insulin. It has been demonstrated that MSCs can differentiate into insulin producing cells and have the capacity to regulate the immunomodulatory effects [118]. For the first time, nestin positive cells were isolated from rat pancreatic islets and differentiated into pancreatic endocrine cells [141]. Nestin positive cells were isolated from human pancreas and transplanted to diabetic nonobese diabetic/severe combined immunodeficiency (NOD-SCID) mice, which helped in the improvement of hyperglycaemic condition [142]. However, these studies were found controversial and it was suggested that besides pancreatic tissues, other tissues can be used as an alternative for MSCs isolation to treat type1 diabetes. Human BM-MSCs were found effective in differentiating into glucose competent pancreatic endocrine cells invitro as well as invivo [108]. Studies on UCB-MSCs presented a fascinating option for the use of these cells for insulin producing cells. It was demonstrated that UCB-MSCs behave like human ESCs, following similar steps to form the differentiated -cells [143]. The most recent findings of Unsal et al. [144] showed that MSCs when transplanted together with islets cells into streptozotocin treated diabetic rat model enhance the survival rate of engrafted islets and are found beneficial for treating non-insulin-dependent patients in type1 diabetes.

For myocardial repair, cardiac cells transplantation is a new strategy which is now applied in animal models. MSCs are considered as good source for cardiomyocytes differentiation. However, invivo occurrence of cardiomyocytes differentiation is very rare and invitro differentiation is found effective only from young cell sources [145,146]. MSCs trans-differentiated into cardiomyocytes with cocktail of growth factors [84] were used to treat myocardial infarction and heart failure secondary to left ventricular injury [147]. The systematic injection of BM-MSCs into diseased rodent models partially recompensed the infarcted myocardium [148,149]. Furthermore Katrisis et al. [150] transplanted autologous MSCs along with endothelial progenitor cells and evidenced the improvement in myocardial contractibility, but they did not decrypt the mechanism which brought out these changes. Although MSCs are effective in myocardial infarction and related problems, but still cell retentivity in the heart is rapidly decreased, after 4h of cells injection only 10% and after 24h it was found approximately 1% cell retention [151,152]. Following this study, Roura et al. [153] reported that UCB-MSCs retained for several weeks in acute myocardial infarction mice, proliferated early and then differentiated into endothelial lineage. Most recently, transplantation of UCB-MSCs into myocardial infarction animal model along with fibronectin-immobilized polycaprolactone nanofibres were found very effective [154]. All these studies collectively indicate the role of hMSCs in cellular therapy of cardiac infarction and currently there are approximately 70 registered trials investigating the effect of MSCs therapy for cardiac diseases (clinicaltrials.gov).

Homing is the term used when cells are delivered to the site of injury, which is still challenging for cell-based therapies. Most of the time local delivery and homing of cells are found beneficial due to interaction with the host tissues, accompanied by the secretion of trophic factors [114]. There are a number of factors, like cells age, culturing conditions, cell passage number and the delivery method, which influence the homing ability of MSCs to the injured site.

Higher passage number decreases the engraftment efficiency of MSCs and it has been shown that freshly isolated MSCs had greater homing efficiency than the cultured cells. Besides this, the source from which MSCs are being isolated also influences the homing capacity of MSCs. While culturing MSCs, it was shown that oxygen condition, availability of cytokines and growth factors supplements in the culture media triggers important factors which are helpful in the homing of MSCs. Matrix metallo-proteases (MMPs), the important proteases which are involve in the cell migration, also plays important role in the MSCs migration [155]. The higher cell numbers and hypoxic condition of the culturing environment influence the expression of these MMPs [156]. The inflammatory cytokines, i.e. IL-1, TNF- and TGF-1 , enhance the migration of MSCs by up-regulating the level of MMPs [155]. The next important factor is delivery method via which the MSCs are administered to the desired tissue. Intravenous infusion was the most commonly administered route [157], because if MSCs were administered systemically it will trap in the capillaries sheet of various tissues, especially in lungs [158]. That is the reason why most of the time intra-arterial injections of MSCs has been advised, but the most convenient and feasible way of MSCs transplantation is local injection to the site of injury or near the site of injury which provides more number of cells and increases its functional capacity.

The exact mechanism via which MSCs migrate and home to the injured site is still unknown, although it is believed that certain chemokine and its receptors are involved in the migration and homing of MSCs to the tissue of interest. MSCs express many receptors and adhesion molecules which assist in its migration process. The chemokine receptor type4 (CXCR4) and its binding protein stromal-derived factor 1- (SDF-1) play a vital role in this process [159]. In order to know the homing capacity and to monitor the therapeutic efficiency of MSCs, invivo tracking by non-invasive method are pre-requisite. Some advance techniques, i.e. single photon emission CT (SPECT), bioluminescence imaging (BLI), positron emission tomography (PET) were being applied for tracking the MSCs.

As we discussed earlier that MSCs have higher trans-differentiation potential and exhibits immunomodulatory features, but their off target homing, especially lodging in the lungs, is a major obstacle. There is need for in-depth study of MSCs homing mechanism and finding appropriate tracking without any negative effect on the cells and host.

From all the previous studies, it is obvious that the use of hMSCs for clinical applications will increase in future. For clinical applications, a large number of MSCs in an off the shelf format are required. For this purpose, a proper set up of invitro MSCs expansion and subsequent cryopreservation and banking are necessary to be established. This will provide unique opportunities to bring forward the potential uses and widespread implementation of these cells in research and clinical applications. Keeping in mind its use in future clinical and therapeutic applications, there is a need to ensure the safety and efficacy of these cells while cryopreserving and banking. For the selection of optimal cryopreservation media, uniform change in temperature during freezing and thawing, employed freezing device and long-term storage in liquid nitrogen are the indispensable factors to consider.

First considerable factor is the optimal cryopreservation media in which cells can maintain their stem cells abilities for long time. In the cryopreservation media, the cells require the animal base reagent, like FBS, as a source of their nutrients, but previous studies have suggested that animal proteins are difficult to remove from the hMSCs and that these resident protein may enhance adverse reactions in the patients who receive these cells for treatment [35]. Therefore, a serum-free media is substantial for the cryopreservation of MSCs and researchers have successfully used the serum-free media for cryopreservation of MSCs [160,161]. Most recently, human albumin and neuropeptide were used instead of FBS and MSCs maintained their cell survival and proliferation potential in the culture conditions. Additionally, cryoprotective agents (CPAs) are required for the cryopreservation media to prevent any freezing damage to cells. A large number of CPAs are available [162] among which DMSO is the most common CPAs used in cryopreservation of MSCs. However, DMSO is toxic to both humans and animals which make it complicated in the use of MSCs freezing for clinical applications and it has been showed that DMSO has bad effects in both animals and humans [163]. On the infusion of MSCs frozen in DMSO, patients develop mild complications like nausea, vomiting, headache, hypertension, diarrhoea and hypotension [164] and also severe effects like cardiovascular and respiratory issues were reported [165]. Due to these toxic effects, it is necessary to remove (washing with isotonic solutions) or replace DMSO with an alternate CPA. There are several methods along with the introduction of automated cells washing for the removal of DMSO from the frozen thawed cells [166]. Most recently for tissue cryopreservation, a new method was introduced using the mixture of 0.05M glucose, 0.05M sucrose and 1.5M ethylene glycol in phosphate buffer saline [167], shown successful isolation and characterization of MSCs after 3 months of cryopreservation of the tissue. Hence, this method is without any DMSO and animal serum, but it is not yet applied for MSCs cryopreservation. From these findings, it is clear that for clinical grade cells, there is a need of a cryopreservation protocol either with low concentration of DMSO or to replace DMSO with non-toxic alternative.

For cryopreservation of MSCs, the second important factor is the freezing temperature rate. Mostly slow freezing at the rate of 1C/min is the optimum rate for MSCs preservation [168]. For this purpose, current controlled rate freezers (CRFs) are suitable for controlling temperature, maintaining the rate of temperature during cryopreservation. These CRFs can be programmed to find out the exact temperature which the sample is experiencing during freezing [169]. Despite of these benefits, these CRFs lack the uniformity of temperature to all vials during large-scale banking of MSCs [170], so for large-scale banking, the development of advance CRFs are mandatory. Recently more advanced CRF, which provides unidirectional flow of cryogen to each sample, were created by Praxair Inc. On large-scale MSCs banking, along with the safe and efficient cryopreservation, the regulatory guidelines are also important. Like in the U.S.A., Food and Drug Administration (FDA) is responsible whereas in Europe, European Medicines Agency is responsible in Europe for supervising MSCs based cell therapy products.

MSCs have a promising future in the world of clinical medicine and the number of clinical trials has been rising since the last decade. Along with preclinical studies, MSCs have been found to be persuasive in the treatment of many diseases [1]. A large number of clinical trials have been conducted and this trend is gradually increasing (). Currently, there are 463 registered clinical trials in different clinical phases (phase I, II etc.), evaluating the potential of MSC-based cell therapy throughout the world (ClinicalTrials.gov). Most of these trials are phase I/II studies and combination of phase II/III studies, whereas very small numbers of these trials are in phase IV or phase III/IV. Among 463 registered trials, 264 trials are in open status which is open for recruitment whereas 199 trials are closed; out of which 106 studies are completed whereas the rest are in active phases. Clinical trials conducted with MSCs showed very less detrimental effects; however, few of them showed mild adverse effects. Due to immunomodulatory properties, MSCs have been used in many human autoimmune disease clinical trials. However, the exact mechanism by which MSCs regulate the immune response is unclear [171]. To date, 45 autoimmune-disease clinical trials have been registered, out of which seven are completed, 22 are open for recruitment whereas the rest are in active phases (ClinicalTrials.gov). Similarly 70 trials are registered for cardiovascular diseases, 37 for osteoarthritis, 32 for liver disorders, 29 for graft versus host disease (GvHD), 21 for respiratory disorders, 15 for spinal cord injury, 15 for kidney failure, 13 for skin diseases, seven for muscular dystrophy, five for aplastic anaemia, four for Osteogenesis imperfecta, four for AD, two for PD, two for ulcerative colitis and rest are for other diseases (). Although the progress of clinical studies so far registered is slow (only seven studies with final results), but the efficient use of MSCs in large clinical trials with upcoming promising results have proven MSCs as boon for regenerative medicine.

Number of clinical trials registered (per year) for MSCs based therapy (ClinicalTrials.gov)

Number of common diseases registered for MSCs based cell therapy (ClinicalTrials.gov)

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Human mesenchymal stem cells - current trends and future ...

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Mesenchymal stem cell – Wikipedia

Medicinal signaling cells (MSCs) previously known as Mesenchymal stem cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells) and adipocytes (fat cells which give rise to marrow adipose tissue).[1][2]

While the terms mesenchymal stem cell (MSC) and marrow stromal cell have been used interchangeably for many years, neither term is sufficiently descriptive:

Mesenchymal stem cells are characterized morphologically by a small cell body with a few cell processes that are long and thin. The cell body contains a large, round nucleus with a prominent nucleolus, which is surrounded by finely dispersed chromatin particles, giving the nucleus a clear appearance. The remainder of the cell body contains a small amount of Golgi apparatus, rough endoplasmic reticulum, mitochondria and polyribosomes. The cells, which are long and thin, are widely dispersed and the adjacent extracellular matrix is populated by a few reticular fibrils but is devoid of the other types of collagen fibrils.[7][8]

Bone marrow was the original source of MSCs, and still is the most frequently utilized. These bone marrow stem cells do not contribute to the formation of blood cells and so do not express the hematopoietic stem cell marker CD34. They are sometimes referred to as bone marrow stromal stem cells.[9]

The youngest and most primitive MSCs may be obtained from umbilical cord tissue, namely Wharton's jelly and the umbilical cord blood. However MSCs are found in much higher concentration in the Whartons jelly compared to cord blood, which is a rich source of hematopoietic stem cells. The umbilical cord is available after a birth. It is normally discarded and poses no risk for collection. These MSCs may prove to be a useful source of MSCs for clinical applications due to their primitive properties.

Adipose tissue is a rich source of MSCs (or adipose-derived mesenchymal stem cells, AdMSCs).[10]

The developing tooth bud of the mandibular third molar is a rich source of MSCs. While they are described as multipotent, it is possible that they are pluripotent. They eventually form enamel, dentin, blood vessels, dental pulp and nervous tissues. These stem cells are capable of producing hepatocytes.

Stem cells are present in amniotic fluid. As many as 1 in 100 cells collected during amniocentesis are pluripotent mesenchymal stem cells.[11]

MSCs have a great capacity for self-renewal while maintaining their multipotency. Recent work suggests that -catenin, via regulation of EZH2 , is a central molecule in maintaining "stemness" of MSC's.[12] The standard test to confirm multipotency is differentiation of the cells into osteoblasts, adipocytes and chondrocytes as well as myocytes.

MSCs have been seen to even differentiate into neuron-like cells,[13] but doubt remains about whether the MSC-derived neurons are functional.[14] The degree to which the culture will differentiate varies among individuals and how differentiation is induced, e.g., chemical vs. mechanical;[15] and it is not clear whether this variation is due to a different amount of "true" progenitor cells in the culture or variable differentiation capacities of individuals' progenitors. The capacity of cells to proliferate and differentiate is known to decrease with the age of the donor, as well as the time in culture. Likewise, whether this is due to a decrease in the number of MSCs or a change to the existing MSCs is not known.[citation needed]

MSCs have an effect on innate and specific immune cells. MSCs produce many molecules having immunomodulatory effects. These include prostaglandin E2 (PGE2),[16] nitric oxide,[17] indolamin 2,3-dioxigenase (IDO), IL-6, and other surface markers - FasL,[18] PD-L1 / 2.

MSCs have an effect on macrophages, neutrophils, NK cells, mast cells and dendritic cells in innate immunity. MSCs are able to migrate to the site of injury, where they polarize through PGE2 macrophages in M2 phenotype which is characterized by an anti-inflammatory effect.[19] Further, PGE2 inhibits the ability of mast cells to degranulate and produce TNF-.[20][21] Proliferation and cytotoxic activity of NK cells is inhibited by PGE2 and IDO. MSCs also reduce the expression of NK cell receptors - NKG2D, NKp44 and NKp30.[22] MSCs inhibit respiratory flare and apoptosis of neutrophils by production of cytokines IL-6 and IL-8.[23] Differentiation and expression of dendritic cell surface markers is inhibited by IL-6 and PGE2 of MSCs.[24] The immunosuppressive effects of MSC also depend on IL-10, but it is not certain whether they produce it alone, or only stimulate other cells to produce it.[25]

MSC expresses the adhesion molecules VCAM-1 and ICAM-1, which allow T-lymphocytes to adhere to their surface. Then MSC can affect them by molecules which have a short half-life and their effect is in the immediate vicinity of the cell.[17] These include nitric oxide,[26] PGE2, HGF,[27] and activation of receptor PD-1.[28] MSCs reduce T cell proliferation between G0 and G1 cell cycle phases[29] and decrease the expression of IFN of Th1 cells while increasing the expression of IL-4 of Th2 cells.[30] MSCs also inhibit the proliferation of B-lymphocytes between G0 and G1 cell cycle phases.[28][31]

MSCs can produce antimicrobial peptides (AMPs). These include human cathelicidin LL-37,[32] -defensines,[33] lipocalin 2[34] and hepcidin.[35] MSCs effectively decrease number of colonies of both gram negative and gram positive bacteria by production of these AMPs. In addition, the same antimicrobial effect of the enzyme IDO produced by MSCs was found.[36]

Mesenchymal stem cells in the body can be activated and mobilized if needed. However, the efficiency is low. For instance, damage to muscles heals very slowly but further study into mechanisms of MSC action may provide avenues for increasing their capacity for tissue repair.[37][38]

Clinical studies investigating the efficacy of mesenchymal stem cells in treating diseases are in preliminary development, particularly for understanding autoimmune diseases, graft versus host disease, Crohn's disease, multiple sclerosis, systemic lupus erythematosus and systemic sclerosis.[39][40] As of 2014, no high-quality clinical research provides evidence of efficacy, and numerous inconsistencies and problems exist in the research methods.[40]

Many of the early clinical successes using intravenous transplantation came in systemic diseases such as graft versus host disease and sepsis. Direct injection or placement of cells into a site in need of repair may be the preferred method of treatment, as vascular delivery suffers from a "pulmonary first pass effect" where intravenous injected cells are sequestered in the lungs.[41]

The International Society for Cellular Therapy (ISCT) has proposed a set of standards to define MSCs. A cell can be classified as an MSC if it shows plastic adherent properties under normal culture conditions and has a fibroblast-like morphology. In fact, some argue that MSCs and fibroblasts are functionally identical.[42] Furthermore, MSCs can undergo osteogenic, adipogenic and chondrogenic differentiation ex vivo. The cultured MSCs also express on their surface CD73, CD90 and CD105, while lacking the expression of CD11b, CD14, CD19, CD34, CD45, CD79a and HLA-DR surface markers.[43]

The majority of modern culture techniques still take a colony-forming unit-fibroblasts (CFU-F) approach, where raw unpurified bone marrow or ficoll-purified bone marrow Mononuclear cell are plated directly into cell culture plates or flasks. Mesenchymal stem cells, but not red blood cells or haematopoetic progenitors, are adherent to tissue culture plastic within 24 to 48 hours. However, at least one publication has identified a population of non-adherent MSCs that are not obtained by the direct-plating technique.[44]

Other flow cytometry-based methods allow the sorting of bone marrow cells for specific surface markers, such as STRO-1.[45] STRO-1+ cells are generally more homogenous and have higher rates of adherence and higher rates of proliferation, but the exact differences between STRO-1+ cells and MSCs are not clear.[46]

Methods of immunodepletion using such techniques as MACS have also been used in the negative selection of MSCs.[47]

The supplementation of basal media with fetal bovine serum or human platelet lysate is common in MSC culture. Prior to the use of platelet lysates for MSC culture, the pathogen inactivation process is recommended to prevent pathogen transmission.[48]

New research titled Transplantation of human ESC-derived mesenchymal stem cell spheroids ameliorates spontaneous osteoarthritis in rhesus macaques[49]

In 1924, Russian-born morphologist Alexander A. Maximov (Russian: ); used extensive histological findings to identify a singular type of precursor cell within mesenchyme that develops into different types of blood cells.[50]

Scientists Ernest A. McCulloch and James E. Till first revealed the clonal nature of marrow cells in the 1960s.[51][52] An ex vivo assay for examining the clonogenic potential of multipotent marrow cells was later reported in the 1970s by Friedenstein and colleagues.[53][54] In this assay system, stromal cells were referred to as colony-forming unit-fibroblasts (CFU-f).

The first clinical trials of MSCs were completed in 1995 when a group of 15 patients were injected with cultured MSCs to test the safety of the treatment. Since then, more than 200 clinical trials have been started. However, most are still in the safety stage of testing.[5]

Subsequent experimentation revealed the plasticity of marrow cells and how their fate is determined by environmental cues. Culturing marrow stromal cells in the presence of osteogenic stimuli such as ascorbic acid, inorganic phosphate and dexamethasone could promote their differentiation into osteoblasts. In contrast, the addition of transforming growth factor-beta (TGF-b) could induce chondrogenic markers.[citation needed]

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Mesenchymal stem cell - Wikipedia

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Mesenchymal Stromal Cells – PubMed Central (PMC)

Curr Opin Hematol. Author manuscript; available in PMC 2012 Jun 1.

Published in final edited form as:

PMCID: PMC3365862

NIHMSID: NIHMS16948

Mesenchymal stromal cells (MSCs) are the spindle shaped plastic-adherent cells isolated from bone marrow, adipose, and other tissue sources, with multipotent differentiation capacity in vitro. However, whether MSCs truly qualify as stem cells is an area of some debate[1]. MSCs were first described by Friendenstein as hematopoietic supportive cells of bone marrow. He showed that MSCs could differentiate to bone in vitro and a subset of the cells had a high proliferative potential (CFU-F) when plated at low density in tissue culture[2,3]. Based largely on Friendensteins work, Maureen Owen proposed the existence of a stromal stem cell to maintain the marrow microenvironment as the hematopoietic stem cell maintains hematopoiesis[4]. The notion of a mesenchymal stem cell was popularized by Arnold Caplan proposing that MSCs gave rise to bone, cartilage, tendon, ligament, marrow stroma, adipocytes, dermis, muscle and connective tissue[5]. However, convincing data to support the stemness of these cells were not forthcoming, and now most investigators recognize that in vitro isolated MSCs are not a homogenous population of stem cells, although a bona fide mesenchymal stem cell may reside within the adherent cell compartment of marrow[6].

MSCs undoubtedly play a critical role in the marrow microenvironment. Following intramedullary transplantation of eGFP-marked human MSCs into a NOD SCID mouse, the MSCs incorporated into the murine marrow microenvironment and improved the human hematopoietic stem cell activity in the host mouse[7]. MSCs are also thought to be of great value for cell based therapies. This discussion will focus on the properties of MSCs that engender their utility as therapeutic cells and specifically on MSCs as treatment for GVHD and as targeting vehicles for anti-tumor therapies.

As stated above, data to support the designation of MSCs as biologically functional stem cells are lacking. However, the acronym, MSC, is firmly engrained in the vernacular of cell biologists and clinical cell therapists. Thus, the International Society for Cellular Therapy (ISCT) has recommended that these spindle-shaped, plastic-adherent cells be termed, mesenchymal stromal cells [6]. This label allows investigators to continue to use the acronym, MSCs, which should reduce the potential for confusion in the literature. A biologically active stem cell for mesenchymal tissues may exist, but the term mesenchymal stem cell should be reserved for the subset of mesenchymal cells that demonstrate stem cell activity by rigorous criteria.

The defining characteristics of MSCs are inconsistent among investigators due, in part, to the lack of a universally accepted surface marker phenotype. However, all proposed MSC populations are plastic adherent in vitro; hence, this is one defining characteristic. The first important studies of surface antigen markers led to the development of SH2 and SH3, antibodies which seemed to identify MSCs[8]. Subsequently, SH2 and SH3 were shown to recognize epitopes on CD105 and CD73, respectively[9,10]. Furthermore, CD90 is expressed on all cells that we accept as MSCs. These cells do not express hematopoietic antigens, e.g. CD45, CD34, CD14, CD19, or CD3. Additionally, MSCs express MHC Class I molecules in vitro, but not Class II molecules unless stimulated, e.g. by interferon, in tissue culture. Thus, a surface marker phenotype of MSCs is CD105+, CD73+, CD90+, CD45, CD34 CD14, CD19, CD3, HLA DR. While unequivocally identifying MSCs, this surface marker profile is cumbersome. Stable, pancellular expression of surface markers that are unique to MSCs within the bone marrow, the most common source of MSCs, would greatly facilitate the identification of these cells.

The single most characteristic feature of MSCs is the capacity to differentiate to osteoblasts, adipocytes, and chondroblasts in vitro. It is therefore quite reasonable for investigators to demonstrate such trilineage differentiation in vitro to prove their cells under study are MSCs.

In practice, MSCs can be defined by the criteria shown in the Table, as proposed by the ISCT Mesenchymal and Tissue Stem Cell Committee[11]. The criteria are designed not only to define the MSCs, but also to exclude hematopoietic cells, which is important since, as stated above, MSCs are most commonly isolated from bone marrow. CD3 expression is not included in the criteria because T cells are uncommon contaminants of MSC preparations. It is important to avoid hematopoietic cells among the populations of MSCs being used for cell therapy studies because they could alter the scientific outcomes and may be deleterious for patients in clinical trials.

For obvious reasons, if the proposed therapeutic cells are not readily accessible, clinical utility is limited. Effective cell therapy, therefore, begins with a cell type that is relatively easy to isolate. MSCs are most often isolated by adherence selection. For example, bone marrow mononuclear cells are placed in a plastic tissue culture vessel and maintained for 15 days at 37C. Then, the nonadherent cells are removed as the media is changed and the remaining adherent cells are isolated MSCs. At this stage, the MSC cultures are definitely not free of contamination by resident tissue cells, e.g. hematopoietic cells; however, successive passages of the ex vivo expanded cells effectively remove most or all contaminating cells. Thus, tissue culture serves to expand and purify the MSCs. Similarly, when other sources of MSCs, e.g. adipose tissue, a mononuclear cell preparation is maintained in tissue culture to isolate the MSCs.

There are three fundamental questions that must be addressed when using MSCs as cell therapy for tissue regeneration. First, will MSCs differentiate to the tissue of interest in vivo? This is a critically important issue as certain culture conditions may induce atypical differentiation in vitro that may not occur in vivo. Additionally, MSCs may not differentiate to the targeted tissue, but instead generate cell types that function in a beneficial way within the tissue. For example MSCs may secrete useful soluble mediators that foster repair of a tissue so that differentiation is unneeded for clinical benefit. Thus, MSCs may be highly effective for applications in regenerative medicine by several mechanisms.

Second, how can the cells be delivered to the relevant tissue(s)? For example, if intravenously infused, will MSCs home to the desired sites? Although some investigators have suggested that MSCs home to sites of inflammation, it is unclear that MSCs home to sites of other types of local or systemic disease, and there is little data indicating that MSCs home to healthy tissue. Despite the uncertainty of homing to diseased tissues, sufficient intravenously infused MSCs may arrive and incorporate in the desired tissue to generate clinical benefits. For example, Horwitz et al. reported the infusion of MSCs after BMT into children with osteogenesis imperfecta, a metabolic bone disorder. Engraftment and growth acceleration was demonstrated in 5 of 6 patients[12]. Koc et al. reported MSC infusion in children with metachromatic leukodystrophy and Hurlers disease after BMT. In 4 of 6 patients with metachromatic leukodystrophy, an improvement in nerve conduction velocity was observed, but engraftment in the neural tissue was not assessed[13]. In both cases, homing strictly defined was not demonstrated; however the former study showed the presence of intravenously infused cells within the targeted tissue.

Third, how much tissue replacement by donor cells (i.e. engraftment) is needed to achieve correction or improvement of the damage or diseased tissue? The answer will likely be tissue and disease specific, and therefore will require animal models that reliably model the human disease, or more effectively, pilot clinical trials. Importantly, the level of tissue replacement is often quite low, far less than what may be hypothesized; consequently, estimates are useful to determine which diseases should be investigated, but experimental data are essential to formulate therapeutic strategies.

Any cell employed for therapeutic purposes would ideally be immunoprivileged allowing for use in HLA mismatched patients. Further, cells that can regulate the immune response could be effectively used to modulate the immune system to treat immunologic disease. MSCs have been reported to be immunosuppressive and immunoprivileged. The two terms are often used interchangeably; however, this is strictly incorrect. A cell may escape immune recognition (i.e. immunoprivileged) without having an effect on immune effector cells. Similarly, a cell may secrete immunosuppressive molecules while being recognized by an allogeneic immune system. MSCs do seem to exhibit an effect on the immune effector cells in vitro. This property has led to much dialogue whether MSCs could be effective therapy for autoimmune diseases such as rheumatoid arthritis. More important for this discussion is the role of MSCs in the treatment Graft-versus-Host Disease (GVHD).

As mentioned above, MSCs are an essential component of the stromal scaffold of the bone marrow that provides physical and functional support during hematopoiesis. Based on this concept, MSCs have been studied for their ability to improve engraftment of hematopoietic stem cells in vivo[14, 15]. While some reports suggest that MSCs increase engraftment, the data are not particularly impressive, at least in the models utilized. It has been recently shown that MSCs exert a profound immunomodulatory effect by means of both soluble and cell contact-dependent mechanisms[16]. MSCs can act both on T and B cells and although several mechanisms of action have been suggested, the data are contradictory. The ability to inhibit or stimulate T-cell alloresponses appears to be independent of HLA matching. It is still unclear whether MSCs naturally exhibit an immunoregulatory role or whether this is the consequence of a more general, non-specific interference with the cell cycle[17].

In this context, it is interesting to note that stromal cells, together with osteoblasts and endothelial cells, contribute to the formation of the HSC niche. This can be defined as a specialized microenvironment that precisely maintains a long-term storage of quiescent, slowly dividing HSCs by preventing their proliferation, differentiation or apoptosis. It can be hypothesized that MSCs, on one hand, are preventing T lymphocyte activation and proliferation (to prevent possible harm on HSC) and, on the other hand, seem to exert a potent anti-apoptotic effect. Although the mechanisms of immunomodulation are still unfolding, a relevant in vivo immunomodulatory effect has been shown: 1) if given in patients with severe acute GVHD, they are able to reverse the evolution of GVHD in a significant proportion of patients[18, 19], and 2) in a recent in vivo experiment in which injection of MSCs ameliorated the course of chronic progressive experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis[20].

The EBMT MSC Expansion Consortium used MSCs to treat grades IIIIV GVHD in 40 patients who were resistant to second line GVHD treatment. The MSC dose was a median 1.0 x 106 cells/kg recipient body weight (range 0.49 x 106 cells/kg). Adverse effects were not seen after MSC infusions. Nineteen patients received one dose, 19 patients received 2 doses, one patient received 3 doses, and one patient received 5 doses. In some cases, an individual patient received MSC doses from different donors. The MSC donors were HLA-identical siblings in 5 cases, haploidentical donors in 19 cases, and 41 cases of third-party HLA-mismatched donors. Among the 40 patients treated for severe acute GVHD, 19 had complete responses, 9 showed improvement, 7 did not respond, 4 had stable disease and 1 was not evaluated due to short follow-up. Ectopic tissue formation was not seen. MSC dramatically affected tissue repair of severe acute GVHD of the gut, liver, and skin in a consistent proportion of patients. Twenty-one patients are alive with between 6 weeks and 3.5 years follow-up after transplantation. Nine of these patients have extensive chronic GVHD. One patient with ALL has recurrent leukemia and one patient has de novo AML of host origin. In view of the dismal outcome in patients with grades IIIIV acute GVHD, the data from this small trial are promising. However, the optimal strategy for the treatment of GVHD based on MSC infusion has not yet been determined and remains rather complex for a several reasons: 1) the ex vivo cell expansion is expensive and time consuming; 2) there is variation in the expansion capability from donor to donor; 3) often, previously expanded MSCs are required for the timely treatment of GVHD; 4) the optimal dose of MSCs, or the need for multiple infusions, to obtain the maximal effect on GVHD is unknown; 5) expanded MSCs are very difficult to detect after infusion, and the patients marrow stroma remain of host origin with the possible exception of some pediatric patients.

Ongoing efforts within the EBMT Consortium are addressing these challenges in an effort to determine the role of MSC therapy in the treatment for GVHD. At the current state of research, we conclude that MSCs have both immunomodulatory and tissue repairing effects and should be further explored as treatment of severe acute GVHD in prospective randomized trials.

The formation of stroma is essential for tumor growth and involves complex interactions between malignant tumor cells and non-tumor stromal cells. Studeny et al. have demonstrated that MSCs integrate into solid tumors, suggesting the development of anti-cancer therapies based on the intratumoral production of agents by gene-modified MSCs[2123].

Andreeff and colleagues have now conducted a series of experiments to address this issue by noninvasively visualizing MSCs using luciferase bioluminescence. The cells were labeled by a fiber modified adenoviral vector expressing firefly luciferase (AdLux-F/RGD) and the MSC-Lux were injected into normal (healthy) SCID mice or mice bearing established metastatic breast or ovarian tumors. Biodistributed MSC-Lux were imaged utilizing the Xenogen IVIS detection system. In normal mice, human MSC (hMSC) migrated to the lungs where they remained resident for 710 days. In animals bearing established metastatic lung tumors, IV injected hMSC again migrated to the lungs. However, in contrast to control mice, the Lux signal remained strong over a 15-day period with only a slight decrease over the first 10 days. After IP injection, hMSC-LUX were detected in the peritoneum, and after 7 days, no hMSC-LUX was detected in normal animals, while strong punctate regions of LUX-activity were observed in ovarian tumors. In contrast to SCID mice injected with hMSC, when healthy Balb/C mice were injected, Balb/C derived MSC-LUX initially migrated to the lungs, but within 2.5 hrs had exited the lungs to remain liver and spleen resident for 57 days. Tumor cells were then transduced with renilla luciferase constructs allowing for the co-localization and dynamic interactions of firefly luciferase MSCs and renilla luciferase tumors to be demonstrated.

hMSC-producing interferon-beta (IFNb-MSC) were found to inhibit the growth of metastatic tumors in the lungs of SCID mice. When injected IV (4 doses of 106 MSC/week) into SCID mice bearing pulmonary metastases of carcinomas or melanomas, tumor growth was significantly inhibited as compared to untreated or vector-control MSC controls (p= 0.007), while recombinant IFNb protein (50,000 IU qod) was ineffective (p=0.14). IV injected IFNb-MSC prolonged the survival of mice bearing metastatic breast carcinomas (p=0.001). Intraperitoneal (IP) injections of IFN-MSC into mice carrying ovarian carcinomas resulted in doubling of survival in SKOV-3, and cures in 70% of mice carrying OVAR-3 tumors.

A similar strategy is also effective as therapy for brain tumors. MSC injected into the ipsilateral or contralateral carotid artery were found to localize to glioma xenografts in mice and IFNb-MSC significantly (p<0.05) prolonged survival of these mice[24].

These data suggest that systemically administered gene-modified MSC selectively engrafts into the tumor microenvironment and remain resident as part of the tumor architecture. MSC-expressing IFN-b inhibit the growth of melanomas, gliomas, metastatic breast and ovarian cancers in vivo and prolong the survival of mice bearing established tumors. Thus, MSCs are potentially a universal vehicle to deliver localized antitumor therapy. Clinical trials, which are in development, will be conducted to test these experimental findings.

MSCs have an enormous potential as cell therapy in tissue regeneration, immune modulation, and as delivery vehicles for the specific delivery vehicles for anti-tumor agents, but the true clinical utility remains to be proven. MSCs are relatively easy to isolate and purify, and we currently have means to unequivocally identify the cells, although more specific surface markers are needed. MSCs have been infused into well over a hundred patients, including young children, without serious adverse events testifying to the general safety of this strategy. Future efforts in our field must focus on better defining the therapeutic potential of MSCs through clinical trials and better understanding of the biology of MSCs to elucidate the mechanisms of these therapeutic effects.

Table. Summary of Criteria to Identify Mesenchymal Stromal Cells (MSCs).

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Mesenchymal Stem Cells Research Areas: R&D Systems

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Are Mesenchymal Stem Cells a Promising Treatment for COVID …

A recent pilot study in China in which seven COVID-19 patients received intravenous infusions of donor mesenchymal stem cellsmultipotent cells thought to have immunomodulatory capacitiesindicates that the intervention was safe, and that the approach may improve patient outcomes. While all seven patients recovered, scientists are mixed in their opinions on the logic behind the approach and how well it truly performed.

On Sunday (April 5) the US Food and Drug Administraton approved mesenchymal stem cell (MSC) treatments for use in the very sickest COVID-19 patients under whats known as expanded access compassionate use.

The rationale for [the China] study is not clear [and] the results are . . . inconclusive in terms of how effective it is, says developmental biologist and stem cell researcher Christine Mummery of Leiden University, who has no conflicts of interest to declare. One should view it with a certain amount of healthy skepticism.

Regenerative medicine researcher Ashok Shetty of Texas A&M University College of Medicine disagrees. The results of the study in China demonstrate that intravenous infusion of MSCs is a safe and effective approach for treating patients with COVID-19 pneumonia, including elderly patients displaying severe pneumonia, he writes in an email to The Scientist. However, studies in a larger cohort of patients are needed to validate these benefits. Shetty was not involved with the study and says he does not have any conflicts of interest with companies providing MSCs for therapy, but has previously received project funding from CellTexa company involved in MSC-based therapiesfor unrelated work on Alzheimers disease.

COVID-19, the disease caused by the novel SARS-CoV-2 coronavirus, can have vastly different outcomessome infected individuals are symptom-free, others have a mild, flu-like illness, a smaller number of patients become critically ill with severe pneumonia, and some die. Global deaths currently stand at over 92,000.

For the sickest patients, there appears to be a frequently observed pathologyan uncontrolled ramping up of the immune response, of the sort observed in sepsis, known as cytokine release syndrome or, more colloquially, as a cytokine storm.

Cytokines are small proteins released by immune cells that orchestrate the attack-and-destroy mode of the hosts immune system when faced with a foreign invader. But if levels of these proteins surge wildly, and the immune system goes into overdrive, the patients own tissues and organs can be damagedoften fatally.

The rationale for the Chinese pilot study was that MSCs may help to combat a cytokine storm. MSCs are multipotent cells found in various locations in the body including bone marrow, placenta, and umbilical cord that are reported to have immunodulatory abilities. Indeed, on the basis of this ability, MSCs isolated from donors and expanded in culture are infused into patients as experimental treatments for a number of different diseases. For example, there are trials underway examining the use of MSCs for acute respiratory distress syndrome (ARDS)a build up of fluid on the lungs that results in severe oxygen deprivation. ARDS is a common manifestation of cytokine storms, and the cause of death in many COVID-19 patients.

But the evidence for effective immune response modulation is not that strong, says Mummery. Many of [the trials] have turned out not to be significant in terms of clinical outcome. Theres also a great deal of variability in terms of the source tissue of the MSCs and therefore the type or types of cells that are being injected, she says. And the mechanism of action isnt clear. As to whether they work, she says, you have believers and disbelievers.

An expert in cytokine storms, Randy Cron of the University of Alabama at Birmingham points out that there are other drugs in trials for tackling cytokine storms that are already available, including tocilizumab, which was recently approved in China and the US for the treatment of severe COVID-19 cases. MSCs, which are more experimental, he says, therefore wouldnt be the first thing that comes to my mind [for COVID-19 treatment], but, if it works, it works. Cron has links to certain pharmaceutical companies that manufacture drugs for treating cytokine storms.

In Japan, MSCs have been approved to treat another form of cytokine storm called graft-versus-host disease, and are pending such approval in the US. There are also a number of clinical trials starting to test the benefits of MSCs for treating COVID-19.

Theres a lot of circumstantial evidence that suggests [MSCs] should work . . . in this realm, says Martin Grumet, a stem cell researcher at Rutgers University and the chief scientific officer of CytoStormRx, a company developing technologies for MSC therapies. Grumet, who did not participate in the Chinese study, adds that the data look promising.

In the Chinese study, which was reported in Aging and Disease last month, seven COVID-19 patientsone critically ill, four severely ill and two with milder symptomswere given intravenous infusions of MSCs and, in all cases, the patients recovered with some being discharged from the hospital by the end of the 14-day observation period. In contrast, of the three patients in the placebo control group, all of whom had severe disease, one died, one developed ARDS, and one achieved a stable condition.

The two patients with the worst outcomes (death and ARDS), were about 10 years older than the oldest subjects in the test group, points out Daniel OToole of the National University of Ireland who was not involved in the research. Its very well established that the mortality rate [of COVID-19 patients] is probably more connected to age than anything, he says, indicating this may have skewed the results. OToole has no conflicts of interest to declare.

In addition to these seven patients, a 65-year-old female COVID-19 patient received MSC therapy in a separate case study reported in a paper submitted to the preprint site ChinaXiv at the end of February. Her condition also improved, but, says Cron, the patient, at least by many of the lab markers, was getting better . . . before the mesenchymal stem cell [treatment]. So the result is not compelling, he says.

We understand that it is only a small number of cases, says Kunlin Jin of the University of North Texas Health Science Center who is an author of the Aging and Disease paper. But from the results, he says, we can see that MSCs are a very promising approach for treatment of COVID-19 patients.

Stem cell biologist Paul Knoepfler of the University of California, Davis, writes in an email to The Scientist that he is not convinced at all. The disease is so variable and the study numbers so small that, they dont have the power from a few patients to say anything about efficacy. They dont even really show that the approach is safe, he adds. Because MSCs are thought to suppress immunity, there are also risks . . . that MSCs could weaken the overall immune response to the novel coronavirus, he adds. Knoepfler has no conflicts of interest to declare.

Its a great relief that [following] injection of MSCs into these patients, they didnt suddenly all die, says Mummery. But she agrees with Knoepfler that its too early to determine safety. While MSCs are generally considered safe and well tolerated by patients, we dont know in this particular group of patients what the safety record is.

Doctors are likely to get more data on safety and efficacy soon. Lin tells The Scientist that his team now has unpublished data from a further 24 MSC-treated patientsall of whom, he claims, have improved. And the FDAs recent approval of the treatment (for extreme cases and trials) together with the recruitment of COVID-19 patients to existing MSC trials for ARDS around the world, mean data will likely come in fast. Unfortunately, says OToole, my suspicion is there will be large numbers coming soon, because there probably wont be anything else in the ICUs except for COVID-19 ARDS patients.

Z. Leng et al., Transplantation of ACE2- mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia,Aging and Disease, 11:21628, 2020.

B. Liang et al., Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells,ChinaXiv, 202002.00084, 2020.

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At 7% CAGR, Mesenchymal Stem Cells Market Size, Growth Set …

Apr 09, 2020 Xherald --Market Study Report Has Added A New Report On Mesenchymal Stem Cells Market That Provides A Comprehensive Review Of This Industry With Respect To The Driving Forces Influencing The Market Size. Comprising The Current And Future Trends Defining The Dynamics Of This Industry Vertical, This Report Also Incorporates The Regional Landscape Of Mesenchymal Stem Cells Market In Tandem With Its Competitive Terrain.

The global mesenchymal stem cells market size to reach USD 2,518.5 Million by 2026, growing at a CAGR of 7.0% during forecast period, according to a new research report published by The marker research report.

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The report 'Mesenchymal Stem Cells Market, [By Source (Bone Marrow, Umbilical Cord Blood, Peripheral Blood, Lung Tissue, Synovial Tissues, Amniotic Fluids, Adipose Tissues); By Application (Injuries, Drug Discovery, Cardiovascular Infraction, Others); By Region]: Market Size & Forecast, 2018 - 2026' provides an extensive analysis of present market dynamics and predicted future trends. The market was valued at USD 1,335.1 million in 2017. In 2017, the drug discovery application dominated the market, in terms of revenue. North America region is observed to be the leading contributor in the global market revenue in 2017.

are adult stem cells, which are traditionally found in the bone marrow. However, they can also be parted from other available tissues including peripheral blood, cord blood, fallopian tube. These stem cells mainly function for the replacement of damaged cell and tissues. The potential of these cell is to heal the damaged tissue with no pain to the individual. Scientists are majorly focusing on developing new and innovative treatment options for the various chronic diseases like cancer. Additionally, the local governments have also taken various steps for promoting the use of these stem cells.

The significant aspects that are increasing the development in market for mesenchymal stem cells consist of enhancing need for these stem cells as an efficient therapy option for knee replacement. Raising senior populace throughout the world, as well as increasing frequency of numerous persistent conditions consisting of cancer cells, autoimmune illness, bone and cartilage diseases are elements anticipated to enhance the market development throughout the forecast period.

The mesenchymal stem cells market is obtaining favorable assistance by the reliable federal government policies, as well as funding for R&D activities which is anticipated to influence the market growth over coming years. According to the reports released by world health organization (WHO), by 2050 individuals aged over 60 will certainly make up greater than 20% of the globe's population. Of that 20%, a traditional quote of 15% is estimated to have symptomatic OA, as well as one-third of these individuals are expected to be influenced by extreme specials needs. Taking into consideration all these aspects, the market for mesenchymal stem cells will certainly witness a substantial development in the future.

Increasing demand for better healthcare facilities, rising geriatric population across the globe, and continuous research and development activities in this area by the key players is expected to have a positive impact on the growth of Mesenchymal Stem Cells market. North America generated the highest revenue in 2017, and is expected to be the leading region globally during the forecast period. The Asia Pacific market is also expected to witness significant market growth in coming years. Developing healthcare infrastructure among countries such as China, India in this region is observed to be the major factor promoting the growth of this market during the forecast period.

The major key players operating in the industry are Cell Applications, Inc., Cyagen Biosciences Inc. Axol Bioscience Ltd., Cytori Therapeutics Inc., Stem cell technologies Inc., Celprogen, Inc. BrainStorm Cell Therapeutics, Stemedica Cell Technologies, Inc. These companies launch new products and undertake strategic collaboration and partnerships with other companies in this market to expand presence and to meet the increasing needs and requirements of consumers.

The marker research report has segmented the global mesenchymal stem cells market on the basis of source type, application and region:

Mesenchymal Stem Cells Source Type Outlook (Revenue, USD Million, 2015 - 2026)

Bone Marrow

Umbilical Cord Blood

Peripheral Blood

Lung Tissue

Synovial Tissues

Amniotic Fluids

Adipose Tissues

Mesenchymal Stem Cells Application Outlook (Revenue, USD Million, 2015 - 2026)

Injuries

Drug Discovery

Cardiovascular Infraction

Others

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Table of Contents

1.1. Research goal & scope

1.2. Research assumptions

1.3. Research Methodology

1.3.1. Primary data sources

1.3.2. Secondary data sources

1.4. Key take-away

1.5. Stakeholders

2.1. Market Definition

2.2. Market Segmentation

3.1. Mesenchymal Stem Cells - Industry snapshot

3.2. Mesenchymal Stem Cells - Ecosystem analysis

3.3. Mesenchymal Stem Cells Market Dynamics

3.3.1. Mesenchymal Stem Cells - Market Forces

3.3.2. Mesenchymal Stem Cells Market Driver Analysis

3.3.3. Mesenchymal Stem Cells Market Restraint/Challenges analysis

3.3.4. Mesenchymal Stem Cells Market Opportunity Analysis

3.4. Industry analysis - Porter's five force

3.4.1. Bargaining power of supplier

3.4.2. Bargaining power of buyer

3.4.3. Threat of substitute

3.4.4. Threat of new entrant

3.4.5. Degree of competition

3.5. Mesenchymal Stem Cells Market PEST Analysis

3.6. Mesenchymal Stem Cells Market Value Chain Analysis

3.7. Mesenchymal Stem Cells Industry Trends

3.8. Competitive Ranking Analysis

4.1. Key Findings

4.2. Bone Marrow

4.3. Umbilical Cord Blood

4.4. Peripheral Blood

4.5. Lung Tissue

4.6. Synovial Tissues

4.7. Amniotic Fluids

4.8. Adipose Tissues.

5.1. Key Findings

5.2. Injuries

5.3. Drug Discovery

5.4. Cardiovascular Infraction

5.5. Others

6.1. Key Findings

6.2. North America

6.2.1. U. S.

6.2.2. Canada

6.3. Europe

6.3.1. Germany

6.3.2. UK

6.3.3. France

6.3.4. Italy

6.3.5. Spain

6.3.6. Russia

6.3.7. Rest of Europe

6.4. Asia-Pacific

6.4.1. China

6.4.2. India

6.4.3. Japan

6.4.4. Singapore

6.4.5. Malaysia

6.4.6. Australia

6.4.7. Rest of Asia-Pacific

6.5. Latin America

6.5.1. Mexico

6.5.2. Brazil

6.5.3. Argentina

6.5.4. Rest of LATAM

6.6. Middle East & Africa

7.1. Cell Applications, Inc.

7.1.1. Overview

7.1.2. Financials

7.1.3. Product Benchmarking

7.1.4. Recent Developments

7.2. Cyagen Biosciences Inc.

7.2.1. Overview

7.2.2. Financials

7.2.3. Product Benchmarking

7.2.4. Recent Developments

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New clinical trial launches to test efficacy of cell therapy for severe COVID-19 cases – News-Medical.Net

Reviewed by Emily Henderson, B.Sc.Apr 11 2020

After a lightening round of proposals and reviews, an international team of scientists led by Dr. Camillo Ricordi was granted immediate FDA authorization for a 24-patient clinical trial to test the safety and exploratory efficacy of umbilical cord-derived mesenchymal stem cells (UC-MSCs) to block the life-threatening lung inflammation that accompanies severe cases of COVID-19.

We are very grateful to the FDA's Center for Biologics Evaluations and Research, Office of Tissues and Advanced Therapies for performing four rounds of reviews in a record time -- one week.

There is no time to waste, patients who die from COVID-19 have a median time of just 10 days between first symptoms and death. In severe cases oxygen levels in the bloodstream drop, and the inability to breathe pushes patients towards their end very quickly; any intervention that might prevent that trajectory would be highly desirable."

Dr. Camillo Ricordi, principal investigator, is the Stacy Joy Goodman Professor of Surgery and Director of the Diabetes Research institute (DRI) and Cell Transplant Center at the University of Miami Miller School of Medicine

The trial will be based at the University of Miami Health System and Jackson Health System in Miami, Florida. It is the result of a collaborative, international, academic initiative sponsored by The Cure Alliance, a non-profit group of scientists and innovators dedicated to sharing knowledge and accelerating cures for all diseases. In response to the COVID-19 pandemic, The Cure Alliance has pivoted all resources to fighting the virus. The clinical protocol has been already shared with other academic institutions throughout the world who want to test similar treatment strategies in the fastest and most efficient way possible.

One hundred per cent of the philanthropic contributions raised by The Cure Alliance are being directed to this clinical trial and to expand manufacturing of UC-MSC products. If the clinical trial proves to be safe and effective, The Cure Alliance will continue to direct any contribution received for this initiative, to support future manufacturing and distribution of these cellular therapies

The FDA had previously authorized the testing of UC-MSC cell products in patients with Type 1 Diabetes and Alzheimer's Disease at the University of Miami as part of other clinical trials. For the COVID-19 trial, Dr. Ricordi enlisted additional experts from around the world with extensive experience in infectious diseases, pulmonary medicine and critical care, while others provided expertise in cell-based product development and their use in clinical trials. The cell therapy is administered intravenously.

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Mesenchymal Stem Cells Market 2026 Growth Trends by Manufacturers, Regions, Type and Application, Forecast – Red & Black Student Newspaper

The Mesenchymal Stem Cells Market is expected to have a highly positive outlook for the next eight years 2019-2026. This Research Reports emphasizes on key industry analysis, market size, Share, growth and extensive industry dynamics with respect to drivers, opportunities, pricing details and latest trends in the industry.

The global Mesenchymal Stem Cells Market analysis further provides pioneering landscape of market along with market augmentation history and key development involved in the industry. The report also features comprehensive research study for high growth potential industries professional survey with market analysis. Mesenchymal Stem Cells Market report helps the companies to understand the market trends and future market prospective,opportunities and articulate the critical business strategies.

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Geographical segmentation of Mesenchymal Stem Cells Market involves the regional outlook which further covers United States, China, Europe, Japan, Southeast Asia and Middle East & Africa. This report categorizes the market based on manufacturers, regions, type and application.

Mesenchymal Stem Cells Market: Competitive Landscape

Leading players operating in the global Mesenchymal Stem Cells Market include: Pluristem Therapeutics, LonzaThermo, Fisher, ATCC, Bio-Techne, MilliporeSigma, Genlantis, Celprogen, Cell Applications, PromoCell GmbH, Cyagen Biosciences, Human Longevity Inc., Axol Bioscience, Cytori Therapeutics, Eutilex Co.Ltd., ID Pharma Co. Ltd., BrainStrom Cell Therapeutics, Cytori Therapeutics Inc., Neovii Biotech, Angel Biotechnology, California Stem Cell Inc., Stemcelltechnologies Inc., and Celgene Corporation Inc.

Scope of the Report

The key features of the Mesenchymal Stem Cells Market report 2019-2026 are the organization, extensive amount of analysis and data from previous and current years as well as forecast data for the next five years. Most of the report is made up from tables, charts and figures that give our clients a clear picture of the Mesenchymal Stem Cells Market. The structure of Mesenchymal Stem Cells Market by identifying its various segments and sub-segments to help understanding the report.

Mesenchymal Stem Cells Market Research Report gives current competitive analysis and also valuable insights to clients/industries, which will assist them to prepare a new strategy to expand or penetrate in a global Mesenchymal Stem Cells Market.

As the report proceeds further, it covers the analysis of key market participants paired with development plans and policies, production techniques, price structure of the Mesenchymal Stem Cells Market. The report also identifies the other essential elements such as product overview, supply chain relationship, raw material supply and demand statistics, expected developments, profit and consumption ratio.

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Important Mesenchymal Stem Cells Market Data Available In This Report:

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Stem Cell Therapy for Colon Cancer – Yahoo Finance

WASHINGTON, April 2, 2020 /PRNewswire/ -- An article published in Experimental Biology and Medicine (Volume 245, Issue 6, March 2020) (https://journals.sagepub.com/doi/pdf/10.1177/1535370220910690) examines the safety of stem cell therapy for the treatment of colon cancer.The study, led by Dr. J. Liu in the State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design at the East China University of Science and Technology in Shanghai (China), reports that mesenchymal stem cells from a variety of sources promote the growth and metastasis of colon cancer cells in an animal model.

Mesenchymal stem (MSCs), a category of adult stem cells, are being evaluated as therapy for numerous cancers.MSCs are excellent carriers for tumor treatment because they migrate to tumor tissues, can be genetically modified to secrete anticancer molecules and do not elicit immune responses.Clinical trials have shown that MSCs carrying modified genes can be used to treat colon cancer as well as ulcerative colitis. However, some studies have demonstrated MSCs can differentiate into cancer-associated fibroblasts and promote tumor growth.Therefore, additional studies are needed to evaluate the safety of MSCs for targeted treatment of colon cancer.

In the current study, Dr. Liu and colleagues examined the effects of mesenchymal stem cells (MSCs) from three sources (bone marrow, adipose and placenta) on colon cancer cells.MSCs from all three sources promoted tumor growth and metastasis in vivo. In vitro studies demonstrated that MSCs promote colon cancer cell stemness and epithelial to mesenchymal transition, which would enhance tumor growth and metastasis respectively.Finally, the detrimental effects of MSCs could be reversed by blocking IL-8 signaling pathways. Dr. Ma, co-author on the study, said that "Mesenchymal stem cells have a dual role: promoting and/or suppressing cancer. Which effect is dominant depends on the type of tumor cell, the tissue source of the MSC and the interaction between the MSC and the cancer cell. This is the major issue in the clinical application research of MSCs, and additional preclinical experimental data will be needed to evaluate the safety of MSCs for colon cancer treatment."

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Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology & Medicine, said: "Lui and colleagues have performed elegant studies on the impact of mesenchymal stem cells (MSCs), from various sources, upon the proliferation, stemness and metastasis of colon cancer stem cells (CSCs) in vitro and in vivo. They further demonstrate that IL-8 stimulates the interaction between colon CSCs and MSCs, and activates the MAPK signaling pathway in colon CSCs.This provides a basis for the further study of MSCs as a biologic therapy for colon cancer."

Experimental Biology and Medicine is a global journal dedicated to the publication of multidisciplinary and interdisciplinary research in the biomedical sciences. The journal was first established in 1903. Experimental Biology and Medicine is the journal of the Society of Experimental Biology and Medicine. To learn about the benefits of society membership, visit http://www.sebm.org. For anyone interested in publishing in the journal, please visit http://ebm.sagepub.com.

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