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Miracle Cell

James Battey

My father has had several difficult and serious heart surgeries. Why have I never heard about stem cells for repairing his damaged heart (as was done for the teenager shot in the heart with the nail gun)? He is in his mid-60's ... not elderly. Is the cost of stem cell treatment prohibitive or are there only a few facilities providing this treatment?

For those suffering from common, but deadly, heart diseases, stem cell biology represents a new medical frontier. Researchers are working toward using stem cells to replace damaged heart muscles and literally restore cardiac function. How might stem cells play a part in repairing the heart? To answer this question, researchers are building their knowledge base about how stem cells are directed to become specialized cells. One important type of cell that may be developed is the cardiomyocyte, the heart muscle cell that contracts to eject the blood out of the heart's main pumping chamber (the ventricle). Two other cell types that are important to a properly functioning heart are the vascular endothelial cell, which forms the inner lining of new blood vessels, and the smooth muscle cell, which forms the wall of blood vessels. The heart has a large demand for blood flow, and these specialized cells are important for developing a new network of arteries to bring nutrients and oxygen to the cardiomyocytes after a heart has been damaged. The potential capability of both embryonic and adult stem cells to develop into cell types not characteristic of the organ of origin in the damaged heart is now being explored as part of a strategy to restore heart function to people who have had heart attacks or have congestive heart failure. It is important that work with stem cells is not confused with recent reports that human cardiac myocytes may undergo cell division after myocardial infarction [1]. This work suggests that injured heart cells can shift from a quiescent state into active cell division. This is not different from the ability of a host of other cells in the body that begin to divide after injury. There is still no evidence that there are true stem cells in the heart which can proliferate and differentiate. Researchers now know that under highly specific growth conditions in laboratory culture dishes, stem cells may be coaxed into developing as new cardiomyocytes and vascular endothelial cells, but more research needs to be done. Scientists are interested in exploiting this ability to provide replacement tissue for the damaged heart. This approach has immense advantages over heart transplant, particularly in light of the paucity of donor hearts available to meet current transplantation needs.

What is the evidence that such an approach to restoring cardiac function might work? In the research laboratory, investigators often use a mouse or rat model of a heart attack to study new therapies. To create a heart attack in a mouse or rat, a ligature is placed around a major blood vessel serving the heart muscle, thereby depriving the cardiomyocytes of their oxygen and nutrient supplies. During 1999, researchers using such models have made several key discoveries that kindled interest in the application of adult stem cells to heart muscle repair in animal models of heart disease. Recently, Orlic and colleagues [9] reported on an experimental application of hematopoietic stem cells for the regeneration of the tissues in the heart. In this study, a heart attack was induced in mice by tying off a major blood vessel, the left main coronary artery. Through the identification of unique cellular surface markers, the investigators then isolated a select group of adult primitive bone marrow cells with a high capacity to develop into cells of multiple types. When injected into the damaged wall of the ventricle, these cells led to the formation of new cardiomyocytes, vascular endothelium, and smooth muscle cells, thus generating de novo myocardium, including coronary arteries, arterioles, and capillaries. The newly formed myocardium occupied 68 percent of the damaged portion of the ventricle nine days after the bone marrow cells were transplanted, in effect replacing the dead myocardium with living, functioning tissue. The researchers found that mice that received the transplanted cells survived in greater numbers than mice with heart attacks that did not receive the mouse stem cells. Follow-up experiments are now being conducted to extend the posttransplantation analysis time to determine the longer-range effects of such therapy. The partial repair of the damaged heart muscle suggests that the transplanted mouse hematopoietic stem cells responded to signals in the environment near the injured myocardium. The cells migrated to the damaged region of the ventricle, where they multiplied and became "specialized" cells that appeared to be cardiomyocytes.

A second study, by Jackson et al. [3], demonstrated that cardiac tissue can be regenerated in the mouse heart attack model through the introduction of adult stem cells from mouse bone marrow. In this model, investigators purified a "side population" of hematopoietic stem cells from a genetically altered mouse strain. These cells were then transplanted into the marrow of lethally irradiated mice approximately 10 weeks before the recipient mice were subjected to heart attack via the tying off of a different major heart blood vessel, the left anterior descending (LAD) coronary artery. At two to four weeks after the induced cardiac injury, the survival rate was 26 percent. As with the study by Orlic et al., analysis of the region surrounding the damaged tissue in surviving mice showed the presence of donor-derived cardiomyocytes and endothelial cells. Thus, the mouse hematopoietic stem cells transplanted into the bone marrow had responded to signals in the injured heart, migrated to the border region of the damaged area, and differentiated into several types of tissue needed for cardiac repair. This study suggests that mouse hematopoietic stem cells may be delivered to the heart through bone marrow transplantation as well as through direct injection into the cardiac tissue, thus providing another possible therapeutic strategy for regenerating injured cardiac tissue.

More evidence for potential stem cell-based therapies for heart disease is provided by a study that showed that human adult stem cells taken from the bone marrow are capable of giving rise to vascular endothelial cells when transplanted into rats [6]. As in the Jackson study, these researchers induced a heart attack by tying off the LAD coronary artery. They took great care to identify a population of human hematopoietic stem cells that give rise to new blood vessels. These stem cells demonstrate plasticity meaning that they become cell types that they would not normally be. The cells were used to form new blood vessels in the damaged area of the rats' hearts and to encourage proliferation of preexisting vasculature following the experimental heart attack.

Like the mouse stem cells, these human hematopoietic stem cells can be induced under the appropriate culture conditions to differentiate into numerous tissue types, including cardiac muscle [10]. When injected into the bloodstream leading to the damaged rat heart, these cells prevented the death of hypertrophied or thickened but otherwise viable myocardial cells and reduced progressive formation of collagen fibers and scars. Control rats that underwent surgery with an intact LAD coronary artery, as well as LAD-ligated rats injected with saline or control cells, did not demonstrate an increase in the number of blood vessels. Furthermore, the hematopoietic cells could be identified on the basis of highly specific cell markers that differentiate them from cardiomyocyte precursor cells, enabling the cells to be used alone or in conjunction with myocyte-regeneration strategies or pharmacological therapies.

Exciting new advances in cardiomyocyte regeneration are being made in human embryonic stem cell research. Because of their ability to differentiate into cell types other than their organ of origin, embryonic stem cells are another possible source population for cardiac repair cells. The first step in this application was taken by Itskovitz-Eldor et al. [2] who demonstrated that human embryonic stem cells can reproducibly differentiate in culture into embryoid bodies made up of many different cell types. Among the various cell types noted were cells that had the physical appearance of cardiomyocytes, showed cellular markers consistent with heart cells, and demonstrated contractile activity similar to cardiomyocytes when observed under the microscope.


Can Stem Cells Repair a Damaged Heart?

In a continuation of this early work, Kehat et al. [4] displayed structural and functional properties of early stage cardiomyocytes in the cells that develop from the embryoid bodies. The cells that have spontaneously contracting activity are positively identified by using markers with antibodies to proteins found in heart tissue. These investigators have done genetic analysis of these cells and found that the transcription-factor genes expressed are consistent with early stage cardiomyocytes. Electrical recordings from these cells, changes in calcium-ion movement within the cells, and contractile responsiveness to catecholamine hormone stimulation by the cells were similar to the recordings, changes, and responsiveness seen in early cardiomyocytes observed during mammalian development. A next step in this research is to see whether the experimental evidence of improvement in outcome from heart attack in rodents can be reproduced using embryonic stem cells.

These breakthrough discoveries in rodent models present new opportunities for using stem cells to repair damaged heart muscle. The results of the studies discussed above are growing evidence that adult stem cells may develop into more cell types than first thought. In those studies, hematopoietic stem cells appear to be able to develop not only into blood, but also into cardiac muscle and endothelial issue. This capacity of adult stem cells, increasingly referred to as "plasticity," may make such adult stem cells a viable candidate for heart repair. But this evidence is not complete; the mouse hematopoietic stem cell populations that give rise to these replacement cells are not homogenous. Rather, they are enriched for the cells of interest through specific and selective stimulating factors that promote cell growth. Thus, the originating cell population for these injected cells has not been identified, and the possibility exists for inclusion of other cell populations that could cause the recipient to reject the transplanted cells. This is a major issue to contend with in clinical applications, but it is not as relevant in the experimental models described here because the rodents have been bred to be genetically similar.

What are the implications for extending the research on differentiated growth of replacement tissues for damaged hearts? There are some practical aspects of producing a sufficient number of cells for clinical application. The repair of one damaged human heart would likely require millions of cells. The unique capacity for embryonic stem cells to replicate in culture may give them an advantage over adult stem cells by providing large numbers of replacement cells in tissue culture for transplantation purposes. Given the current state of the science, it is unclear how adult stem cells could be used to generate sufficient heart muscle outside the body to meet patients' demand [7].

Although there is much excitement because researchers now know that adult and embryonic stem cells may repair damaged heart tissue, many questions remain to be answered before clinical applications can be made. Are we truly seeing replacement of cardiac myocytes, or are we seeing the stem cells fusing with the host cells? In addition, if stem cells are truly differentiating into cardiac myocytes, how long will the replacement cells continue to function? Do the rodent research models accurately reflect human heart conditions and transplantation responses? Do these new replacement cardiomyocytes derived from stem cells have the electrical-signal-conducting capabilities of native cardiac muscle cells? More research in this area still needs to be completed to answer these questions.

Stem cells may well serve as the foundation upon which a future form of cell-based therapy is constructed. In the current animal models, the time between the injury to the heart and the application of stem cells affects the degree to which regeneration takes place, and this has real implications for the patient who is rushed unprepared to the emergency room in the wake of a heart attack. In the future, could the patient's cells be harvested and expanded for use in an efficient manner? Alternatively, can at-risk patients donate their cells in advance, thus minimizing the preparation necessary for the cells' administration? Moreover, can these stem cells be genetically "programmed" to migrate directly to the site of injury and to synthesize immediately the heart proteins necessary for the regeneration process? Investigators are currently using stem cells from all sources to address these questions, thus providing a promising future for therapies for repairing or replacing the damaged heart and addressing the Nation's leading causes of death.

Finally, clinical trials are happening sporadically in the United States using stem cells to repair damaged heart muscles, however, more research is needed in both animal models and humans before this work will result in proven medical therapies: www.clinicaltrials.gov is a Web site that provides information on clinical trails sponsored by the federal government.

REFERENCES
  1. Beltrami, A.P., Urbanek, K., Kajstura, J., Yan, S.M., Finato, N., Bussani, R., Nadal-Ginard, B., Silvestri, F., Leri, A., Beltrami, C.A., and Anversa, P. (2001). Evidence that human cardiac myocytes divide after myocardial infarction. N. Engl. J. Med. 344, 1750-1757.
  2. Itskovitz-Eldor, J., Schuldiner, M., Karsenti, D., Eden, A., Yanuka, O., Amit, M., Soreq, H., and Benvenisty, N. (2000). Differentiation of human embryonic stem cells into embryoid bodies comprising the three embryonic germ layers. Mol. Med. 6, 88-95.
  3. Jackson, K.A., Majka, S.M., Wang, H., Pocius, J., Hartley, C.J., Majesky, M.W., Entman, M.L., Michael, L.H., Hirschi, K.K., and Goodell, M.A. (2001). Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107, 1-8.
  4. Kehat, I., Kenyagin-Karsenti, D., Druckmann, M., Segev, H., Amit, M., Gepstein, A., Livne, E., Binah, O., Itskovitz-Eldor, J., and Gepstein, L. (2001). Human embryonic stem cells can differentiate into myocytes portraying cardiomyocytic structural and functional properties. J. Clin. Invest.
  5. Kessler, P.D. and Byrne, B.J. (1999). Myoblast cell grafting into heart muscle: cellular biology and potential applications. Annu. Rev. Physiol. 61, 219-242.
  6. Kocher, A.A., Schuster, M.D., Szabolcs, M.J., Takuma, S., Burkhoff, D., Wang, J., Homma, S., Edwards, N.M., and Itescu, S. (2001). Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat. Med. 7, 430-436.
  7. Lanza, R., personal communication.
  8. Orlic, D., personal communication.
  9. Orlic, D., Kajstura, J., Chimenti, S., Jakoniuk, I., Anderson, S.M., Li, B., Pickel, J., McKay, R., Nadal-Ginard, B., Bodine, D.M., Leri, A., and Anversa, P. (2001). Bone marrow cells regenerate infarcted myocardium. Nature. 410, 701-705.
  10. Pittenger, M.F., Mackay, A.M., Beck, S.C., Jaiswal, R.K., Douglas, R., Mosca, J.D., Moorman, M.A., Simonetti, D.W.,Craig, S., and Marshak, D.R. (1999). Multilineage potential of adult human mesenchymal stem cells. Science. 284, 143-147.

Who are some leading stem cell researchers in the United States? Are adult stem cell transplants currently available within the United States? If not, can we expect them to be anytime in the near future?

There are many leading stem cell researchers in the United States today. You can find some of them by searching the NIH Stem Cell Web site at http://stemcells.nih.gov under "Meet our Scientists" or searching the Web site under "Research Topics, Scientific Literature" for recent peer-reviewed articles by leading scientists in the United States and the world.

Some nonembryonic (adult) stem cell transplants are currently available within the United States to treat specific diseases. A listing of those diseases compiled by the National Marrow Donor Program include:

    Stem Cell Disorders
    • Aplastic Anemia (Severe)
    • Fanconi Anemia
    • Paroxysmal Nocturnal Hemoglobinuria (PNH)
    Acute Leukemias
    • Acute Lymphoblastic Leukemia (ALL)
    • Acute Myelogenous Leukemia (AML)
    • Acute Biphenotypic Leukemia
    • Acute Undifferentiated Leukemia
    Chronic Leukemias
    • Chronic Myelogenous Leukemia (CML)
    • Chronic Lymphocytic Leukemia (CLL)
    • Juvenile Chronic Myelogenous Leukemia (JCML)
    • Juvenile Myelomonocytic Leukemia (JMML)
    Myeloproliferative Disorders
    • Acute Myelofibrosis
    • Agnogenic Myeloid Metaplasia (myelofibrosis)
    • Polycythemia Vera
    • Essential Thrombocythemia
    Myelodysplastic Syndromes
    • Refractory Anemia (RA)
    • Refractory Anemia with Ringed Sideroblasts (RARS)
    • Refractory Anemia with Excess Blasts (RAEB)
    • Refractory Anemia with Excess Blasts in Transformation (RAEB-T)
There are claims that adult stem cell transplants have been used to alleviate human suffering of spinal cord injuries, Parkinson's disease, ALS, and other degenerative diseases, but the claims cannot be substantiated through the peer-reviewed literature or by scientists at the National Institutes of Health.


Since stem cells are more effective when harvested from young people, does that mean that people at large should be looking into freezing a supply of their stem cells so they can be more effectively used when they are getting older?

We do not know enough about stem cells (non-embryonic or embryonic), with the exception of hematopoetic cells, to make any recommendations to the public about storing stem cells for future use. More research is needed using both animal models and later, human trials, before we could make a recommendation such as that.


I understand the Federal Funding issues revolving around research grants, but what are the legal limitations to privately funded research on either type of stem cell (adult or embryonic)? And where and when were these laws (if any) enacted? Have any of the laws been tested in court?

There are no legal limits to privately funded research using non-embryonic or embryonic stem cells at the federal level.

Currently, state laws may restrict some or all sources for embryonic stem cells or specifically permit certain activities. State laws on the issue vary widely. Approaches to stem cell research policy range from laws in California and New Jersey, which encourage embryonic stem cell research (including on cloned embryos) to South Dakota's law, which strictly forbids research on embryos regardless of the source. If, however, a fetus is aborted for the health of the mother in South Dakota, the fetus may be used for research purposes with maternal consent. Many states restrict research on aborted fetuses or embryos, but research is often permitted with consent of the patient. Almost half of the states also restrict the sale of fetuses or embryos. Louisiana is the only state that specifically prohibits research on IVF embryos. Illinois and Michigan also prohibit research on live embryos. Finally, Arkansas, Iowa, Michigan, and North Dakota prohibit research on cloned embryos. Virginia's law also may ban research on cloned embryos, but the statute may leave room for interpretation because human being is not defined. Therefore, there may be disagreement about whether human being includes blastocysts, embryos, or fetuses. California, New Jersey, and Rhode Island also have human cloning laws, but these laws prohibit cloning only for the purpose of initiating a pregnancy, or reproductive cloning, but allow cloning for research. Missouri also forbids the use of state funds for reproductive cloning but not for cloning for the purpose of stem cell research, and Nebraska prohibits the use of state funds for embryonic stem cell research.

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