Posts Tagged ‘dermal fibroblast’

Reporter and Curator: Dr. Sudipta Saha, Ph.D.


Heart attack patients could one day have their heart repaired using their own skin cells. This research focused on the potential use of human pluripotent stem cells such as human embryonic stem cells for the treatment of post-myocardial infarction heart failure and on the utilization of genetically-engineered cell grafts for the treatment of cardiac arrhythmias by modifying the electrophysiological properties. Myocardial cell replacement therapies are hampered by a paucity of sources for human cardiomyocytes and by the expected immune rejection of allogeneic cell grafts. The ability to derive patient-specific human-induced pluripotent stem cells (hiPSCs) may provide a solution to these challenges. That is using a patient’s own cells would avoid the problem of patients’ immune systems rejecting the cells as ‘foreign’. It was aimed to derive hiPSCs from heart failure (HF) patients, to induce their cardiomyocyte differentiation, to characterize the generated hiPSC-derived cardiomyocytes (hiPSC-CMs), and to evaluate their ability to integrate with pre-existing cardiac tissue. Dermal fibroblasts from HF patients were reprogrammed by retroviral delivery of Oct4, Sox2, and Klf4 or by using an excisable polycistronic lentiviral vector. The resulting HF-hiPSCs displayed adequate reprogramming properties and could be induced to differentiate into cardiomyocytes with the same efficiency as control hiPSCs (derived from human foreskin fibroblasts). Gene expression and immunostaining studies confirmed the cardiomyocyte phenotype of the differentiating HF-hiPSC-CMs. Multi-electrode array recordings revealed the development of a functional cardiac syncytium and adequate chronotropic responses to adrenergic and cholinergic stimulation. That is the resulting stem cells were able to differentiate to become heart muscle cells (cardiomyocytes) just as effectively as those that had been developed from healthy, young volunteers who acted as controls for the study. Next, functional integration and synchronized electrical activities were demonstrated between hiPSC-CMs and neonatal rat cardiomyocytes in co-culture studies. Finally, in vivo transplantation studies in the rat heart revealed the ability of the HF-hiPSC-CMs to engraft, survive, and structurally integrate with host cardiomyocytes. That is it was possible to make the cardiomyocytes develop into heart muscle tissue, which was joined together with existing cardiac tissue and within 48 hours the tissues were beating together. Human-induced pluripotent stem cells thus can be established from patients with advanced heart failure and coaxed to differentiate into cardiomyocytes, which can integrate with host cardiac tissue. This novel source for patient-specific heart cells may bring a unique value to the emerging field of cardiac regenerative medicine. This technology needs to be refined before it can be used for the treatment of patients with heart failure, but these findings are encouraging and take us a step closer to the goal of identifying an effective means of repairing the heart and limiting the consequences of heart failure.


Articles may be reviewed:


Zwi-Dantsis L, Huber I, Habib M, Winterstern A, Gepstein A, Arbel G, Gepstein L. 2012. Derivation and cardiomyocyte differentiation of induced pluripotent stem cells from heart failure patients. Eur Heart J. [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed?term=Derivation%20and%20cardiomyocyte%20differentiation%20of%20induced%20pluripotent%20stem%20cells%20from%20heart%20failure%20patients)


Yankelson, L., Feld, Y., Bressler-Stramer, T., Itzhaki, I., Huber, I., Gepstein, A., Aronson, D., Marom, S., Gepstein, L. 2008. Cell therapy for modification of the myocardial electrophysiological substrate. Circulation 117, 720-731. (http://www.ncbi.nlm.nih.gov/pubmed/18212286)


Caspi, O., Huber, I., Kehat, I., Habib, M., Arbel, G., Gepstein, A., Yankelson, L., Aronson, D., Beyar, R., Gepstein, L. 2007. Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. J Am Coll Cardiol 50, 1884-1893. (http://www.ncbi.nlm.nih.gov/pubmed?term=Transplantation%20of%20human%20embryonic%20stem%20cell-derived%20cardiomyocytes%20improves%20myocardial%20performance%20in%20infarcted%20rat%20hearts)

Huber, I., Itzhaki, I., Caspi, O., Arbel, G., Tzukerman, M., Gepstein, A., Habib, M., Yankelson, L., Kehat, I., Gepstein, L. 2007. Identification and selection of cardiomyocytes during human embryonic stem cell differentiation. FASEB J 21, 2551-2563. (http://www.ncbi.nlm.nih.gov/pubmed/17435178)







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