DOI: 10.1016/S0140-6736(01)05670-7 PII: S0140-6736(01)05670-7 Copyright © 2001 Elsevier Science Ltd. All rights reserved.
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Researchers turn human stem cells into heart tissue Helen Frankish Available online 14 August 2001.
Helen Frankish
Human embryonic stem cells can differentiate into spontaneously contracting cells that have structural and functional properties of human cardiomyocytes, according to a study by Israeli researchers. The researchers say their findings may eventually lead to treatments to replace cardiac tissue damaged during myocardial infarction. "A potential novel therapeutic approach may be to increase the number of functioning myocytes within the depressed region by transplantation of myogenic cells", says lead researcher Lior Gepstein (Technion-Israel Institute of Technology, Haifa, Israel).
(17K) Fig. 1. New approach to replace damaged tissue?
(17K)
Fig. 1. New approach to replace damaged tissue?
The differentiation of cardiac cells from embryonic stem cells has been shown in mice (Cardiovasc Res 1997; 36: 149¯62), but this is the first report in human stem cells. The investigators detected areas that contracted spontaneously in 8กค1% of embryonic bodies, which are aggregates of stem cells. The researchers then subjected the contracting cells to a barrage of tests to confirm that they were indeed cardiomyocytes (J Clin Invest 2001; 108: 407¯14).
"Since human fetal cardiomyocytes cannot be obtained in sufficient numbers for clinical purposes, the use of the human embryonic stem cell line as a novel source of human cardiomyocytes may become an attractive option", says Gepstein. Identification of a cardiomyocyte line "opens the possibility of using such cells clinically in humans", agrees Silviu Itescu (Columbia-Presbyterian Medical Center, New York, NY, USA). However, Itescu comments that much needs to be determined before this becomes a reality, including whether such cells can function in vivo and whether enough cells can be obtained. Itescu also adds that "if cardiomyocyte differentiation can be as efficiently obtained from autologous adult stem cells as from embryonic sources, this would be preferable since it would avoid issues of immunosuppression in the recipient".
Martin Pera (Monash University, Melbourne, Australia) also cautions that more work is needed before human embryonic stem cells can be used for clinical purposes. "To enable production of cardiomyocytes on a large scale, we will have to learn more about the factors that induce their formation, and it will be important to discover what their direct progenitors are", he says. "Until we understand these mechanisms better, it may prove difficult to produce this cell type on a large scale."
To provide enough cells for therapeutic use, scientists would also need to improve the efficiency of generating cardiomyocytes from embryonic stem cells. As Ray Chiu (McGill University, Montreal, Canada) points out, "only 8กค1% of embryoid body cell aggregates revealed pulsating areas, and of these only about a third were positive for cardiomyocyte-specific cTn1 stain".
Nadia Rosenthal (European Molecular Biology Laboratory, Rome, Italy) warns against over-interpretation of the findings. "No new insights into the capacity of embryonic stem cells to differentiate into cardiocyte-like cells have been gained", she says. "Nevertheless, the use of human embryonic stem cells in this study was very important to show it could be done, and to lay the groundwork for future studies on the capacity of these cells to integrate into damaged human myocardium."
Meanwhile, US researchers have reported that a strain of mice has the remarkable capacity to regenerate cardiac tissue (Proc Natl Acad Sci 2001; 98: 9830¯35). In 1998, the investigators discovered that MRL (Murphy/ Roths/Large) mice whose ears were punched could close the ear holes without evidence of scarring. The team, led by Ellen Heber-Katz (The Wistar Institute, Philadelphia, PA, USA), has now studied the effect of damage to the myocardium, caused by a cryoprobe. "MRL mice and control mice both showed clear signs of massive injury within the first few days", explains Heber-Katz. "However, within 2 months, the C57Bl/6 mouse [control] had vast scarring in the right ventricle while the MRL mouse had almost normal-looking heart tissue."
"This is a lovely study", comments Rosenthal. "The group has published previously on the remarkable wound-healing capacity of the MRL mouse strain. They now turn their attention to the hardest of tissues to heal¯¯the myocardium." The investigators identified the cells in the injury site of MRL mice as dividing myocytes, whereas control mice had only a small number of dividing cells. The control mice had increased scar tissue after injury, but the amount of scar tissue in MRL mice decreased. "We believe that the MRL mouse has the ability to block scar formation, and under these circumstances cardiomyocytes can divide", explains Heber-Katz. "Possibly by blocking or eliminating scar formation other mammals can show this regenerative response."
"The application of these findings to human clinical practice is still some way off¯¯the genes must be identified, and their action characterised", comments Rosenthal. "Still, the information gained along the way is likely to enlighten our understanding of the regeneration process."
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