Why Pluristem Therapeutics Trading Higher Today – Benzinga

Pluristem Therapeutics(NASDAQ: PSTI) shares are trading higher on Tuesday, after the company reported preliminary data from its coronavirus compassionate use program, treating seven patients with acute respiratory failure.

Pluristem Therapeutics is an Israeli company engaged in the development of human placental adherent stromal cells for commercial use in disease treatment. According to the company's website, it extracts adult stem cells exclusively from postnatal placentas.

Pluristem Therapeutics shares were trading up 37.20% at $4.61 on Tuesday at the time of publication. The stock has a 52-week high of $7.30 and a 52-week low of $2.82.

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Stem Cell Characterization Kits Market Prospects & Upcoming Trends and Opportunities Analyzed for Coming Years – The Cloud Tribune

Stem cells are biological cells that can be converted into specific type of cells as per the bodys requirement. Stem cells are of two types, i.e., adult stem cells and embryonic stem cells. Stem cells can be used to treat various diseases such as cancer, neurodegenerative disorder, cardiovascular disorder and tissue regeneration. Stem cell characterization is the initial step for stem cell research. Stem cell characterization is a challenging and also an evolving process. Stem cell characterization kits are used for identification of stem cell biology markers. In stem cell characterization, stem cell biology marker profiles differ based on their species, maturity and site of origin. Stem cell characterization kit is required to understand the utility of the stem cells in downstream experiments and to confirm the pluripotency of the stem cell.Request Free Sample Report-https://www.factmr.com/connectus/sample?flag=S&rep_id=2691

Based on type of stem cell, the stem cell characterization kits market is segmented into:Stem Cell Characterization Kits for Adult Stem CellsStem Cell Characterization Kits for Induced Pluripotent Stem CellsStem Cell Characterization Kits for Mesenchymal Stem CellsStem Cell Characterization Kits for Neural Stem CellsStem Cell Characterization Kits for Hematopoietic Stem CellsStem Cell Characterization Kits for Umbilical Cord Stem CellsStem Cell Characterization Kits for Human Embryonic Stem CellsBased on application, the stem cell characterization kits market is segmented into:ResearchDrug Discovery & DevelopmentRegenerative Medicine

Based on end user, the stem cell characterization kits market is segmented into:Biopharmaceutical CompaniesContract Research OrganizationsAcademics and Research InstitutesBiotechnology CompaniesHave Any Query? Ask our Industry Experts-https://www.factmr.com/connectus/sample?flag=AE&rep_id=2691

Examples of some of the key participants in the stem cell characterization kits market identified across the value chain include Merck KGaA, Celprogen, Inc., Creative Bioarray, Thermo Fisher Scientific Inc., BD Biosciences, R&D Systems, Inc., System Biosciences, Cosmo Bio USA, BioCat GmbH, and DS Pharma Biomedical Co., Ltd.Pertinent aspects this study on the Stem Cell Characterization Kits market tries to answer exhaustively are:

What is the forecast size (revenue/volumes) of the most lucrative regional market? What is the share of the dominant product/technology segment in the Stem Cell Characterization Kits market? What regions are likely to witness sizable investments in research and development funding? What are Covid 19 implication on Stem Cell Characterization Kits market and learn how businesses can respond, manage and mitigate the risks? Which countries will be the next destination for industry leaders in order to tap new revenue streams? Which new regulations might cause disruption in industry sentiments in near future? Which is the share of the dominant end user? Which region is expected to rise at the most dominant growth rate? Which technologies will have massive impact of new avenues in the Stem Cell Characterization Kits market? Which key end-use industry trends are expected to shape the growth prospects of the Stem Cell Characterization Kits market? What factors will promote new entrants in the Stem Cell Characterization Kits market? What is the degree of fragmentation in the Stem Cell Characterization Kits market, and will it increase in coming years?

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Autologous Stem Cell and Non-Stem Cell Based Therapies Market: Incredible Possibilities, Growth With Industry Study, Detailed Analysis And Forecast To…

The Autologous Stem Cell and Non-Stem Cell Based Therapies market research encompasses an exhaustive analysis of the market outlook, framework, and socio-economic impacts. The report covers the accurate investigation of the market size, share, product footprint, revenue, and progress rate. Driven by primary and secondary researches, the Autologous Stem Cell and Non-Stem Cell Based Therapies market study offers reliable and authentic projections regarding the technical jargon.

All the players running in the global Autologous Stem Cell and Non-Stem Cell Based Therapies market are elaborated thoroughly in the Autologous Stem Cell and Non-Stem Cell Based Therapies market report on the basis of proprietary technologies, distribution channels, industrial penetration, manufacturing processes, and revenue. In addition, the report examines R&D developments, legal policies, and strategies defining the competitiveness of the Autologous Stem Cell and Non-Stem Cell Based Therapies market players.

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The major players profiled in this report include:U.S. STEM CELL, INC.Brainstorm Cell TherapeuticsCytoriDendreon CorporationFibrocellLion BiotechnologiesCaladrius BiosciencesOpexa TherapeuticsOrgenesisRegenexxGenzymeAntriaRegeneusMesoblastPluristem Therapeutics IncTigenixMed cell EuropeHolostemMiltenyi Biotec

The end users/applications and product categories analysis:On the basis of product, this report displays the sales volume, revenue (Million USD), product price, market share and growth rate of each type, primarily split into-Embryonic Stem CellResident Cardiac Stem CellsAdult Bone MarrowDerived Stem CellsUmbilical Cord Blood Stem Cells

On the basis on the end users/applications, this report focuses on the status and outlook for major applications/end users, sales volume, market share and growth rate of Autologous Stem Cell and Non-Stem Cell Based Therapies for each application, including-Neurodegenerative DisordersAutoimmune Diseases Cancer and TumorsCardiovascular Diseases

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Objectives of the Autologous Stem Cell and Non-Stem Cell Based Therapies Market Study:

The Autologous Stem Cell and Non-Stem Cell Based Therapies market research focuses on the market structure and various factors (positive and negative) affecting the growth of the market. The study encloses a precise evaluation of the Autologous Stem Cell and Non-Stem Cell Based Therapies market, including growth rate, current scenario, and volume inflation prospects, on the basis of DROT and Porters Five Forces analyses. In addition, the Autologous Stem Cell and Non-Stem Cell Based Therapies market study provides reliable and authentic projections regarding the technical jargon.

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After reading the Autologous Stem Cell and Non-Stem Cell Based Therapies market report, readers can:

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Coronavirus updates: Masks required for take out; N.J. hospitalizations to peak within 3 weeks; Stimulus paym – NJ.com

The number of people in New Jersey hospitalized with the coronavirus could peak at around 16,000 in the next two to three weeks, state officials said Saturday.

Under normal circumstances, the state has 18,000 total hospital beds, including 2,000 in critical care, state Health Commissioner Judith Persichilli said.

Another big concern is protective gear for healthcare workers, enough workers in general, and medical equipment especially much-needed ventilators, Persichilli said.

For example, New Jersey is down to just 61 reserve ventilators in its state stockpile. The state has been seeking more from the federal government and private companies.

Persichilli emphasized that officials have worked in recent weeks to aggressively expand the number of beds in the Garden State, including doubling critical care beds, to handle the peak. That includes placing patients at closed hospitals, field hospitals, hotel rooms, and dormitories.

On Saturday, officials announced 251 new deaths and 3,599 cases. There have been 2,183 COVID-19 related deaths and at least 58,151 cases, though some have recovered. Officials estimate 80 to 85% of cases involve mild or moderate symptoms.

The latest updates on coronavirus news:

45 dead at 3 nursing homes in Elizabeth: There have been at least 45 deaths at three different nursing homes in Elizabeth in recent days, but it is unclear how many were due to the coronavirus, city officials said.

More than two dozen residents have died at the Elizabeth Nursing and Rehabilitation Center on Grove Street since at least March 21, a city spokeswoman said Saturday. NJ Advance Media previously reported at least 12 of those who died had tested positive for COVID-19.

First batch of stimulus payments has arrived for some, IRS says: Americans are starting to see the first wave of payments from the coronavirus stimulus package, the IRS said in a tweet on Saturday.

The first batch of deposits was expected to start with those who have filed tax returns for 2019 or 2018, or those who have their direct deposit information on file with Social Security.

Murphy cuts NJ Transit capacity to 50%, requires face masks: Gov. Phil Murphy on Saturday announced new rules and restrictions for public transportation in New Jersey as part of his continued use of executive orders to increase social distancing and slow the spread of the coronavirus.

Murphys latest executive order cuts NJ Transit trains and buses to 50% capacity and requires employees and riders to wear face coverings. It takes effect Monday at 8 pm.

N.J. hospital is 1st in U.S to try placenta therapy on critically ill coronavirus patient: Using a cutting-edge experimental therapy, doctors at a Bergen County hospital on Saturday injected stem cells into a critically ill coronavirus patient, in the hope they will bolster his immune system and save his life.

Its believed to be the first time the procedure was performed in the United States to combat COVID-19, according to Holy Name Medical Center in Teaneck. The cells, drawn from a human placenta, will hopefully aide the previously healthy 49-year-old mans immune response and could potentially also heal tissue damage to his lungs.

The show must go on. See how 3 N.J. churches are creating a virtual Easter this year: Amid the coronavirus pandemic, worshippers in New Jersey wont be packing into pews on what is normally the highest-attended service of the year, and one that takes months of meticulous planning. But churches across the state are continuing to bring consolation to congregants during dark times albeit from a safe distance through Facebook and Youtube.

Longtime N.J. firefighter who died from coronavirus gets heros goodbye from afar: An 85-year-old man who served as a firefighter in his Somerset County hometown for the majority of his adult life died of the coronavirus after contracting pneumonia. Only his son was allowed to attend the funeral in person, while the rest of the family watched on Zoom.

The Bound Brook Fire Department honored him with a funeral procession Friday that featured 52 pieces of apparatus from around the county. Due to social distancing guidelines, a maximum of two firefighters occupied each vehicle.

Worldwide coronavirus cases: At least 405,792 of the approximately 1.78 million people who have tested positive for the virus have recovered as of early Sunday, according to the Center for Systems Science and Engineering at Johns Hopkins University. There have been more than 109,000 deaths.

U.S. coronavirus cases: More than 20,600 of the roughly 530,000 people who have tested positive for COVID-19 have died, Johns Hopkins University said early Sunday. The center says more than 32,000 in the U.S. have recovered.

If you would like updates on New Jersey-specific coronavirus news, subscribe to our Coronavirus in N.J. newsletter. Tell us your coronavirus stories, whether its a news tip, a topic you want us to cover, or a personal story you want to share. If you would like updates on New Jersey-specific coronavirus news, subscribe to our Coronavirus in N.J. newsletter.

NJ Advance Media staff writers Rebecca Everett, Rebecca Panico, Karin Price Mueller, Chris Ryan, Chris Sheldon, Riley Yates and Avalon Zoppo contributed to this report.

Jeff Goldman may be reached at jeff_goldman@njadvancemedia.com. Follow him on Twitter @JeffSGoldman. Find NJ.com on Facebook.

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Types of Adult Stem Cells – Stem Cell Institute

Stem cells reside in adult bone marrow and fat, as well as other tissues and organs of the body including the umbilical cord. These cells have a natural ability to repair damaged tissue, however in people with degenerative diseases they are not released quickly enough to fully repair damaged tissue. In the case of fat stem cells they may not be released at all. The process of actively extracting, concentrating and administering these stem cells has been shown in clinical trials to have beneficial effects in degenerative conditions. Few patients have access to clinical trials. We offer patients and their doctors access to these therapies now. Stem cell treatments are not covered by insurance.

Adult stem cells can be extracted from most tissues in the body, including the bone marrow, fat, and peripheral blood. They can also be isolated from human umbilical cords and placental tissue. Once the cells have been harvested, they are sent to the lab where they are purified and assessed for quality before being reintroduced back in the patient. Common types of adult stem cells are mesenchymal and hematopoietic stem cells.

Umbilical cord mesenchymal stem cells reside in the *umbilical cords of newborn babies. HUCT-MSC stem cells, like all post-natal cells, are adult stem cells.

The Stem Cell Institute utilizes cord-derived mesenchymal stem cells that are separated from the umbilical cord tissue. For certain indications, these cells are expanded into greater numbers at Medistem laboratory in Panama under very strict, internationally recognized guidelines.

Among many other things, mesenchymal stem cells from the umbilical cord tissue are known to help reduce inflammation, modulate the immune system and secrete factors that may help various tissues throughout the body to regenerate.

The bodys immune system is unable to recognize HUCT mesenchymal stem cells as foreign and therefore they are not rejected. Weve treated hundreds of patients with umbilical cord stem cells and there has never been a single instance rejection (graft vs. host disease). HUCT MSCs also proliferate/differentiate more efficiently than older cells, such as those found in the bone marrow and therefore, they are considered to be more potent.

Through retrospective analysis of our cases, weve identified proteins and genes that allow us to screen several hundred umbilical cord donations to find the ones that we know are most effective. We only use these cells and we call them golden cells.

We go through a very high throughput screening process to find cells that we know have the best anti-inflammatory activity, the best immune modulating capacity, and the best ability to stimulate regeneration.

Human umbilical cord tissue-derived mesenchymal stem cells (MSCs) that were isolated and grown in our laboratory in Panama to create master cell banks are currently being used in the United States.

These cells serve as the starting material for cellular products used in MSC clinical trials for two Duchennes muscular dystrophy patients under US FDAs designation of Investigational New Drug (IND) for single patient compassionate use. (IND 16026 DMD Single Patient)

The bone marrow stem cell is the most studied of the stem cells, since it was first discovered to in the 1960s. Originally used in bone marrow transplant for leukemias and hematopoietic diseases, numerous studies have now expanded experimental use of these cells for conditions such as peripheral vascular disease, diabetes, heart failure, and other degenerative disorders.

At Stem Cell Institute, we use purified autologous (patients own) mesenchymal stem cells from bone marrow in our spinal cord injury protocol along with umbilical cord tissue mesenchymal stem cells.

Fat stem cells are essentially sequestered and are not available to the rest of the body for repair or immune modulation. Fat derived stem cells have been used for successful treatment of companion animals and horses with bone and joint injuries for the last 10 years with positive results.

Experimental studies suggest fat derived stem cells not only can develop into new tissues but also suppress pathological immune responses as seen in autoimmune diseases. In addition to orthopedic conditions, Stem Cell Institute pioneered treating patients with osteoarthritis, rheumatoid arthritis, multiple sclerosis, and other autoimmune diseases using fat derived stem cells. However, we no longer use a patients own stem cells from fat because weve found that mesenchymal stem cells from umbilical cord tissue are superior.

Dr. Riordan published the first scientific article on treating humans (3 multiple sclerosis patients) with adipose-derived stem cells. We have treated many patients with adipose-derived mesenchymal stem cells in Panama but we no longer do so because we have found that umbilical cord-derived MSCs modulate the immune system and control inflammation better. HUCT MSCs also proliferate much more efficiently.

Articles Authored by our Doctors and Scientists about Fat Derived Stem Cells:

*All donated cords are the by-products of normal, healthy births. Each cord is carefully screened for sterility and infectious diseases under International Blood Bank standards.

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Stem cells: What they are and what they do – Mayo Clinic

Stem cells: What they are and what they do

Stem cells and derived products offer great promise for new medical treatments. Learn about stem cell types, current and possible uses, ethical issues, and the state of research and practice.

You've heard about stem cells in the news, and perhaps you've wondered if they might help you or a loved one with a serious disease. You may wonder what stem cells are, how they're being used to treat disease and injury, and why they're the subject of such vigorous debate.

Here are some answers to frequently asked questions about stem cells.

Stem cells: The body's master cells


Stem cells are the body's master cells. All other cells arise from stem cells, including blood cells, nerve cells and others.

Stem cells are the body's raw materials cells from which all other cells with specialized functions are generated. Under the right conditions in the body or a laboratory, stem cells divide to form more cells called daughter cells.

These daughter cells either become new stem cells (self-renewal) or become specialized cells (differentiation) with a more specific function, such as blood cells, brain cells, heart muscle cells or bone cells. No other cell in the body has the natural ability to generate new cell types.

Researchers and doctors hope stem cell studies can help to:

Generate healthy cells to replace diseased cells (regenerative medicine). Stem cells can be guided into becoming specific cells that can be used to regenerate and repair diseased or damaged tissues in people.

People who might benefit from stem cell therapies include those with spinal cord injuries, type 1 diabetes, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, heart disease, stroke, burns, cancer and osteoarthritis.

Stem cells may have the potential to be grown to become new tissue for use in transplant and regenerative medicine. Researchers continue to advance the knowledge on stem cells and their applications in transplant and regenerative medicine.

Test new drugs for safety and effectiveness. Before using investigational drugs in people, researchers can use some types of stem cells to test the drugs for safety and quality. This type of testing will most likely first have a direct impact on drug development first for cardiac toxicity testing.

New areas of study include the effectiveness of using human stem cells that have been programmed into tissue-specific cells to test new drugs. For the testing of new drugs to be accurate, the cells must be programmed to acquire properties of the type of cells targeted by the drug. Techniques to program cells into specific cells continue to be studied.

For instance, nerve cells could be generated to test a new drug for a nerve disease. Tests could show whether the new drug had any effect on the cells and whether the cells were harmed.

Researchers have discovered several sources of stem cells:

Embryonic stem cells. These stem cells come from embryos that are three to five days old. At this stage, an embryo is called a blastocyst and has about 150 cells.

These are pluripotent (ploo-RIP-uh-tunt) stem cells, meaning they can divide into more stem cells or can become any type of cell in the body. This versatility allows embryonic stem cells to be used to regenerate or repair diseased tissue and organs.

Adult stem cells. These stem cells are found in small numbers in most adult tissues, such as bone marrow or fat. Compared with embryonic stem cells, adult stem cells have a more limited ability to give rise to various cells of the body.

Until recently, researchers thought adult stem cells could create only similar types of cells. For instance, researchers thought that stem cells residing in the bone marrow could give rise only to blood cells.

However, emerging evidence suggests that adult stem cells may be able to create various types of cells. For instance, bone marrow stem cells may be able to create bone or heart muscle cells.

This research has led to early-stage clinical trials to test usefulness and safety in people. For example, adult stem cells are currently being tested in people with neurological or heart disease.

Adult cells altered to have properties of embryonic stem cells (induced pluripotent stem cells). Scientists have successfully transformed regular adult cells into stem cells using genetic reprogramming. By altering the genes in the adult cells, researchers can reprogram the cells to act similarly to embryonic stem cells.

This new technique may allow researchers to use reprogrammed cells instead of embryonic stem cells and prevent immune system rejection of the new stem cells. However, scientists don't yet know whether using altered adult cells will cause adverse effects in humans.

Researchers have been able to take regular connective tissue cells and reprogram them to become functional heart cells. In studies, animals with heart failure that were injected with new heart cells experienced improved heart function and survival time.

Perinatal stem cells. Researchers have discovered stem cells in amniotic fluid as well as umbilical cord blood. These stem cells also have the ability to change into specialized cells.

Amniotic fluid fills the sac that surrounds and protects a developing fetus in the uterus. Researchers have identified stem cells in samples of amniotic fluid drawn from pregnant women to test for abnormalities a procedure called amniocentesis.

More study of amniotic fluid stem cells is needed to understand their potential.

Embryonic stem cells are obtained from early-stage embryos a group of cells that forms when a woman's egg is fertilized with a man's sperm in an in vitro fertilization clinic. Because human embryonic stem cells are extracted from human embryos, several questions and issues have been raised about the ethics of embryonic stem cell research.

The National Institutes of Health created guidelines for human stem cell research in 2009. The guidelines define embryonic stem cells and how they may be used in research, and include recommendations for the donation of embryonic stem cells. Also, the guidelines state embryonic stem cells from embryos created by in vitro fertilization can be used only when the embryo is no longer needed.

The embryos being used in embryonic stem cell research come from eggs that were fertilized at in vitro fertilization clinics but never implanted in a woman's uterus. The stem cells are donated with informed consent from donors. The stem cells can live and grow in special solutions in test tubes or petri dishes in laboratories.

Although research into adult stem cells is promising, adult stem cells may not be as versatile and durable as are embryonic stem cells. Adult stem cells may not be able to be manipulated to produce all cell types, which limits how adult stem cells can be used to treat diseases.

Adult stem cells also are more likely to contain abnormalities due to environmental hazards, such as toxins, or from errors acquired by the cells during replication. However, researchers have found that adult stem cells are more adaptable than was first thought.

A stem cell line is a group of cells that all descend from a single original stem cell and are grown in a lab. Cells in a stem cell line keep growing but don't differentiate into specialized cells. Ideally, they remain free of genetic defects and continue to create more stem cells. Clusters of cells can be taken from a stem cell line and frozen for storage or shared with other researchers.

Stem cell therapy, also known as regenerative medicine, promotes the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. It is the next chapter in organ transplantation and uses cells instead of donor organs, which are limited in supply.

Researchers grow stem cells in a lab. These stem cells are manipulated to specialize into specific types of cells, such as heart muscle cells, blood cells or nerve cells.

The specialized cells can then be implanted into a person. For example, if the person has heart disease, the cells could be injected into the heart muscle. The healthy transplanted heart muscle cells could then contribute to repairing defective heart muscle.

Researchers have already shown that adult bone marrow cells guided to become heart-like cells can repair heart tissue in people, and more research is ongoing.

Yes. Doctors have performed stem cell transplants, also known as bone marrow transplants. In stem cell transplants, stem cells replace cells damaged by chemotherapy or disease or serve as a way for the donor's immune system to fight some types of cancer and blood-related diseases, such as leukemia, lymphoma, neuroblastoma and multiple myeloma. These transplants use adult stem cells or umbilical cord blood.

Researchers are testing adult stem cells to treat other conditions, including a number of degenerative diseases such as heart failure.

For embryonic stem cells to be useful in people, researchers must be certain that the stem cells will differentiate into the specific cell types desired.

Researchers have discovered ways to direct stem cells to become specific types of cells, such as directing embryonic stem cells to become heart cells. Research is ongoing in this area.

Embryonic stem cells can also grow irregularly or specialize in different cell types spontaneously. Researchers are studying how to control the growth and differentiation of embryonic stem cells.

Embryonic stem cells might also trigger an immune response in which the recipient's body attacks the stem cells as foreign invaders, or the stem cells might simply fail to function normally, with unknown consequences. Researchers continue to study how to avoid these possible complications.

Therapeutic cloning, also called somatic cell nuclear transfer, is a technique to create versatile stem cells independent of fertilized eggs. In this technique, the nucleus, which contains the genetic material, is removed from an unfertilized egg. The nucleus is also removed from the cell of a donor.

This donor nucleus is then injected into the egg, replacing the nucleus that was removed, in a process called nuclear transfer. The egg is allowed to divide and soon forms a blastocyst. This process creates a line of stem cells that is genetically identical to the donor's cells in essence, a clone.

Some researchers believe that stem cells derived from therapeutic cloning may offer benefits over those from fertilized eggs because cloned cells are less likely to be rejected once transplanted back into the donor and may allow researchers to see exactly how a disease develops.

No. Researchers haven't been able to successfully perform therapeutic cloning with humans despite success in a number of other species.

However, in recent studies, researchers have created human pluripotent stem cells by modifying the therapeutic cloning process. Researchers continue to study the potential of therapeutic cloning in people.


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What are Adult Stem Cells? | Adult Stem Cell Treatment

The primary role of adult stem cells in humans is to maintain and repair the tissue in which they are found. While we call them adult stem cells, they are more accurately called somatic (from the Greek word soma = body) because they come virtually any body tissue, not only in adults but children and babies as well.

Stem cells are very flexible cells, sometimes considered immature, that have not developed to a final specialized cell type (like skin, liver, heart, etc.) Since they have not yet specialized, stem cells can respond to different signals and needs in the body by becoming any of the various cell types needed, e.g., after an injury to repair an organ. In that sense they are a bit like a maintenance crew that keeps repairing and replacing damaged or worn out cells in the body.

A stem cell is essentially a blank cell, capable of becoming another more differentiated cell type in the body, such as a skin cell, a muscle cell, or a nerve cell. Microscopic in size, stem cells are big news in medical and science circles because they can be used to replace or even heal damaged tissues and cells in the body. They can serve as a built-in repair system for the human body, replenishing other cells as long as a person is still alive.

Adult stem cells are a natural solution. They naturally exist in our bodies, and they provide a natural repair mechanism for many tissues of our bodies. They belong in the microenvironment of an adult body, while embryonic stem cells belong in the microenvironment of the early embryo, not in an adult body, where they tend to cause tumors and immune system reactions.

Most importantly,adult stem cells have already been successfully used in human therapies for many years.As of this moment,no therapies in humans have ever been successfully carried out using embryonic stem cells.New therapies using adult type stem cells, on the other hand, are being developed all the time.

Stem Cells are being used today to help people suffering from dozens of diseases and conditions. This list reveals the wide range of applications that adult stem cells are having right now:


Auto-Immune Diseases



Neural Degenerative Diseases and Injuries

Anemias and Other Blood Conditions

Wounds and Injuries

Other Metabolic Disorders

Liver Disease

The primary reason would be the ethics, since getting embryonic stem cells requires destruction of a young human embryo. The other, practical reasons are that people feel money spent on embryonic stem cell research could be better spent on other stem cell research.

The biggest misconception people have about stem cell research is that it is only embryonic that are useful. In fact, other stem cell types are proving to be much more useful. The best stem cells for patients are Adult Stem Cells; these are taken from the body (e.g., bone marrow, muscle, even fat tissue) or umbilical cord blood and can be used to treat dozens of diseases and conditions. Over 1 million people have already been treated with adult stem cells. (versus no proven success with embryonic stem cells.)https://lozierinstitute.org/fact-sheet-adult-stem-cell-research-transplants/Yet most people dont know about adult stem cells and their practical success.

Another type of stem cell that is proving very useful is induced pluripotent stem cells (iPS cells.) These can be made from any cell, such as skin, and from any person. They act like embryonic stem cells, but are made from ordinary cells and so dont require embryo destruction, making them an ethical source for that type of cell. They have already been used to create lab models of different diseases.

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4. The Adult Stem Cell | stemcells.nih.gov

For many years, researchers have been seeking to understand the body's ability to repair and replace the cells and tissues of some organs, but not others. After years of work pursuing the how and why of seemingly indiscriminant cell repair mechanisms, scientists have now focused their attention on adult stem cells. It has long been known that stem cells are capable of renewing themselves and that they can generate multiple cell types. Today, there is new evidence that stem cells are present in far more tissues and organs than once thought and that these cells are capable of developing into more kinds of cells than previously imagined. Efforts are now underway to harness stem cells and to take advantage of this new found capability, with the goal of devising new and more effective treatments for a host of diseases and disabilities. What lies ahead for the use of adult stem cells is unknown, but it is certain that there are many research questions to be answered and that these answers hold great promise for the future.

Adult stem cells, like all stem cells, share at least two characteristics. First, they can make identical copies of themselves for long periods of time; this ability to proliferate is referred to as long-term self-renewal. Second, they can give rise to mature cell types that have characteristic morphologies (shapes) and specialized functions. Typically, stem cells generate an intermediate cell type or types before they achieve their fully differentiated state. The intermediate cell is called a precursor or progenitor cell. Progenitor or precursor cells in fetal or adult tissues are partly differentiated cells that divide and give rise to differentiated cells. Such cells are usually regarded as "committed" to differentiating along a particular cellular development pathway, although this characteristic may not be as definitive as once thought [82] (see Figure 4.1. Distinguishing Features of Progenitor/Precursor Cells and Stem Cells).

Figure 4.1. Distinguishing Features of Progenitor/Precursor Cells and Stem Cells. A stem cell is an unspecialized cell that is capable of replicating or self renewing itself and developing into specialized cells of a variety of cell types. The product of a stem cell undergoing division is at least one additional stem cell that has the same capabilities of the originating cell. Shown here is an example of a hematopoietic stem cell producing a second generation stem cell and a neuron. A progenitor cell (also known as a precursor cell) is unspecialized or has partial characteristics of a specialized cell that is capable of undergoing cell division and yielding two specialized cells. Shown here is an example of a myeloid progenitor/precursor undergoing cell division to yield two specialized cells (a neutrophil and a red blood cell).

( 2001 Terese Winslow, Lydia Kibiuk)

Adult stem cells are rare. Their primary functions are to maintain the steady state functioning of a cellcalled homeostasisand, with limitations, to replace cells that die because of injury or disease [44, 58]. For example, only an estimated 1 in 10,000 to 15,000 cells in the bone marrow is a hematopoietic (bloodforming) stem cell (HSC) [105]. Furthermore, adult stem cells are dispersed in tissues throughout the mature animal and behave very differently, depending on their local environment. For example, HSCs are constantly being generated in the bone marrow where they differentiate into mature types of blood cells. Indeed, the primary role of HSCs is to replace blood cells [26] (see Chapter 5. Hematopoietic Stem Cells). In contrast, stem cells in the small intestine are stationary, and are physically separated from the mature cell types they generate. Gut epithelial stem cells (or precursors) occur at the bases of cryptsdeep invaginations between the mature, differentiated epithelial cells that line the lumen of the intestine. These epithelial crypt cells divide fairly often, but remain part of the stationary group of cells they generate [93].

Unlike embryonic stem cells, which are defined by their origin (the inner cell mass of the blastocyst), adult stem cells share no such definitive means of characterization. In fact, no one knows the origin of adult stem cells in any mature tissue. Some have proposed that stem cells are somehow set aside during fetal development and restrained from differentiating. Definitions of adult stem cells vary in the scientific literature range from a simple description of the cells to a rigorous set of experimental criteria that must be met before characterizing a particular cell as an adult stem cell. Most of the information about adult stem cells comes from studies of mice. The list of adult tissues reported to contain stem cells is growing and includes bone marrow, peripheral blood, brain, spinal cord, dental pulp, blood vessels, skeletal muscle, epithelia of the skin and digestive system, cornea, retina, liver, and pancreas.

In order to be classified as an adult stem cell, the cell should be capable of self-renewal for the lifetime of the organism. This criterion, although fundamental to the nature of a stem cell, is difficult to prove in vivo. It is nearly impossible, in an organism as complex as a human, to design an experiment that will allow the fate of candidate adult stem cells to be identified in vivo and tracked over an individual's entire lifetime.

Ideally, adult stem cells should also be clonogenic. In other words, a single adult stem cell should be able to generate a line of genetically identical cells, which then gives rise to all the appropriate, differentiated cell types of the tissue in which it resides. Again, this property is difficult to demonstrate in vivo; in practice, scientists show either that a stem cell is clonogenic in vitro, or that a purified population of candidate stem cells can repopulate the tissue.

An adult stem cell should also be able to give rise to fully differentiated cells that have mature phenotypes, are fully integrated into the tissue, and are capable of specialized functions that are appropriate for the tissue. The term phenotype refers to all the observable characteristics of a cell (or organism); its shape (morphology); interactions with other cells and the non-cellular environment (also called the extracellular matrix); proteins that appear on the cell surface (surface markers); and the cell's behavior (e.g., secretion, contraction, synaptic transmission).

The majority of researchers who lay claim to having identified adult stem cells rely on two of these characteristicsappropriate cell morphology, and the demonstration that the resulting, differentiated cell types display surface markers that identify them as belonging to the tissue. Some studies demonstrate that the differentiated cells that are derived from adult stem cells are truly functional, and a few studies show that cells are integrated into the differentiated tissue in vivo and that they interact appropriately with neighboring cells. At present, there is, however, a paucity of research, with a few notable exceptions, in which researchers were able to conduct studies of genetically identical (clonal) stem cells. In order to fully characterize the regenerating and self-renewal capabilities of the adult stem cell, and therefore to truly harness its potential, it will be important to demonstrate that a single adult stem cell can, indeed, generate a line of genetically identical cells, which then gives rise to all the appropriate, differentiated cell types of the tissue in which it resides.

Adult stem cells have been identified in many animal and human tissues. In general, three methods are used to determine whether candidate adult stem cells give rise to specialized cells. Adult stem cells can be labeled in vivo and then they can be tracked. Candidate adult stem cells can also be isolated and labeled and then transplanted back into the organism to determine what becomes of them. Finally, candidate adult stem cells can be isolated, grown in vitro and manipulated, by adding growth factors or introducing genes that help determine what differentiated cells types they will yield. For example, currently, scientists believe that stem cells in the fetal and adult brain divide and give rise to more stem cells or to several types of precursor cells, which give rise to nerve cells (neurons), of which there are many types.

It is often difficultif not impossibleto distinguish adult, tissue-specific stem cells from progenitor cells, which are found in fetal or adult tissues and are partly differentiated cells that divide and give rise to differentiated cells. These are cells found in many organs that are generally thought to be present to replace cells and maintain the integrity of the tissue. Progenitor cells give rise to certain types of cellssuch as the blood cells known as T lymphocytes, B lymphocytes, and natural killer cellsbut are not thought to be capable of developing into all the cell types of a tissue and as such are not truly stem cells. The current wave of excitement over the existence of stem cells in many adult tissues is perhaps fueling claims that progenitor or precursor cells in those tissues are instead stem cells. Thus, there are reports of endothelial progenitor cells, skeletal muscle stem cells, epithelial precursors in the skin and digestive system, as well as some reports of progenitors or stem cells in the pancreas and liver. A detailed summary of some of the evidence for the existence of stem cells in various tissues and organs is presented later in the chapter.

It was not until recently that anyone seriously considered the possibility that stem cells in adult tissues could generate the specialized cell types of another type of tissue from which they normally resideeither a tissue derived from the same embryonic germ layer or from a different germ layer (see Table 1.1. Embryonic Germ Layers From Which Differentiated Tissues Develop). For example, studies have shown that blood stem cells (derived from mesoderm) may be able to generate both skeletal muscle (also derived from mesoderm) and neurons (derived from ectoderm). That realization has been triggered by a flurry of papers reporting that stem cells derived from one adult tissue can change their appearance and assume characteristics that resemble those of differentiated cells from other tissues.

The term plasticity, as used in this report, means that a stem cell from one adult tissue can generate the differentiated cell types of another tissue. At this time, there is no formally accepted name for this phenomenon in the scientific literature. It is variously referred to as "plasticity" [15, 52], "unorthodox differentiation" [10] or "transdifferentiation" [7, 54].

To be able to claim that adult stem cells demonstrate plasticity, it is first important to show that a cell population exists in the starting tissue that has the identifying features of stem cells. Then, it is necessary to show that the adult stem cells give rise to cell types that normally occur in a different tissue. Neither of these criteria is easily met. Simply proving the existence of an adult stem cell population in a differentiated tissue is a laborious process. It requires that the candidate stem cells are shown to be self-renewing, and that they can give rise to the differentiated cell types that are characteristic of that tissue.

To show that the adult stem cells can generate other cell types requires them to be tracked in their new environment, whether it is in vitro or in vivo. In general, this has been accomplished by obtaining the stem cells from a mouse that has been genetically engineered to express a molecular tag in all its cells. It is then necessary to show that the labeled adult stem cells have adopted key structural and biochemical characteristics of the new tissue they are claimed to have generated. Ultimatelyand most importantlyit is necessary to demonstrate that the cells can integrate into their new tissue environment, survive in the tissue, and function like the mature cells of the tissue.

In the experiments reported to date, adult stem cells may assume the characteristics of cells that have developed from the same primary germ layer or a different germ layer (see Figure 4.2. Preliminary Evidence of Plasticity Among Nonhuman Adult Stem Cells). For example, many plasticity experiments involve stem cells derived from bone marrow, which is a mesodermal derivative. The bone marrow stem cells may then differentiate into another mesodermally derived tissue such as skeletal muscle [28, 43], cardiac muscle [51, 71] or liver [4, 54, 97].

Figure 4.2. Preliminary Evidence of Plasticity Among Nonhuman Adult Stem Cells.

( 2001 Terese Winslow, Lydia Kibiuk, Caitlin Duckwall)

Alternatively, adult stem cells may differentiate into a tissue thatduring normal embryonic developmentwould arise from a different germ layer. For example, bone marrow-derived cells may differentiate into neural tissue, which is derived from embryonic ectoderm [15, 65]. Andreciprocallyneural stem cell lines cultured from adult brain tissue may differentiate to form hematopoietic cells [13], or even give rise to many different cell types in a chimeric embryo [17]. In both cases cited above, the cells would be deemed to show plasticity, but in the case of bone marrow stem cells generating brain cells, the finding is less predictable.

In order to study plasticity within and across germ layer lines, the researcher must be sure that he/she is using only one kind of adult stem cell. The vast majority of experiments on plasticity have been conducted with adult stem cells derived either from the bone marrow or the brain. The bone marrow-derived cells are sometimes sortedusing a panel of surface markersinto populations of hematopoietic stem cells or bone marrow stromal cells [46, 54, 71]. The HSCs may be highly purified or partially purified, depending on the conditions used. Another way to separate population of bone marrow cells is by fractionation to yield cells that adhere to a growth substrate (stromal cells) or do not adhere (hematopoietic cells) [28].

To study plasticity of stem cells derived from the brain, the researcher must overcome several problems. Stem cells from the central nervous system (CNS), unlike bone marrow cells, do not occur in a single, accessible location. Instead, they are scattered in three places, at least in rodent brainthe tissue around the lateral ventricles in the forebrain, a migratory pathway for the cells that leads from the ventricles to the olfactory bulbs, and the hippocampus. Many of the experiments with CNS stem cells involve the formation of neurospheres, round aggregates of cells that are sometimes clonally derived. But it is not possible to observe cells in the center of a neurosphere, so to study plasticity in vitro, the cells are usually dissociated and plated in monolayers. To study plasticity in vivo, the cells may be dissociated before injection into the circulatory system of the recipient animal [13], or injected as neurospheres [17].

The differentiated cell types that result from plasticity are usually reported to have the morphological characteristics of the differentiated cells and to display their characteristic surface markers. In reports that transplanted adult stem cells show plasticity in vivo, the stem cells typically are shown to have integrated into a mature host tissue and assumed at least some of its characteristics [15, 28, 51, 65, 71]. Many plasticity experiments involve injury to a particular tissue, which is intended to model a particular human disease or injury [13, 54, 71]. However, there is limited evidence to date that such adult stem cells can generate mature, fully functional cells or that the cells have restored lost function in vivo [54]. Most of the studies that show the plasticity of adult stem cells involve cells that are derived from the bone marrow [15, 28, 54, 65, 77] or brain [13, 17]. To date, adult stem cells are best characterized in these two tissues, which may account for the greater number of plasticity studies based on bone marrow and brain. Collectively, studies on plasticity suggest that stem cell populations in adult mammals are not fixed entities, and that after exposure to a new environment, they may be able to populate other tissues and possibly differentiate into other cell types.

It is not yet possible to say whether plasticity occurs normally in vivo. Some scientists think it may [14, 64], but as yet there is no evidence to prove it. Also, it is not yet clear to what extent plasticity can occur in experimental settings, and howor whetherthe phenomenon can be harnessed to generate tissues that may be useful for therapeutic transplantation. If the phenomenon of plasticity is to be used as a basis for generating tissue for transplantation, the techniques for doing it will need to be reproducible and reliable (see Chapter 10. Assessing Human Stem Cell Safety). In some cases, debate continues about observations that adult stem cells yield cells of tissue types different than those from which they were obtained [7, 68].

More than 30 years ago, Altman and Das showed that two regions of the postnatal rat brain, the hippocampus and the olfactory bulb, contain dividing cells that become neurons [5, 6]. Despite these reports, the prevailing view at the time was that nerve cells in the adult brain do not divide. In fact, the notion that stem cells in the adult brain can generate its three major cell typesastrocytes and oligodendrocytes, as well as neuronswas not accepted until far more recently. Within the past five years, a series of studies has shown that stem cells occur in the adult mammalian brain and that these cells can generate its three major cell lineages [35, 48, 63, 66, 90, 96, 104] (see Chapter 8. Rebuilding the Nervous System with Stem Cells).

Today, scientists believe that stem cells in the fetal and adult brain divide and give rise to more stem cells or to several types of precursor cells. Neuronal precursors (also called neuroblasts) divide and give rise to nerve cells (neurons), of which there are many types. Glial precursors give rise to astrocytes or oligodendrocytes. Astrocytes are a kind of glial cell, which lend both mechanical and metabolic support for neurons; they make up 70 to 80 percent of the cells of the adult brain. Oligodendrocytes make myelin, the fatty material that ensheathes nerve cell axons and speeds nerve transmission. Under normal, in vivo conditions, neuronal precursors do not give rise to glial cells, and glial precursors do not give rise to neurons. In contrast, a fetal or adult CNS (central nervous systemthe brain and spinal cord) stem cell may give rise to neurons, astrocytes, or oligodendrocytes, depending on the signals it receives and its three-dimensional environment within the brain tissue. There is now widespread consensus that the adult mammalian brain does contain stem cells. However, there is no consensus about how many populations of CNS stem cells exist, how they may be related, and how they function in vivo. Because there are no markers currently available to identify the cells in vivo, the only method for testing whether a given population of CNS cells contains stem cells is to isolate the cells and manipulate them in vitro, a process that may change their intrinsic properties [67].

Despite these barriers, three groups of CNS stem cells have been reported to date. All occur in the adult rodent brain and preliminary evidence indicates they also occur in the adult human brain. One group occupies the brain tissue next to the ventricles, regions known as the ventricular zone and the sub-ventricular zone (see discussion below). The ventricles are spaces in the brain filled with cerebrospinal fluid. During fetal development, the tissue adjacent to the ventricles is a prominent region of actively dividing cells. By adulthood, however, this tissue is much smaller, although it still appears to contain stem cells [70].

A second group of adult CNS stem cells, described in mice but not in humans, occurs in a streak of tissue that connects the lateral ventricle and the olfactory bulb, which receives odor signals from the nose. In rodents, olfactory bulb neurons are constantly being replenished via this pathway [59, 61]. A third possible location for stem cells in adult mouse and human brain occurs in the hippocampus, a part of the brain thought to play a role in the formation of certain kinds of memory [27, 34].

Central Nervous System Stem Cells in the Subventricular Zone. CNS stem cells found in the forebrain that surrounds the lateral ventricles are heterogeneous and can be distinguished morphologically. Ependymal cells, which are ciliated, line the ventricles. Adjacent to the ependymal cell layer, in a region sometimes designated as the subependymal or subventricular zone, is a mixed cell population that consists of neuroblasts (immature neurons) that migrate to the olfactory bulb, precursor cells, and astrocytes. Some of the cells divide rapidly, while others divide slowly. The astrocyte-like cells can be identified because they contain glial fibrillary acidic protein (GFAP), whereas the ependymal cells stain positive for nestin, which is regarded as a marker of neural stem cells. Which of these cells best qualifies as a CNS stem cell is a matter of debate [76].

A recent report indicates that the astrocytes that occur in the subventricular zone of the rodent brain act as neural stem cells. The cells with astrocyte markers appear to generate neurons in vivo, as identified by their expression of specific neuronal markers. The in vitro assay to demonstrate that these astrocytes are, in fact, stem cells involves their ability to form neurospheresgroupings of undifferentiated cells that can be dissociated and coaxed to differentiate into neurons or glial cells [25]. Traditionally, these astrocytes have been regarded as differentiated cells, not as stem cells and so their designation as stem cells is not universally accepted.

A series of similar in vitro studies based on the formation of neurospheres was used to identify the subependymal zone as a source of adult rodent CNS stem cells. In these experiments, single, candidate stem cells derived from the subependymal zone are induced to give rise to neurospheres in the presence of mitogenseither epidermal growth factor (EGF) or fibroblast growth factor-2 (FGF-2). The neurospheres are dissociated and passaged. As long as a mitogen is present in the culture medium, the cells continue forming neurospheres without differentiating. Some populations of CNS cells are more responsive to EGF, others to FGF [100]. To induce differentiation into neurons or glia, cells are dissociated from the neurospheres and grown on an adherent surface in serum-free medium that contains specific growth factors. Collectively, the studies demonstrate that a population of cells derived from the adult rodent brain can self-renew and differentiate to yield the three major cell types of the CNS cells [41, 69, 74, 102].

Central Nervous System Stem Cells in the Ventricular Zone. Another group of potential CNS stem cells in the adult rodent brain may consist of the ependymal cells themselves [47]. Ependymal cells, which are ciliated, line the lateral ventricles. They have been described as non-dividing cells [24] that function as part of the blood-brain barrier [22]. The suggestion that ependymal cells from the ventricular zone of the adult rodent CNS may be stem cells is therefore unexpected. However, in a recent study, in which two molecular tagsthe fluorescent marker Dil, and an adenovirus vector carrying lacZ tagswere used to label the ependymal cells that line the entire CNS ventricular system of adult rats, it was shown that these cells could, indeed, act as stem cells. A few days after labeling, fluorescent or lacZ+ cells were observed in the rostral migratory stream (which leads from the lateral ventricle to the olfactory bulb), and then in the olfactory bulb itself. The labeled cells in the olfactory bulb also stained for the neuronal markers III tubulin and Map2, which indicated that ependymal cells from the ventricular zone of the adult rat brain had migrated along the rostral migratory stream to generate olfactory bulb neurons in vivo [47].

To show that Dil+ cells were neural stem cells and could generate astrocytes and oligodendrocytes as well as neurons, a neurosphere assay was performed in vitro. Dil-labeled cells were dissociated from the ventricular system and cultured in the presence of mitogen to generate neurospheres. Most of the neurospheres were Dil+; they could self-renew and generate neurons, astrocytes, and oligodendrocytes when induced to differentiate. Single, Dil+ ependymal cells isolated from the ventricular zone could also generate self-renewing neurospheres and differentiate into neurons and glia.

To show that ependymal cells can also divide in vivo, bromodeoxyuridine (BrdU) was administered in the drinking water to rats for a 2- to 6-week period. Bromodeoxyuridine (BrdU) is a DNA precursor that is only incorporated into dividing cells. Through a series of experiments, it was shown that ependymal cells divide slowly in vivo and give rise to a population of progenitor cells in the subventricular zone [47]. A different pattern of scattered BrdU-labeled cells was observed in the spinal cord, which suggested that ependymal cells along the central canal of the cord occasionally divide and give rise to nearby ependymal cells, but do not migrate away from the canal.

Collectively, the data suggest that CNS ependymal cells in adult rodents can function as stem cells. The cells can self-renew, and most proliferate via asymmetrical division. Many of the CNS ependymal cells are not actively dividing (quiescent), but they can be stimulated to do so in vitro (with mitogens) or in vivo (in response to injury). After injury, the ependymal cells in the spinal cord only give rise to astrocytes, not to neurons. How and whether ependymal cells from the ventricular zone are related to other candidate populations of CNS stem cells, such as those identified in the hippocampus [34], is not known.

Are ventricular and subventricular zone CNS stem cells the same population? These studies and other leave open the question of whether cells that directly line the ventriclesthose in the ventricular zoneor cells that are at least a layer removed from this zonein the subventricular zone are the same population of CNS stem cells. A new study, based on the finding that they express different genes, confirms earlier reports that the ventricular and subventricular zone cell populations are distinct. The new research utilizes a technique called representational difference analysis, together with cDNA microarray analysis, to monitor the patterns of gene expression in the complex tissue of the developing and postnatal mouse brain. The study revealed the expression of a panel of genes known to be important in CNS development, such as L3-PSP (which encodes a phosphoserine phosphatase important in cell signaling), cyclin D2 (a cell cycle gene), and ERCC-1 (which is important in DNA excision repair). All of these genes in the recent study were expressed in cultured neurospheres, as well as the ventricular zone, the subventricular zone, and a brain area outside those germinal zones. This analysis also revealed the expression of novel genes such as A16F10, which is similar to a gene in an embryonic cancer cell line. A16F10 was expressed in neurospheres and at high levels in the subventricular zone, but not significantly in the ventricular zone. Interestingly, several of the genes identified in cultured neurospheres were also expressed in hematopoietic cells, suggesting that neural stem cells and blood-forming cells may share aspects of their genetic programs or signaling systems [38]. This finding may help explain recent reports that CNS stem cells derived from mouse brain can give rise to hematopoietic cells after injection into irradiated mice [13].

Central Nervous System Stem Cells in the Hippocampus. The hippocampus is one of the oldest parts of the cerebral cortex, in evolutionary terms, and is thought to play an important role in certain forms of memory. The region of the hippocampus in which stem cells apparently exist in mouse and human brains is the subgranular zone of the dentate gyrus. In mice, when BrdU is used to label dividing cells in this region, about 50% of the labeled cells differentiate into cells that appear to be dentate gyrus granule neurons, and 15% become glial cells. The rest of the BrdU-labeled cells do not have a recognizable phenotype [90]. Interestingly, many, if not all the BrdU-labeled cells in the adult rodent hippocampus occur next to blood vessels [33].

In the human dentate gyrus, some BrdU-labeled cells express NeuN, neuron-specific enolase, or calbindin, all of which are neuronal markers. The labeled neuron-like cells resemble dentate gyrus granule cells, in terms of their morphology (as they did in mice). Other BrdU-labeled cells express glial fibrillary acidic protein (GFAP) an astrocyte marker. The study involved autopsy material, obtained with family consent, from five cancer patients who had been injected with BrdU dissolved in saline prior to their death for diagnostic purposes. The patients ranged in age from 57 to 72 years. The greatest number of BrdU-labeled cells were identified in the oldest patient, suggesting that new neuron formation in the hippocampus can continue late in life [27].

Fetal Central Nervous System Stem Cells. Not surprisingly, fetal stem cells are numerous in fetal tissues, where they are assumed to play an important role in the expansion and differentiation of all tissues of the developing organism. Depending on the developmental stage of an animal, fetal stem cells and precursor cellswhich arise from stem cellsmay make up the bulk of a tissue. This is certainly true in the brain [48], although it has not been demonstrated experimentally in many tissues.

It may seem obvious that the fetal brain contains stem cells that can generate all the types of neurons in the brain as well as astrocytes and oligodendrocytes, but it was not until fairly recently that the concept was proven experimentally. There has been a long-standing question as to whether or not the same cell type gives rise to both neurons and glia. In studies of the developing rodent brain, it has now been shown that all the major cell types in the fetal brain arise from a common population of progenitor cells [20, 34, 48, 80, 108].

Neural stem cells in the mammalian fetal brain are concentrated in seven major areas: olfactory bulb, ependymal (ventricular) zone of the lateral ventricles (which lie in the forebrain), subventricular zone (next to the ependymal zone), hippocampus, spinal cord, cerebellum (part of the hindbrain), and the cerebral cortex. Their number and pattern of development vary in different species. These cells appear to represent different stem cell populations, rather than a single population of stem cells that is dispersed in multiple sites. The normal development of the brain depends not only on the proliferation and differentiation of these fetal stem cells, but also on a genetically programmed process of selective cell death called apoptosis [76].

Little is known about stem cells in the human fetal brain. In one study, however, investigators derived clonal cell lines from CNS stem cells isolated from the diencephalon and cortex of human fetuses, 10.5 weeks post-conception [103]. The study is unusual, not only because it involves human CNS stem cells obtained from fetal tissue, but also because the cells were used to generate clonal cell lines of CNS stem cells that generated neurons, astrocytes, and oligodendrocytes, as determined on the basis of expressed markers. In a few experiments described as "preliminary," the human CNS stem cells were injected into the brains of immunosuppressed rats where they apparently differentiated into neuron-like cells or glial cells.

In a 1999 study, a serum-free growth medium that included EGF and FGF2 was devised to grow the human fetal CNS stem cells. Although most of the cells died, occasionally, single CNS stem cells survived, divided, and ultimately formed neurospheres after one to two weeks in culture. The neurospheres could be dissociated and individual cells replated. The cells resumed proliferation and formed new neurospheres, thus establishing an in vitro system that (like the system established for mouse CNS neurospheres) could be maintained up to 2 years. Depending on the culture conditions, the cells in the neurospheres could be maintained in an undifferentiated dividing state (in the presence of mitogen), or dissociated and induced to differentiate (after the removal of mitogen and the addition of specific growth factors to the culture medium). The differentiated cells consisted mostly of astrocytes (75%), some neurons (13%) and rare oligodendrocytes (1.2%). The neurons generated under these conditions expressed markers indicating they were GABAergic, [the major type of inhibitory neuron in the mammalian CNS responsive to the amino acid neurotransmitter, gammaaminobutyric acid (GABA)]. However, catecholamine-like cells that express tyrosine hydroxylase (TH, a critical enzyme in the dopamine-synthesis pathway) could be generated, if the culture conditions were altered to include different medium conditioned by a rat glioma line (BB49). Thus, the report indicates that human CNS stem cells obtained from early fetuses can be maintained in vitro for a long time without differentiating, induced to differentiate into the three major lineages of the CNS (and possibly two kinds of neurons, GABAergic and TH-positive), and engraft (in rats) in vivo [103].

Central Nervous System Neural Crest Stem Cells. Neural crest cells differ markedly from fetal or adult neural stem cells. During fetal development, neural crest cells migrate from the sides of the neural tube as it closes. The cells differentiate into a range of tissues, not all of which are part of the nervous system [56, 57, 91]. Neural crest cells form the sympathetic and parasympathetic components of the peripheral nervous system (PNS), including the network of nerves that innervate the heart and the gut, all the sensory ganglia (groups of neurons that occur in pairs along the dorsal surface of the spinal cord), and Schwann cells, which (like oligodendrocytes in the CNS) make myelin in the PNS. The non-neural tissues that arise from the neural crest are diverse. They populate certain hormone-secreting glandsincluding the adrenal medulla and Type I cells in the carotid bodypigment cells of the skin (melanocytes), cartilage and bone in the face and skull, and connective tissue in many parts of the body [76].

Thus, neural crest cells migrate far more extensively than other fetal neural stem cells during development, form mesenchymal tissues, most of which develop from embryonic mesoderm as well as the components of the CNS and PNS which arises from embryonic ectoderm. This close link, in neural crest development, between ectodermally derived tissues and mesodermally derived tissues accounts in part for the interest in neural crest cells as a kind of stem cell. In fact, neural crest cells meet several criteria of stem cells. They can self-renew (at least in the fetus) and can differentiate into multiple cells types, which include cells derived from two of the three embryonic germ layers [76].

Recent studies indicate that neural crest cells persist late into gestation and can be isolated from E14.5 rat sciatic nerve, a peripheral nerve in the hindlimb. The cells incorporate BrdU, indicating that they are dividing in vivo. When transplanted into chick embryos, the rat neural crest cells develop into neurons and glia, an indication of their stem cell-like properties [67]. However, the ability of rat E14.5 neural crest cells taken from sciatic nerve to generate nerve and glial cells in chick is more limited than neural crest cells derived from younger, E10.5 rat embryos. At the earlier stage of development, the neural tube has formed, but neural crest cells have not yet migrated to their final destinations. Neural crest cells from early developmental stages are more sensitive to bone morphogenetic protein 2 (BMP2) signaling, which may help explain their greater differentiation potential [106].

The notion that the bone marrow contains stem cells is not new. One population of bone marrow cells, the hematopoietic stem cells (HSCs), is responsible for forming all of the types of blood cells in the body. HSCs were recognized as a stem cells more than 40 years ago [9, 99]. Bone marrow stromal cellsa mixed cell population that generates bone, cartilage, fat, fibrous connective tissue, and the reticular network that supports blood cell formationwere described shortly after the discovery of HSCs [30, 32, 73]. The mesenchymal stem cells of the bone marrow also give rise to these tissues, and may constitute the same population of cells as the bone marrow stromal cells [78]. Recently, a population of progenitor cells that differentiates into endothelial cells, a type of cell that lines the blood vessels, was isolated from circulating blood [8] and identified as originating in bone marrow [89]. Whether these endothelial progenitor cells, which resemble the angioblasts that give rise to blood vessels during embryonic development, represent a bona fide population of adult bone marrow stem cells remains uncertain. Thus, the bone marrow appears to contain three stem cell populationshematopoietic stem cells, stromal cells, and (possibly) endothelial progenitor cells (see Figure 4.3. Hematopoietic and Stromal Stem Cell Differentiation).

Figure 4.3. Hematopoietic and Stromal Stem Cell Differentiation.

( 2001 Terese Winslow, Lydia Kibiuk)

Two more apparent stem cell types have been reported in circulating blood, but have not been shown to originate from the bone marrow. One population, called pericytes, may be closely related to bone marrow stromal cells, although their origin remains elusive [12]. The second population of blood-born stem cells, which occur in four species of animals testedguinea pigs, mice, rabbits, and humansresemble stromal cells in that they can generate bone and fat [53].

Hematopoietic Stem Cells. Of all the cell types in the body, those that survive for the shortest period of time are blood cells and certain kinds of epithelial cells. For example, red blood cells (erythrocytes), which lack a nucleus, live for approximately 120 days in the bloodstream. The life of an animal literally depends on the ability of these and other blood cells to be replenished continuously. This replenishment process occurs largely in the bone marrow, where HSCs reside, divide, and differentiate into all the blood cell types. Both HSCs and differentiated blood cells cycle from the bone marrow to the blood and back again, under the influence of a barrage of secreted factors that regulate cell proliferation, differentiation, and migration (see Chapter 5. Hematopoietic Stem Cells).

HSCs can reconstitute the hematopoietic system of mice that have been subjected to lethal doses of radiation to destroy their own hematopoietic systems. This test, the rescue of lethally irradiated mice, has become a standard by which other candidate stem cells are measured because it shows, without question, that HSCs can regenerate an entire tissue systemin this case, the blood [9, 99]. HSCs were first proven to be blood-forming stem cells in a series of experiments in mice; similar blood-forming stem cells occur in humans. HSCs are defined by their ability to self-renew and to give rise to all the kinds of blood cells in the body. This means that a single HSC is capable of regenerating the entire hematopoietic system, although this has been demonstrated only a few times in mice [72].

Over the years, many combinations of surface markers have been used to identify, isolate, and purify HSCs derived from bone marrow and blood. Undifferentiated HSCs and hematopoietic progenitor cells express c-kit, CD34, and H-2K. These cells usually lack the lineage marker Lin, or express it at very low levels (Lin-/low). And for transplant purposes, cells that are CD34+ Thy1+ Lin- are most likely to contain stem cells and result in engraftment.

Two kinds of HSCs have been defined. Long-term HSCs proliferate for the lifetime of an animal. In young adult mice, an estimated 8 to 10 % of long-term HSCs enter the cell cycle and divide each day. Short-term HSCs proliferate for a limited time, possibly a few months. Long-term HSCs have high levels of telomerase activity. Telomerase is an enzyme that helps maintain the length of the ends of chromosomes, called telomeres, by adding on nucleotides. Active telomerase is a characteristic of undifferentiated, dividing cells and cancer cells. Differentiated, human somatic cells do not show telomerase activity. In adult humans, HSCs occur in the bone marrow, blood, liver, and spleen, but are extremely rare in any of these tissues. In mice, only 1 in 10,000 to 15,000 bone marrow cells is a long-term HSC [105].

Short-term HSCs differentiate into lymphoid and myeloid precursors, the two classes of precursors for the two major lineages of blood cells. Lymphoid precursors differentiate into T cells, B cells, and natural killer cells. The mechanisms and pathways that lead to their differentiation are still being investigated [1, 2]. Myeloid precursors differentiate into monocytes and macrophages, neutrophils, eosinophils, basophils, megakaryocytes, and erythrocytes [3]. In vivo, bone marrow HSCs differentiate into mature, specialized blood cells that cycle constantly from the bone marrow to the blood, and back to the bone marrow [26]. A recent study showed that short-term HSCs are a heterogeneous population that differ significantly in terms of their ability to self-renew and repopulate the hematopoietic system [42].

Attempts to induce HSC to proliferate in vitroon many substrates, including those intended to mimic conditions in the stromahave frustrated scientists for many years. Although HSCs proliferate readily in vivo, they usually differentiate or die in vitro [26]. Thus, much of the research on HSCs has been focused on understanding the factors, cell-cell interactions, and cell-matrix interactions that control their proliferation and differentiation in vivo, with the hope that similar conditions could be replicated in vitro. Many of the soluble factors that regulate HSC differentiation in vivo are cytokines, which are made by different cell types and are then concentrated in the bone marrow by the extracellular matrix of stromal cellsthe sites of blood formation [45, 107]. Two of the most-studied cytokines are granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) [40, 81].

Also important to HSC proliferation and differentiation are interactions of the cells with adhesion molecules in the extracellular matrix of the bone marrow stroma [83, 101, 110].

Bone Marrow Stromal Cells. Bone marrow (BM) stromal cells have long been recognized for playing an important role in the differentiation of mature blood cells from HSCs (see Figure 4.3. Hematopoietic and Stromal Stem Cell Differentiation). But stromal cells also have other important functions [30, 31]. In addition to providing the physical environment in which HSCs differentiate, BM stromal cells generate cartilage, bone, and fat. Whether stromal cells are best classified as stem cells or progenitor cells for these tissues is still in question. There is also a question as to whether BM stromal cells and so-called mesenchymal stem cells are the same population [78].

BM stromal cells have many features that distinguish them from HSCs. The two cell types are easy to separate in vitro. When bone marrow is dissociated, and the mixture of cells it contains is plated at low density, the stromal cells adhere to the surface of the culture dish, and the HSCs do not. Given specific in vitro conditions, BM stromal cells form colonies from a single cell called the colony forming unit-F (CFU-F). These colonies may then differentiate as adipocytes or myelosupportive stroma, a clonal assay that indicates the stem cell-like nature of stromal cells. Unlike HSCs, which do not divide in vitro (or proliferate only to a limited extent), BM stromal cells can proliferate for up to 35 population doublings in vitro [16]. They grow rapidly under the influence of such mitogens as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and insulin-like growth factor-1 (IGF-1) [12].

To date, it has not been possible to isolate a population of pure stromal cells from bone marrow. Panels of markers used to identify the cells include receptors for certain cytokines (interleukin-1, 3, 4, 6, and 7) receptors for proteins in the extracellular matrix, (ICAM-1 and 2, VCAM-1, the alpha-1, 2, and 3 integrins, and the beta-1, 2, 3 and 4 integrins), etc. [64]. Despite the use of these markers and another stromal cell marker called Stro-1, the origin and specific identity of stromal cells have remained elusive. Like HSCs, BM stromal cells arise from embryonic mesoderm during development, although no specific precursor or stem cell for stromal cells has been isolated and identified. One theory about their origin is that a common kind of progenitor cellperhaps a primordial endothelial cell that lines embryonic blood vesselsgives rise to both HSCs and to mesodermal precursors. The latter may then differentiate into myogenic precursors (the satellite cells that are thought to function as stem cells in skeletal muscle), and the BM stromal cells [10].

In vivo, the differentiation of stromal cells into fat and bone is not straightforward. Bone marrow adipocytes and myelosupportive stromal cellsboth of which are derived from BM stromal cellsmay be regarded as interchangeable phenotypes [10, 11]. Adipocytes do not develop until postnatal life, as the bones enlarge and the marrow space increases to accommodate enhanced hematopoiesis. When the skeleton stops growing, and the mass of HSCs decreases in a normal, age-dependent fashion, BM stromal cells differentiate into adipocytes, which fill the extra space. New bone formation is obviously greater during skeletal growth, although bone "turns over" throughout life. Bone forming cells are osteoblasts, but their relationship to BM stromal cells is not clear. New trabecular bone, which is the inner region of bone next to the marrow, could logically develop from the action of BM stromal cells. But the outside surface of bone also turns over, as does bone next to the Haversian system (small canals that form concentric rings within bone). And neither of these surfaces is in contact with BM stromal cells [10, 11].

It is often difficultif not impossibleto distinguish adult, tissue-specific stem cells from progenitor cells. With that caveat in mind, the following summary identifies reports of stem cells in various adult tissues.

Endothelial Progenitor Cells. Endothelial cells line the inner surfaces of blood vessels throughout the body, and it has been difficult to identify specific endothelial stem cells in either the embryonic or the adult mammal. During embryonic development, just after gastrulation, a kind of cell called the hemangioblast, which is derived from mesoderm, is presumed to be the precursor of both the hematopoietic and endothelial cell lineages. The embryonic vasculature formed at this stage is transient and consists of blood islands in the yolk sac. But hemangioblasts, per se, have not been isolated from the embryo and their existence remains in question. The process of forming new blood vessels in the embryo is called vasculogenesis. In the adult, the process of forming blood vessels from pre-existing blood vessels is called angiogenesis [50].

Evidence that hemangioblasts do exist comes from studies of mouse embryonic stem cells that are directed to differentiate in vitro. These studies have shown that a precursor cell derived from mouse ES cells that express Flk-1 [the receptor for vascular endothelial growth factor (VEGF) in mice] can give rise to both blood cells and blood vessel cells [88, 109]. Both VEGF and fibroblast growth factor-2 (FGF-2) play critical roles in endothelial cell differentiation in vivo [79].

Several recent reports indicate that the bone marrow contains cells that can give rise to new blood vessels in tissues that are ischemic (damaged due to the deprivation of blood and oxygen) [8, 29, 49, 94]. But it is unclear from these studies what cell type(s) in the bone marrow induced angiogenesis. In a study which sought to address that question, researchers found that adult human bone marrow contains cells that resemble embryonic hemangioblasts, and may therefore be called endothelial stem cells.

In more recent experiments, human bone marrow-derived cells were injected into the tail veins of rats with induced cardiac ischemia. The human cells migrated to the rat heart where they generated new blood vessels in the infarcted muscle (a process akin to vasculogenesis), and also induced angiogenesis. The candidate endothelial stem cells are CD34+(a marker for HSCs), and they express the transcription factor GATA-2 [51]. A similar study using transgenic mice that express the gene for enhanced green fluorescent protein (which allows the cells to be tracked), showed that bone-marrow-derived cells could repopulate an area of infarcted heart muscle in mice, and generate not only blood vessels, but also cardiomyocytes that integrated into the host tissue [71] (see Chapter 9. Can Stem Cells Repair a Damaged Heart?).

And, in a series of experiments in adult mammals, progenitor endothelial cells were isolated from peripheral blood (of mice and humans) by using antibodies against CD34 and Flk-1, the receptor for VEGF. The cells were mononuclear blood cells (meaning they have a nucleus) and are referred to as MBCD34+ cells and MBFlk1+ cells. When plated in tissue-culture dishes, the cells attached to the substrate, became spindle-shaped, and formed tube-like structures that resemble blood vessels. When transplanted into mice of the same species (autologous transplants) with induced ischemia in one limb, the MBCD34+ cells promoted the formation of new blood vessels [8]. Although the adult MBCD34+ and MBFlk1+ cells function in some ways like stem cells, they are usually regarded as progenitor cells.

Skeletal Muscle Stem Cells. Skeletal muscle, like the cardiac muscle of the heart and the smooth muscle in the walls of blood vessels, the digestive system, and the respiratory system, is derived from embryonic mesoderm. To date, at least three populations of skeletal muscle stem cells have been identified: satellite cells, cells in the wall of the dorsal aorta, and so-called "side population" cells.

Satellite cells in skeletal muscle were identified 40 years ago in frogs by electron microscopy [62], and thereafter in mammals [84]. Satellite cells occur on the surface of the basal lamina of a mature muscle cell, or myofiber. In adult mammals, satellite cells mediate muscle growth [85]. Although satellite cells are normally non-dividing, they can be triggered to proliferate as a result of injury, or weight-bearing exercise. Under either of these circumstances, muscle satellite cells give rise to myogenic precursor cells, which then differentiate into the myofibrils that typify skeletal muscle. A group of transcription factors called myogenic regulatory factors (MRFs) play important roles in these differentiation events. The so-called primary MRFs, MyoD and Myf5, help regulate myoblast formation during embryogenesis. The secondary MRFs, myogenin and MRF4, regulate the terminal differentiation of myofibrils [86].

With regard to satellite cells, scientists have been addressing two questions. Are skeletal muscle satellite cells true adult stem cells or are they instead precursor cells? Are satellite cells the only cell type that can regenerate skeletal muscle. For example, a recent report indicates that muscle stem cells may also occur in the dorsal aorta of mouse embryos, and constitute a cell type that gives rise both to muscle satellite cells and endothelial cells. Whether the dorsal aorta cells meet the criteria of a self-renewing muscle stem cell is a matter of debate [21].

Another report indicates that a different kind of stem cell, called an SP cell, can also regenerate skeletal muscle may be present in muscle and bone marrow. SP stands for a side population of cells that can be separated by fluorescence-activated cell sorting analysis. Intravenously injecting these muscle-derived stem cells restored the expression of dystrophin in mdx mice. Dystrophin is the protein that is defective in people with Duchenne's muscular dystrophy; mdx mice provide a model for the human disease. Dystrophin expression in the SP cell-treated mice was lower than would be needed for clinical benefit. Injection of bone marrow- or muscle-derived SP cells into the dystrophic muscle of the mice yielded equivocal results that the transplanted cells had integrated into the host tissue. The authors conclude that a similar population of SP stem cells can be derived from either adult mouse bone marrow or skeletal muscle, and suggest "there may be some direct relationship between bone marrow-derived stem cells and other tissue- or organ-specific cells" [43]. Thus, stem cell or progenitor cell types from various mesodermally-derived tissues may be able to generate skeletal muscle.

Epithelial Cell Precursors in the Skin and Digestive System. Epithelial cells, which constitute 60 percent of the differentiated cells in the body are responsible for covering the internal and external surfaces of the body, including the lining of vessels and other cavities. The epithelial cells in skin and the digestive tract are replaced constantly. Other epithelial cell populationsin the ducts of the liver or pancreas, for exampleturn over more slowly. The cell population that renews the epithelium of the small intestine occurs in the intestinal crypts, deep invaginations in the lining of the gut. The crypt cells are often regarded as stem cells; one of them can give rise to an organized cluster of cells called a structural-proliferative unit [93].

The skin of mammals contains at least three populations of epithelial cells: epidermal cells, hair follicle cells, and glandular epithelial cells, such as those that make up the sweat glands. The replacement patterns for epithelial cells in these three compartments differ, and in all the compartments, a stem cell population has been postulated. For example, stem cells in the bulge region of the hair follicle appear to give rise to multiple cell types. Their progeny can migrate down to the base of the follicle where they become matrix cells, which may then give rise to different cell types in the hair follicle, of which there are seven [39]. The bulge stem cells of the follicle may also give rise to the epidermis of the skin [95].

Another population of stem cells in skin occurs in the basal layer of the epidermis. These stem cells proliferate in the basal region, and then differentiate as they move toward the outer surface of the skin. The keratinocytes in the outermost layer lack nuclei and act as a protective barrier. A dividing skin stem cell can divide asymmetrically to produce two kinds of daughter cells. One is another self-renewing stem cell. The second kind of daughter cell is an intermediate precursor cell which is then committed to replicate a few times before differentiating into keratinocytes. Self-renewing stem cells can be distinguished from this intermediate precusor cell by their higher level of 1 integrin expression, which signals keratinocytes to proliferate via a mitogen-activated protein (MAP) kinase [112]. Other signaling pathways include that triggered by -catenin, which helps maintain the stem-cell state [111], and the pathway regulated by the oncoprotein c-Myc, which triggers stem cells to give rise to transit amplifying cells [36].

Stem Cells in the Pancreas and Liver. The status of stem cells in the adult pancreas and liver is unclear. During embryonic development, both tissues arise from endoderm. A recent study indicates that a single precursor cell derived from embryonic endoderm may generate both the ventral pancreas and the liver [23]. In adult mammals, however, both the pancreas and the liver contain multiple kinds of differentiated cells that may be repopulated or regenerated by multiple types of stem cells. In the pancreas, endocrine (hormone-producing) cells occur in the islets of Langerhans. They include the beta cells (which produce insulin), the alpha cells (which secrete glucagon), and cells that release the peptide hormones somatostatin and pancreatic polypeptide. Stem cells in the adult pancreas are postulated to occur in the pancreatic ducts or in the islets themselves. Several recent reports indicate that stem cells that express nestinwhich is usually regarded as a marker of neural stem cellscan generate all of the cell types in the islets [60, 113] (see Chapter 7. Stem Cells and Diabetes).

The identity of stem cells that can repopulate the liver of adult mammals is also in question. Recent studies in rodents indicate that HSCs (derived from mesoderm) may be able to home to liver after it is damaged, and demonstrate plasticity in becoming into hepatocytes (usually derived from endoderm) [54, 77, 97]. But the question remains as to whether cells from the bone marrow normally generate hepatocytes in vivo. It is not known whether this kind of plasticity occurs without severe damage to the liver or whether HSCs from the bone marrow generate oval cells of the liver [18]. Although hepatic oval cells exist in the liver, it is not clear whether they actually generate new hepatocytes [87, 98]. Oval cells may arise from the portal tracts in liver and may give rise to either hepatocytes [19, 55] and to the epithelium of the bile ducts [37, 92]. Indeed, hepatocytes themselves, may be responsible for the well-know regenerative capacity of liver.

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Moderna: A $12 Billion Brand Built On Hope And mRNA – Seeking Alpha

Moderna (MRNA) put mRNA technology on the map, however, this technology has not yet proven itself convincingly in clinical trials. The concept of making your own body behave like a drug manufacturing engine is interesting, but it has its hurdles. One hurdle is the body's own immune system, which may reject the mRNA; the other is whether the technology will produce enough proteins to make a difference - with the human body, you never know what will trigger a cascade of unpredictable events that could foil the "best laid plans of men," however smart. Delivery into cells is another issue. Everything always boils down to human trials - and here, Moderna is not there yet.

Most of the biotech investing rules I follow tell me Moderna is an absolute avoid. One, a $12bn market valuation based on a pipeline of near 20 candidates. These are based on a single all-curing drug platform. Not a single drug candidate is beyond phase 2. Two, the current price of the one-year old IPO is at 52-week and all time highs based on a fear and hope around a sudden pandemic like coronavirus. Three, a corollary of point one, there is little phase 2 efficacy data anywhere, therefore the platform, however promising, is absolutely unproven. However, on the other hand, another critical business rule I also follow is "follow the cash," and this early stage biopharma has $2bn of it. This is more cash than the entire current market cap of a company like Amarin (AMRN) with an approved and blockbuster potential product.

In order to understand this anomaly, I looked into the science behind the company, because the valuation of a pre-market pre-approval stage biopharma is mostly based on the science. And the science does look promising.

First, let us understand that the company says that mRNA-based therapeutic protein synthesis is the next step to recombinant protein technology, which has spawned an industry worth over $200bn. However, recombinant technology cannot create certain major types of proteins - intracellular and membrane proteins which represent as much as two-thirds of the proteins in humans. This is a major part of what mRNA technology can do.

There are various competitive advantages to mRNA over recombinance - for one, since the proteins are made naturally, there's less chance of rejection and immunogenicity. Another advantage, as the company says, "A vast number of potential mRNA medicines can be developed, therefore, with only minor changes to the underlying chemical structure of the molecule or manufacturing processes, a significant advantage over small molecule or protein therapeutics."

Moderna was founded in 2010 and IPO-ed in late 2018. Reading through the 10-K, what struck me was that there's a huge number of programs, all of them early stages, each demonstrating, to some extent, the development of critical antibodies upon using the drug candidate. However, instead of developing any particular program to fruition, including BLA and approval, this company focuses on advancing the entire pipeline at the same time.

Here's a snapshot of the pipeline:


Next, let me present a set of 6 slides, each for one of the modalities above, which shows the latest available trial data for that drug candidate:-

Source - 10-K

Now, we have multiple programs progressing through phase 2 - which is really the datapoint that first gets us interested (or not) in a company. Then, just today, we read about the company's plans to start a phase 3 trial "soon." However, like we said, we still couldn't find enough that could justify this huge $11.8bn valuation. I mean, the science is good, in theory, but this sort of high-grade technology has so many pitfalls it really doesn't make sense to have too much expectation until we see phase 3 data.

The above 6 slides basically show that in the lab and in primates and in healthy subjects, there's constructive antibody activity on dosing with these mRNA medicines. Some of the measures of these activities are promising, for example, for mRNA-1944, "participants had measured antibody levels exceeding the levels of antibody expected to be protective against chikungunya infection (> 1 g/mL) following a single dose, with the middle and high doses projected to maintain antibody levels above protective levels for at least 16 weeks." But this was a phase 1 study in healthy volunteers, and while promising, like I said, this alone does not justify the valuation.

Sometimes, companies like these justify their valuations on the basis of their founders, or the founding technology; Juno comes to mind. Again, nothing like that was clearly apparent to me on reading either the 10-K or the Corporate Presentation. Besides a lot of basic and advanced genetic science, I could not figure out who is behind the science; admittedly, though, MRNA does have a vast patent estate comprising more than 550 patents worldwide, applied for and granted.

A much better overview of the history of the science is found here. There are basically five key figures behind it; the original science was developed by University of Pennsylvania scientist Katalin Karik, but her startup didn't go anywhere directly. "Later, in 2010 Harvard University scientist Derrick Rossi used modified mRNA to encode proteins that reprogrammed adult cells into embryonic-like stem cells. Harvard cardiovascular scientist Kenneth Chien, now at the Karolinska Institute, and Massachusetts Institute of Technologys famed serial entrepreneur Robert Langer spotted mRNAs therapeutic potential and joined Rossi in pitching a stem cell company to the venture capital firm Flagship Pioneering." This led to Moderna.

In recent times, under the coronavirus pandemic, Moderna has suppressed the rest of its pipeline and is focusing almost entirely on mRNA-1273, its candidate for treating COVID-19. Although mRNA can in theory target multiple types of diseases, vaccines are still their easiest application, since "the mRNA needs to produce only a small amount of protein for the vaccine to work, and setting off the bodys RNA immune sensors a little wont hurt." The company already had multiple viral vaccine targets under development, including one on MERS-COV in the lab, so it is understandable that a little tweak could set things off in coronavirus targeting.

From its press release, the latest that is happening in this regard is

On March 27, 2020, the NIH announced that Emory University in Atlanta will begin enrolling healthy adult volunteers ages 18 to 55 years in the NIH-led Phase 1 study of mRNA-1273.

According to a PR dated 4/7/2020, Moderna will host a virtual Vaccines Day for analysts and investors on 4/14/2020. The Vaccines Day will include presentations from Stphane Bancel, Chief Executive Officer, Tal Zaks, Chief Medical Officer, and key opinion leaders with a focus on mRNA vaccines and the Companys core prophylactic vaccines modality.

According to another PR dated 4/8/2020, Lorence Kim, M.D., the company's Chief Financial Officer, will participate in the 19th Annual Needham Healthcare Conference on 4/15/2020.

Currently, everything in this $12bn behemoth hinges around producing a working vaccine for SARS-COV-2. There are pitfalls - efficacy, timeline, positioning, market - that could determine how it all works out. Success or failure here could determine what happens to the company as a whole, because the market seems to be in an over-expectant mode right now.

In 2018, when the company IPO-ed, CEO Bancel said This is a 20-year job...We believe we are just starting. It seems to this author that $12bn is just a little too much to start with for something that may be promising, but still unproven. The science looks good - although there's a lot of secrecy behind it as of now - so if these prices go down for whatever reason, I would be much more interested. The company's vast and diverse collaborations - with AstraZeneca (NYSE:AZN), Merck (NYSE:MRK) and others - does build confidence that big pharma is looking at it favorably.

Thanks for reading. At the Total Pharma Tracker, we do more than follow biotech news. Using our IOMachine, our team of analysts work to be ahead of the curve.

That means that when the catalyst comes that will make or break a stock, we've positioned ourselves for success. And we share that positioning and all the analysis behind it with our members.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Additional disclosure: I own AMRN.

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Funding roundup: At-home medical exams and a Parkinson’s treatment – MedCity News

Tyto Cares kit includes a connected otoscope among other things

Numerous startups offering telehealth or remote monitoring solutions closed funding rounds this week, despite slowing activity due to the Covid-19 pandemic. One of them is Tyto Care, a startup with a platform for at-home medical exams. It actually includes a kit with several tools that can allow physicians to remotely listen to a patients heart, measure their temperature, and image their throat and ears. Several hospitals in Israel, including Sheba Medical Center, deployed its technology to care for patients remotely.

On the biotech side, there were some notable rounds, too, including $70 million for Aspen Neuroscience, which is developing a new treatment for Parkinsons disease. The company was founded by Scripps Research Professor Emeritus Jeanne Loring, who developed a way to turn pluripotent skin cells derived from skin cells or other adult cells into neurons that produce dopamine.

Read more about the companies that recently raised funding:

Tyto Care

Funding amount: $50 million

Headquarters: New York, Israel

Tyto Care, a company that lets people conduct at-home medical exams, already saw rising demand before the Covid-19 pandemic. The company said it saw threefold growth in sales last year and has continued to see its users increase during the pandemic. Its at-home telehealth kit includes a handheld device with attachments that allow physicians to remotely listen to the heart and lungs, measure temperature, and look at the throat and ears during an exam.

The company closed an oversubscribed $50 million round, co-led by Insight Partners, Olive Tree Ventures and Qualcomm Ventures. Tyto Care plans to use the additional funds to further expand its footprint in the U.S., Europe and Asia, and add new features to its platform, such as home diagnostics.

Aspen Neuroscience

Funding amount: $70 million

Headquarters: San Diego, California

Aspen Neuroscience is developing a treatment for Parkinsons disease using a patients own cells. The company uses induced pluripotent stem cells to make dopamine-producing neurons, which are affected by the disease.

The company closed a $70 million series A round, led by New York-based healthcare investor OrbiMed, with participation from ARCH Venture Partners, Frazier Healthcare Partners, Domain Associates, Section 32 and Sam Altman.

We are impressed by the progress Aspen has made to date against its goals to develop innovative therapies to treat Parkinson disease and encouraged by the broader investment communitys support of the company, OrbiMed Managing Partner Jonathan Silverstein said in a news release.

The company plans to use the capital to fund the development of its lead candidate, including completing studies needed to submit an investigational new drug application to the FDA, and recruiting for clinical trials.

Tango Therapeutics

Funding amount: $60 million

Headquarters: Cambridge, Massachusetts

Tango Therapeutics, a biotechnology company focusing on developing cancer therapies, closed a $60 million series B round. The company is working on developing treatments to counteract the loss of tumor suppressor genes, reverse cancer cells ability to evade the immune system, and identify new combinations that are more effective than single-agent therapies. The oversubscribed financing was led by Boxer Capital, with additional new investors in Cormorant Asset Management and Casdin Capital.


Funding amount: $27 million

Headquarters: Denver, Colorado

SonderMind, a startup that matches users with in-network therapists, raised $27 million in funding. The series B round was led by prominent VC General Catalyst and F-Prime Capital. Existing investors include the Kickstart Seed Fund, Di?ko Ventures and Jonathan Bush.

The company has a large network of behavioral providers in Colorado, and is expanding in Texas and Arizona. It plans to use the proceeds of the funding round to expand its partnership with payors, employers and health systems.


Funding amount: $16 million

Headquarters: Boston, Massachusetts

SilverCloud has seen an uptick in users tapping into its mental health programs for depression, anxiety and other conditions. The company raised a $16 million series B round, led by MemorialCare Innovation Fund, the VC arm of MemorialCare Health System. Other participating investors included LRVHealth, OSF Ventures and UnityPoint Health Ventures. To date, the company has raised a total of $30 million.

So far, the company had drummed up partnerships with more than 300 companies. Notably, it was also one of the products selected for Express Scripts first digital health formulary. SilverCloud said it would use the additional funds to expand access to mental health support services for healthcare professionals, as well as their families and their patients.


Funding: $20 million

Headquarters: New York

Healthcare security startup CyberMDX closed a $20 million funding round. Sham, a French risk management and insurance provider, led the funding round, with participation from Pitango Venture Capital and Oure Ventures.

CyberMDX monitors a providers network for threats to its IT systems, connected medical devices, and other IoT devices. The company said it will use the $20 million to expand its platform to new markets.

Photo credit: Tyto Care

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