FAQ's

GENERAL

A stem cell is an uncommitted cell that has the potential to develop into cells of a specific tissue (such as the hematopoietic stem cell developing into all of the blood cells). Within the fetus and the adult, stem cells are found in various areas of the body. Embryonic stem cells are the precursors to all stem cells as well as all other tissues of the body.

(Cairns J, PNAS 2002;99:10567; Rambhatla L et al, Can Res 2005;65:3155 ; Rosenthal N, N Engl J Med 2003;349:267; Cai J et al, Exp Hematol 2004;32:585)

The New Jersey legislature has passed a bill authorizing funding for research with all types of stem cells. Currently, several research institutions in New Jersey are engaged in stem cell research for neurological and cardiac disorders. A better understanding of the causes and possible treatments for a variety of disorders are likely to result from the New Jersey initiative on stem cell research.

Embryonic stem cells are different from other types of stem cells in that their main function is to make all of the different tissues of the body. Most other stem cells, such as the above-mentioned hematopoietic stem cell, function in the body to make at least cells of one tissue.

All stem cells are termed pluripotent, meaning one stem cell could form multiples types of cells. The difference between embryonic stem cells and other types of stem cells are the former can take the cells they produce to form whole body organs while the other stem cells form replacement cells within an organ.

A cell lineage is the maturational step of a stem cell, as shown in the cartoon below.

Pluripotency is the most immature stage of a stem cell. That is they could form different types of cells without losing their `stemness’. Multipotent cells are no longer stem cells, but can still form cells of different lineages. A monopotent cell is still immature, but has selected its lineage forming only one type of mature cell.

• Other than embryonic stem cells, stem cells can be found in the fetal liver, bone marrow and yolk sac, among other areas of the body. (Put link to yolk sac diagram here and also in next question) Umbilical cord blood is taken from the cord attached to the placenta. This source of blood is a major source of hematopoietic stem cells, but also consists of other types of stem cells. The population of hematopoietic stem cells are functionally similar to similar cells stem cells found in the fetal liver.


• One type of embryonic stem cell not generally discussed is embryonic germ cells. These are stem cells that develop into oocytes (eggs) or sperm.

(Huang S et al, Exp Hematol 26:1162, 1998)

There are several stem cells found after the development process of embryonic stem cells begins. The most studied of these cells are those that migrate to the bone marrow. These are the hematopoietic stem cells first detected in the yolk sac and the embryo from a stem cell referred to as the hemangioblast. The blood vessels needed by the hematopoietic stem cells are also formed from the hemangioblasts and are referred as the angioblast. The hematopoietic stem cells and angioblasts form the blood and immune systems of the fetus. Both stem cells remain in the body during and after birth, although at low levels. The angioblasts in the adult are renamed endothelial progenitor cells. These progenitor cells are capable of forming new blood vessels, as seen in the fetus.

(Liang L & Bickenbach JR, Stem Cells 2002;20:21; Magdaleno SM et al, Adv Ped 1998;45:363; Sata M et al, Nature Med 2002;8:403; Masuya M et al, Blood 2003;101:2215; Caplice NM et al, PNAS 2003;100:4754; Urbanek K et al, PNAS 2003;100:10440)

Stem cells are present within various organs of the adult body and are called ‘adult stem cells’. The prototypical adult stem cell, the hematopoietic stem cell, is found in the bone marrow. The hematopoietic stem cells have the genetic `blueprint' for forming all of the blood and immune cells. Thus, their main function is to be available to respond to infection and blood loss, while replacing cells on a day-to-day basis.

This is a controversial topic. While some scientists have reported evidence that hematopoietic stem cells can repair cardiac tissue, others have proven otherwise. Another research group reported that the bone marrow contained cells that could repair the liver. Later studies showed that the bone marrow cells did not form liver cells, but rather fused with those cells. Despite these negative results, interesting new information has been gained. For example, in the case of studies with liver repair, we have learned that there are genes that are activated in response to injury and thus are important in the repair process.

(Yoon S et al, Biol Cell 2005;97:253; Deten A et al, Cardiovasc Res 2005;65:52; Kollet O et al, J Clin Invest 2003;112:160; Fausto N, Hepatology 2004;39:1477)

Stem cells have been reported in the: brain, termed neural stem cells, gut, root of teeth, skin, heart, kidney and teeth. Scientists are still finding different stem cells.

The bone marrow is an example of an organ within the body where two types of stem cells co-exist: Hematopoietic stem cells that form blood and immune cells, and mesenchymal stem cells that form bone.

What is the difference between adult and embryonic stem cells with regard to the types of cells each subset generates?

Adult stem cells, which are found throughout the body, can be considered as a set of young cells. These cells can self-renew indicating that their numbers are maintained throughout life. The day-to-day function of an adult stem cell is to maintain, replenish and repair many tissues of the body. Embryonic stem cells, on the other hand, function to produce all the tissues of the body during development.

The answer to this question depends on the type of stem cell. While stem cells can replicate (termed expansion) without changing into a different cell type, some suffer the consequence of genetic changes as a result of extensive replication. Extensive replication can lead to genetic changes that cause the stem cells to mature, termed terminal differentiation, such that they are no longer stem cells. These genetic changes would make the terminally differentiated cells inappropriate for research or infusion into patients. For these reasons, research studies are aimed at understanding how ‘stemness’ is maintained. If scientists fully understood this mechanism it would be possible to expand any type of stem cell outside of the body.

(Scheding et al., Semin Hematol 35:232-240, 1998; Glimm et al., Blood 96:4185-4193, 2000)

Mobilized Peripheral Blood is obtained from subjects who are infused with an agent (for example, G-CSF) to get their bone marrow stem cells into the blood circulation. The stem cells that enter the blood are similar to those taken from bone marrow. Mobilized Peripheral Blood cells are obtained by methods similar to blood donation. The stem cells are good for transfusion into subjects; this is known as `bone marrow stem cell transplantation'.

PHYSIOLOGY

• Stem cells function to replenish dead or lost cells in areas of the body, as needed. This could occur in the organ where the stem cell resides or in other organs. For example, bone marrow stem cells (also referred to as hematopoietic stem cells) would be able to replenish lost blood and provide new immune cells during infection. At the same time, these stem cells might have the capacity to detect damaged organs and migrate to repair the injured tissues. Another example is neural stem cells (brain). The exact role of these stem cells is not known. It is suspected that they may play a role in brain repair following injury and also in the replacement of dying neurons (brain cells). These subjects are the focus of active research in labs around the world.


• In some cases, the function of a stem cell is linked to the organ where it resides. For example, a cardiac stem cell is considered to be a stem cell that repairs and/or replaces only cells of the heart. Other organs are irrelevant to the cardiac stem cell.


(Rosenthal N, N Engl J Med 2003;349:267; Nat Med 2002;8:647; Stewart et al, Blood 2001;98:1246; Burt et al, Blood 2002;99:768; Myers LA et al., Blood 2002;99:872)

 

CLONING

Cloning is a procedure where the genetic material (DNA) of an individual is taken from an adult cell (for example, a skin cell) and then transferred into an oocyte (an egg). Before the adult cell DNA is placed into the egg, the scientist removes the egg's existing DNA. Thus, after the adult DNA is transferred into the egg, the new egg has the DNA of the skin cell. To put what would occur in perspective, if the skin cell is from Mr. Jones and the egg is from Ms. Smith, the egg is now converted into the DNA blueprint of Mr. Jones. The eggs are then treated chemically in the dish to develop into clones (exact replicas) of embryonic stem cells.

Therapeutic cloning is the same as cloning, except that it is designed only for the purpose of clinical treatment. For example, if a patient has liver damage, it is theoretically possible to manipulate the environment in which a cloned cell is growing so that it becomes a liver cell. If the cells are allowed to replicate, they can then regenerate the liver.

At times it is assumed that stem cell research is exclusively cloning. This is a misconception since stem cell research covers a wide range of topics – partly described in this FAQ section. At times it is difficult to separate stem cell research from cloning, since the latter might generate embryonic stem cells. To reiterate, the majority of stem cell research is exclusive of cloning. In general, most of the research studies aim to find cures for diseases with existing embryonic stem cells and also adult stem cells. In cases of therapeutic cloning and embryonic stem cell research, ethical considerations and current legal restrictions are always primary concerns of the investigator.

(Gurdon JB et al, PNAS 2003;100:11819; Mombaerts P, PNAS 2003;100:11924)

TISSUE REPAIR

Some research studies show rare events by some adult stem cells to repair tissue. Tissue repair by hematopoietic stem cells is controversial, due to questions of cell fusion. However, hematopoietic stem cells have been successfully used in bone marrow transplants to repopulate the immune and blood systems. Research is ongoing to determine if adult stem cells can help repair the damaged heart and brain, among other tissues.

(Morigi M et al, Blood 2001;98:1828; Ruggeri ZM, Blood 98:1644; Brummendorf TH et al, Exp Hematol 2003;31:475; Abedi M et al, Exp Hematol 2004;32:426; Simard AR & Rivest S, FASEB J 2004;18:998; Sigurjonsson OE et al, PNAS 2005;102:5227)

EMBRYONIC STEM CELLS

The embryo is formed in early stages of fetal development and contains the embryonic stem cell. During development, the embryonic stem cells begin the process of forming tissues that will eventually compose the organs of the fetus. Embryonic stem cells give rise to all of the tissues of the embryo, excluding the placenta.

(Gilbert DM, Med Sci Monit 2004;10:RA99; Rossant J, Stem Cells 2001;19:477; Nature 2001;414:122-8; Yamazaki Y et al., PNAS 2003;100:12207)

Under experimental conditions, a stem cell line is created when a single stem cell is allowed to divide (expand). These dividing cells, if maintained properly, will maintain their stem cell properties for a long period of time. Primary embryonic stem cells are those cells that have been directly obtained from the donor embryo. The expansion of primary embryonic stem cells is not generated from a single cell, but from all that were initially obtained from the embryo.

The use of embryonic stem cells in research is controversial because some individuals consider a stem cell as the earliest form of human life, and they believe they should not be tampered with. The use of adult stem cells, which are derived at birth, is not ethically controversial.

(Vogel G, Science 2003;302:1875)

With respect to federal funding for research, only the embryonic stem cell lines approved for research by President Bush in 2001 may be used. Detailed information on these cells can be found at: http://escr.nih.gov. Several laboratories around the country also conduct embryonic stem cell research using private funding. This research is monitored by an Institutional Review Board (IRB) within a privately funded institution.

Although there are many ethical and scientific issues with embryonic stem cells, these cells have the greatest capacity to make new tissues. To date, adult stem cells have not been shown to give rise to the variety of tissues that embryonic stem cells potentially can. Additionally, under certain conditions, embryonic stem cells can form cancerous cells. For this reason, embryonic stem cells have the potential to be studied as a model of cancer development.

USE OF STEM CELLS TO TREAT DISEASE

In spinal cord injury and Parkinson’s disease, the body is unable to naturally heal the damaged axons and dopamine-producing neurons of the spinal cord and brain, respectively. In spinal cord injury, loss of muscle and sensory function is seen below the site of the injury. In Parkinson’s disease, involuntary movements and tremors result from the damaged neurons in the brain. Current research is examining how stem cells can be used to make specific types of nerve cells to help promote repair and regenerate new neurons within these diseases.

Using stem cells to combat cancer is an interesting prospect. Research into this area is very new and novel. One research group found that they could use mesenchymal stem cells to deliver a cancer-toxic protein to developing tumors. Studies like this combine stem cells and gene therapy. In this study, the scientists engineered the mesenchymal stem cells to produce a specific protein (gene therapy), and made use of the migrating properties of the stem cell to deliver the “knock-out” blow.

(Nakamura K et al, Gene Ther 2004;11:1155)

We are unaware of experiments that place animal stem cells into humans. Research studies are ongoing where human stem cells are placed into animals. However, the studies are only experimental and they are performed under strict regulation by the participating institution. The facts gained from these experiments will provide valuable information for future therapies using stems cells. Hopefully, these experiments will pave the way for getting stem cells to the bedside of patients. It should be noted that animals undergoing these types of studies are not allowed to survive, but are euthanized using humane methods.

(Inzunza J et al, Stem Cells 2005;23:544)

There are issues that have to be considered as a person undergoes stem cell therapy. An obvious concern is the development of unwanted tissue types in the region undergoing treatment. For example, we would not want bone to be formed in the liver if the goal was to regenerate the liver. Rejection is another concern, even though current clinical practice ensures a match between donor and host. Some adult stem cells appear to be resistant to rejection. These adult stem cells are seriously considered for treatment. The formation of cancer cells (teratomas) from embryonic stem cells is another major potential side effect of any embryonic stem cell-based therapy.

(Kuramotot K et al, Blood 2004;103:4070; Kirk AD et al., Nat Med 2002;8:553; Farag SS et al, Blood 2002;100:1935; Reviewed Exp Hematol 2000;28:479; Takahashi K et al, Nature 2003;423:541)

While there is some evidence in animal studies that learning correlates with the birth of new stem cells, the use of stem cells in humans to improve memory is not supported by any current research. However, it is true that if neural stem cell therapy can be used to prevent the death of neurons in Alzheimer's disease, then the decline in mental ability in those patients could be slowed or prevented.

(Schaffer DV and Gage FH, Neuromolecular Med 2004;5:1)

Yes. Bone marrow stem cell transplantation has been a standard form of care for immune cell replacement since the late 1960s/early 1970s. Historically speaking, the first transplant occurred in 1958 to care for a radiation accident. To date, children with leukemia have been known to survive following stem cell transplant. One research study showed that children with leukemia receiving bone marrow stem cell transplantation had a 63% survival rate at 5 years following the transplant.

(Farag SS et al, Blood 2002;100:1935; Baker D et al, J Pediatr Hematol Oncol 2004;26:200; Perry AR and Linch DC, Blood Rev 1996;10:215)

On the surface, stem cells might seem irrelevant to you because you lack any of the disorders mentioned on TV, such as: spinal cord injury, diabetes etc. However, stem cells could be important to any disease due to their unique property of being forever ‘young’ and being responsive to change. An understanding of these properties would lead to insights into the biology of other diseases. For example, an individual might have a condition that could eventually lead to a stem cell disorder such as leukemia. By understanding the biology of stem cells, drugs could be developed to prevent the dysfunction of stem cells.

CANCER AND CANCER STEM CELLS

Some researchers believe that cancer is maintained by a few cancer stem cells, while others believe that it could be a normal stem cell “gone wrong”. Research on any type of stem cells is likely to lead to a better understanding of cancer stem cells. Once this information is fully understood, drugs can be developed to kill the cancer stem cells and thereby improve cancer treatment.

(Pardal R et al. Nature Reviews 2003;3: 895-902; Reya T et al. Nature 2001;414: 105-111; Al-Hajj, M & Clarke MF. Oncogene 2004, 23: 7274-7282 )

Cancer stem cells share many characteristics with normal stem cells. For example, a normal stem cell can self-renew, which means the daughter cells retain their numbers and properties/functions as the mother cells. Cancer stem cells also maintain the ability to self-renew. A few cancer stem cells could evade treatment and later give rise to a tumor, referred to as cancer relapse. The tumors formed are really the progenies of the cancer stem cells. Like all progenies of stem cells, they multiply rapidly. However, the progenies of cancer stem cells are not like normal progenies, whose growth are tightly controlled so that there is never too many or too few. The cancer stem cell could be considered as a normal stem cell “gone wrong”. A major difference between the progenies of a normal stem cell and those from a cancer stem cell is that progenies of normal stem cells eventually form mature cells, whereas progenies of cancer stem cells form rapidly dividing progenitor cells which do not fully mature.

(Reya T et al. Nature, 2001;414: 105-111; Pardal R et al. Nature Reviews 2003;3:895-902; Reya T et al. Nature 2001;414:105-111)

Scientists are working diligently all over the world to find the signature of the cancer stem cells. The question is: Do we have to find the signature of stem cells in different cancers or is there a common signature? Another possibility is that cancer stem cells and healthy stem cells share common signatures. These questions can be explained by the infamous vend diagram illustrated here. Signature— Could be described as an ID-tag. The tag could be on the surface or inside the cells. (Zhou S et al, Nat Med 2001;1028; Schwarzenberger P et al, Can Inves 2002;20:124; Yin AH et al, Blood 1997;90:5002; Murray LJ et al, Exp Hematol 1999;27:1282; Al-Hajj M et al, Curr Opinion Gen Develop 2004;14:43)

At this time no one knows the answer to this question. There may be a few cancer stem cells that are part of our normal tissues that are not detected by current clinical methods. If the cells never develop into tumors or spread to other tissues, then this may be normal for the body. If these cells do lead to cancer, then they become a medical problem. For this reason, it is necessary to understand all aspects of stem cell biology. Research into the basic biology and chemistry of cancer stem cells will allow drug companies to develop the appropriate medication to rid the body of these few cancer stem cells.

(Reya T et al. Nature 2001;414: 105-111)

The origin of cancer stem cells is still unclear. An appropriate analogy to this dilemma would be: Which came first, the chicken or the egg? Just as we do not know which came first, researchers still are unsure whether cancer stem cells come from a normal stem cell gone wrong or the progeny of a stem cell taking on the property of the mother stem cells.

(Reya T et al, Nature 2001;414:105; Pardal R et al, Nature Review 2003;3:895; Al-Hajj & Clarke MF, Oncogene 2004;23:7274; Al-Hajj et al, Curr Opinion Gen Develop 2004;14:43)

For additional information regaring cancer and stem cell research, please visit the New Jersey Medical School/University Hospital - Cancer Center.

UMBILICAL CORD BLOOD

Umbilical cord blood stem cells are mostly used in stem cell transplantation to replace bone marrow cells. For reasons yet unknown, these cells pose less of a risk for rejection when compared to bone marrow stem cells. Due to the limited amount of cord blood, there is generally an insufficient number of cells for adult transplants.

(Ballen KK, Blood 2005;105:3786; Chen BJ et al., Blood 2001;99:364)

Umbilical cord blood is stored because it has a higher number of hematopoietic stem cells than bone marrow. Mothers generally save their babies' umbilical cord blood in case something is wrong, such as the baby needing a stem cell transplant while he or she is still a child. If, for example, the baby develops leukemia, he or she could be infused with his or her own umbilical cord blood. Another point to keep in mind is that the use of umbilical cord blood does not have the controversy associated with it that embryonic stem cells does.

(Ballen KK, Blood 2005;105:3786)

STEM CELL TRANSPLANTATION

Bone marrow stem cell transplants have been commonplace since the late 1960s/early 1970s. The therapy was developed as a method to replace new stem cells in the bone marrow and has been successfully used in patients with cancer. Scientists are able to withdraw the patient’s own bone marrow stem cells, treat the patient for the cancer and then re-infuse the bone marrow stem cells. In other cases, patients receive bone marrow from a matched donor.

(Parkan P & McQueen KL, Nature Rev Immunol 2003;117:108; Suzuki Y et al, Stem Cells 2005;23:365; Askenasy N et al., Stem Cells 2003;21:200; Rondelli D et al, Blood 2005;105:4115 ; Drouet et al, Stem Cells 19:436, 2001; Glimm H et al, Blood 2003;99:3454; Perry AR and Linch DC, Blood Rev 1996;10:215)

A donor ‘match’ means that the host will not reject the donor's stem cells. This could only occur if the stem cells from the donor and host have similar genetic blueprints, as seen in family members or in twins.

Yes, if the two people are matched. That is, cells of the host (the person getting the cells) and donor (the person donating the cells) do not reject each other. This type of sharing is successful in bone marrow transplantation in cancer patients.

(Spyridonidis A et al, Blood 2005;105:4147; Parkan P & McQueen KL, Nature Rev Immunol 2003;117:108; Korblin M & Anderlinin P, Blood 2001;98:2900)