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)
http://rappinst.com/Rappaport/Templates/ShowPage.asp?DBID=1&TMID=610&FID=77&PID=0&IID=241
http://www1.technion.ac.il/_local/includes/blocks/news-items/110814-liorprize11/news-item-en.htm
Dr. Saha,
Thank you for this very important post presenting results on the Role of stem cells in cardiac neogenesis.
“Multi-electrode array recordings revealed the development of a functional cardiac syncytium and adequate chronotropic responses to adrenergic and cholinergic stimulation”
This is a fascinating area of research. May I suggest that you will explore for related forthcoming posts,
Dissociation Between Neural and Vascular Responses to Sympathetic Stimulation
Contribution of Local Adrenergic Receptor Function
http://hyper.ahajournals.org/content/35/1/76.full
Hypertension.
2000; 35: 76-81
Circ Res. 1990 Nov;67(5):1292-8. [Please Update the literature 1990-2012] for
Beta-adrenergic regulation of the muscarinic-gated K+ channel via cyclic AMP-dependent protein kinase in atrial cells.
Repeating this work with our footprint-free, feeder-free, xeno-free human iPSCs could add more clinical relevance to it.
How that is related to your comment above?
http://www.vblrx.com/about/
VBL Therapeutics is a clinical-stage biotechnology company using its unique scientific platforms and drug development capabilities to fight immune-inflammatory diseases and cancer. Because these serious and sometimes life-threatening diseases are inadequately addressed by current therapies, VBL is committed to developing novel treatments that address this unmet need.
VBL Therapeutics pioneered the Lecinoxoid class of novel, oral anti-inflammatory agents. VB-201, the lead candidate from this program, has strong potential as a specific, targeted oral disease-modifying agent for the control of chronic inflammatory disorders via highly selective modulation of innate immunity. In pre-clinical and Phase 1 studies, VB-201 has been shown to specifically modulate patients’ immune systems, thereby demonstrating its potential to reduce the frequency and severity of flare-ups and avoid the adverse events associated with treatments that systemically target the immune system.
VBL has recently completed Phase 2 clinical trials of its lead compound, VB-201, for the treatment of patients with psoriasis and inflammation in atherosclerosis. Data are expected to be announced in the first half of 2012. Preclinical studies indicate that VB-201 also has significant potential to treat inflammation across other chronic inflammatory diseases including rheumatoid arthritis, atherosclerosis, inflammatory bowel disease and multiple sclerosis.
VBL Therapeutics’ proprietary award-winning Vascular Targeting System (VTS™) technology platform has yielded VB-111, a highly targeted anti-angiogenic agent for the specific inhibition of tumor vascular growth. VB-111 has successfully completed Phase 1/2 single dose clinical trials in cancer patients, and has recently entered Phase 2 clinical trials in thyroid cancer and glioblastoma.
The VBL was founded in 2000 and is based in Tel Aviv, Israel. The company has more than 70 granted patents and more than 110 applications pending.
[…] http://pharmaceuticalintelligence.com/2012/08/01/human-embryonic-derived-cardiac-progenitor-cells-fo… […]
[…] http://pharmaceuticalintelligence.com/2012/08/01/human-embryonic-derived-cardiac-progenitor-cells-fo… […]