The Pros and Cons of Mesenchymal Stem Cell-Based Therapies

Cell Transplant. 2019 Jul; 28(7): 801812.

1Department of Transplantation, Jagiellonian University Medical College, Cracow, Poland

*Both the authors contributed equally in this article.

1Department of Transplantation, Jagiellonian University Medical College, Cracow, Poland

*Both the authors contributed equally in this article.

1Department of Transplantation, Jagiellonian University Medical College, Cracow, Poland

1Department of Transplantation, Jagiellonian University Medical College, Cracow, Poland

*Both the authors contributed equally in this article.

Received 2018 Oct 22; Revised 2019 Feb 5; Accepted 2019 Feb 19.

The need to search for new, alternative treatments for various diseases has prompted scientists and physicians to focus their attention on regenerative medicine and broadly understood cell therapies. Currently, stem cells are being investigated for their potentially widespread use in therapies for many untreatable diseases. Nowadays modern treatment strategies willingly use mesenchymal stem cells (MSCs) derived from different sources. Researchers are increasingly aware of the nature of MSCs and new possibilities for their use. Due to their properties, especially their ability to self-regenerate, differentiate into several cell lineages and participate in immunomodulation, MSCs have become a promising tool in developing modern and efficient future treatment strategies. The great potential and availability of MSCs allow for their various clinical applications in the treatment of many incurable diseases. In addition to their many advantages and benefits, there are still questions about the use of MSCs. What are the mechanisms of action of MSCs? How do they reach their destination? Is the clinical use of MSCs safe? These are the main questions that arise regarding MSCs when they are considered as therapeutic tools. The diversity of MSCs, their different clinical applications, and their many traits that have not yet been thoroughly investigated are sources of discussions and controversial opinions about these cells. Here, we reviewed the current knowledge about MSCs in terms of their therapeutic potential, clinical effects and safety in clinical applications.

Keywords: mesenchymal stem cells, somatic cell therapy, transplantation, engraftment, immunomodulatory properties

In the 1960s, Friedenstein et al. identified a population of fibroblast-like cells that formed clonal colonies in vitro (CFU-F, Colony Forming Unit-Fibroblast)1. Friedensteins observations allowed for the discovery of a specific type of cell, currently referred to as mesenchymal stem cells (MSCs). MSCs are primary, non-specialized, nonhematopoietic, plastic adherent cells with great proliferation potential and the capacity for self-renewal and differentation2.

In 2006, the International Society of Cellular Therapy (ISCT) proposed basic criteria for defining human multipotent mesenchymal stromal cells whose name then evolved to MSCs. In addition to their plastic adherent properties under standard culture conditions and trilineage differentiation capacity into osteoblasts, chondrocytes and adipocytes, > 95% of the MSCs population is positive for the three specific surface markersCD73 (SH3/4), CD90 (Thy-1), and CD105 (SH2)and do not express CD45, CD34, CD14, CD11b, CD79a, CD19, or major histocompatibility complex (MHC) class II3,4. MSCs also express others markers, including CD9, CD10, CD13, CD29, CD44, CD49, CD51, CD54 (ICAM-1), CD117 (c-kit), CD146 (MCAM), CD166 (ALCAM), and Stro-1, but the expression of specific combinations of the markers appear to be host tissue dependent5. Although a wide range of positive markers describing MSCs has been identified, no single marker has been indicated as specific for MSCs.

It should be also noted that the potential of MSCs for differentiation and proliferation may vary considerably between different MSC sources6,7. It has been suggested that these differences are a result of the direct influence of the specific microenvironments in which they primarily reside8,9.

Despite increasing numbers of reports describing MSCs, numerous controversies have arisen regarding the proper identification of MSCs. It appears that the criteria proposed by the ISCT are not sufficient because MSCs isolated from different tissues represent a relatively heterogeneous group of cells in terms of differentiation, proliferation abilities, and cell surface expression6,1013.

The fact that MSCs can be isolated from numerous sources1,2,68,10 (), their relative ease to culture in vitro, their ability to differentiate into several different cell types, and their special immunological properties make MSCs a promising tool for cell therapy and tissue regeneration. The best known and the most commonly used source of MSCs is bone marrow (BM)14. BM is the tissue in which MSCs were first identified. Another easily accessible source of MSCs is adipose tissue15. Obtaining MSCs from these sources requires invasive procedures. Interestingly, rich sources of MSCs include birth-associated tissues that are treated as medical waste, such as placenta, umbilical cord, amniotic fluid, and amniotic membrane. Among those tissues, umbilical cord blood16 is believe to contain MSCs; however, the use of this source is questioned by some researchers because of low efficiency of their isolation17. MSCs derived from Whartons jelly of the umbilical cord (WJ-MSCs) appear to have great future clinical utility due to their limited heterogeneity and some unique properties, such as ease of their isolation and culture, availability in several tissues, their immunomodulatory properties, ability to self-regenerate, differentiate into several cell lineages, and the lack of ethical problems resulting from their use18. Moreover, in contrast to BM or adipose tissue, the acquisition and isolation of birth-associated tissues, including WJ-MSCs, do not require invasive surgical procedures; therefore, the isolation process does not pose any risk of complications for the donor, giving them an advantage over other MSC sources. Currently, new sources of MSCs have been proposed. MSCs are found in dental pulp, periodontal ligament, tendon, skin, muscle, and other tissues19 (). However, there are differences in isolation efficiency that are related to the availability, condition, and age of the donor tissue. A very important issue is the age of the donors cells20. Cells obtained from younger donors are less susceptible to oxidative damages and changes, they age considerably more slowly in culture, and they have a higher proliferation rate21,22.

Mesenchymal stem cells sources.

Currently, many studies focus on the use of MSCs in cell therapy. MSCs are used as a tool to treat degenerative changes in joints and to reconstruct bones and cartilage, and are used in plastic surgeries, aesthetic medicine, cardiovascular diseases, endocrine and nervous system diseases, cell transplantation, and in the repair of damaged musculoskeletal tissues23. Due to the special properties of these cells, such as their rapid proliferation, high differentiation capacity, and the ability to migrate into the site of damage, new clinical applications are being tested.

BM-MSCs are the most frequently used in clinical settings24. BM-MSCs were also first to be registed by the Food and Drug Administration as a drug against Graft versus Host Disease called Prochymal25. Recently, Alofisel has been registered by the European Medicines Agency to treat complex perianal fistulas. The drug is based on expanded adipose-derived stem cells26. In both cases the drugs are allogeneic, which provides strong advantage other autologous products due to possibility of detailed testing regarding both safety and potency before release. Nowadays other sources of MSCs are also used for clinical therapies. Our research group used MSCs isolated from Wharton Jelly to treat patients with acute myocardial infarction, showing the safety and feasibility of such therapy27. Currently, we are conducting phase II/III randomized, double-blinded clinical trials with the use of the product CardioCell that is based on WJ-MSCs in three indications: acute myocardial infarction (AMI-Study, EudraCT Number: 2016-004662-25), chronic ischemic heart failure (CIHF-Study, EudraCT Number: 2016-004683-19), and non-option critical limb ischemia (N-O CLI-Study, EudraCT Number: 2016-004684-40).

However, it should be noted that although we possess great knowledge about their in vitro characteristics, we still know much less about the in vivo behaviors of MSCs. They can act both directlydue to their ability to differentiate28and indirectly, by producing and secreting many factors that enhance the endogenous regeneration potential of injured tissue19.

The new approach in stem cell therapy is the use of extracellular vesicles (EVs), which can be used as a substitute for MSCs29. EVs as a therapeutic vector have the paracrine effect without the direct involvement of the cells. They are released from stem cells and they supply many components such as mRNA, DNA, and proteins to the target site30. This approach is described in many recent studies31,32 but a thorough understanding of the mechanism of action of EVs is still required.

The therapeutic effect of MSCs depends on their ability to reach the injured site, which is possible due to their ability to migrate, adhere, and engraft into a target tissue. Several factors affect the therapeutic efficacy of MSCs homing. Among them, culture conditions, the number of passages, donor age, delivery method, and host receptibility play important roles3336. It has been shown that freshly isolated cells compared with in vitro-cultured cells have a higher engraftment efficiency37, which can be a result of the aging/differentiation process that cells undergo in in vitro culture conditions38,39. Culture conditions also have a significant impact on homing capacity, as they can modify the expression of the surface markers involved in this process. As an example, CXCR4, a chemokine receptor, is involved in the migration of MSCs. It has been shown that CXCR4 expression is lost on BM-MSCs during culture37,40,41, whereas the presence of cytokines (e.g., HGF, IL-6), hypoxic conditions, or direct introduction using viral vectors allow for restoration of its expression4244.

In addition, MSCs isolated from older donors show altered compositions and functions of membrane glycerophospholipids45. All of these aspects affect MSCs ability to migrate, home, and engraft into a site of injury.

The efficacy of cell therapy largely depends on the delivery method. The most common method of administration of MSCs is intravenous infusion4648. However, before the cells reach their target, the majority are trapped within capillaries of various organs, especially in the lungs46,4952. This attrition can be explained by the fact that MSCs are relatively large cells and express various adhesion molecules. Despite the fact that MSCs can become trapped in the lungs, numerous pieces of evidence suggest that they are able to home to injured tissue50,53. Interestingly, recent data also suggest that despite the problems associated with intravenous infusions, this route results in similar efficacy as other modes of delivery of MSCs54. In some instances, intra-arterial injection seems to be a more effective route. It has been shown that delivery of MSCs through the internal carotid artery more effectively facilitates their migration and homing into injured brain compared with administration via the femoral vein. The risk associated with this route of delivery includes occlusions, which can arise in microvessels53. When the MSCs were delivered directly to the heart, near the damaged area, the number of cells that reached the peri-infarct region was much higher55.

As has already been mentioned, the necessary condition for effective MSC-based therapy is for the cells to reach the site of injury and home to the affected tissue. There is no doubt that specific receptors and adhesion molecules and interactions with endothelial cells play crucial roles in this migration and homing. Cell adhesion proteins are expressed in the plasma membrane, such as integrins, which are involved in cell adhesion to extracellular matrix proteins (EMC), such as collagen, fibronectin, and laminin38,5660. In vivo studies have shown that MSCs exhibit chemotactic properties and, after intravenous injections, are able to attach to endothelium and migrate between endothelial cells toward injured tissue in response to factors that are upregulated under the inflammatory conditions6164. However, the detailed mechanisms of their transendothelial migration (TEM), diapedesis, and homing to sites of injury and inflammation have not yet been explained in detail. It is presumed that this mechanism may be similar to that of leukocytes ()6567 but is performed with the participation of different adhesion molecules. To date, many chemokines and growth factors have been identified (e.g., EGF, VEGF-A, FGF, PDGF-AB, HGF, TGF-b1, TNF-, SDF-1, IL-6, IL-8, IGF-1), including their receptors, adhesion molecules, and metalloproteinases, that are involved in the MSCs migration process (e.g., CXCL-12, CCL-2, CCL-3, CCR4, CXCR4, VCAM, ICAM)55,59,65,6871. Many reports suggest that damaged tissue expresses specific factors that act as chemoattractants to facilitate the migration, adhesion, and infiltration of MSCs to sites of injury, as in the case of leukocytes trafficking to sites of inflammation. However, although the leukocyte recruitment process (i.e., binding to endothelial cells, rolling, adhesion, and TEM) is well understood, the mechanism of the interaction between MSCs and endothelial cells will require more detailed investigations. Studies by Rster et al. showed that the ability of MSCs to bind and roll on endothelial cells was derived from human umbilical cord vein cells. Once the MSCs adhere to endothelium, they become shaped like protrusions and roll. The molecules involved in this process have been identified and include P-selectin and VLA-4 expressed on MSCs and VCAM-1 on endothelial cells (VLA-4/VCAM-1 interaction)65. It has also been confirmed that a vital role in the homing and migration of MSCs is played by the proteolytic enzymes matrix metalloproteinases (MMPs)37,41.

Schematic of leukocyte transmigration through the endothelium. It is supposed that MSCs migration occurs in a similar manner. The graphic was prepared using modified art elements from Servier Medical Art, found at https://smart.servier.com.

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The Pros and Cons of Mesenchymal Stem Cell-Based Therapies