Biology:Cellular cardiomyoplasty

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Cellular cardiomyoplasty, or cell-based cardiac repair, is a new potential therapeutic modality in which progenitor cells are used to repair regions of damaged or necrotic myocardium. The ability of transplanted progenitor cells to improve function within the failing heart has been shown in experimental animal models and in some human clinical trials.[1] In November 2011, a large group of collaborators at Minneapolis Heart Institute Foundation at Abbott Northwestern found no significant difference in left ventricular ejection fraction (LVEF) or other markers, between a group of patients treated with cellular cardiomyoplasty and a group of control patients.[2] In this study, all patients were post MI, post percutaneous coronary intervention (PCI) and that infusion of progenitor cells occurred 2–3 weeks after intervention. In a study that is currently underway (February 2012), however, more positive results were being reported: In the SCIPIO trial, patients treated with autologous cardiac stem cells post MI have been reported to be showing statistically significant increases in LVEF and reduction in infarct size over the control group at four months after implant. Positive results at the one-year mark are even more pronounced.[3] Yet the SCIPIO trial "was recently called into question".[4][5] Harvard University is "now investigating the integrity of some of the data".[4] The Lancet recently published a non-specific ‘Expression of concern’ about the paper.[6] Subsequently, another preclinical study also raised doubts on the rationale behind using this special kind of cell,[7] as it was found that the special cells only have a minimal ability in generating new cardiomyocytes.[8] Some specialists therefore now raise concerns to continue.[8]

Progenitor cell lines

To date, the ideal progenitor cells have not been found or created. With the goal of recreating human tissue, the use of embryonic stem cells (ESC) was the initial logical choice. These pluripotent cells can conceptually give rise to any somatic cell line in the human body and while animal studies have shown restoration of cardiac function, immunologic rejection issues and teratoma formation have rendered ESC's a high risk.[9][10]

Human-induced pluripotent stem cells (iPSCs) are a cell line derived from somatic cells which have been induced through a combination of transcription factors. The iPSC line is very similar or identical to ESCs in many regards and also shows great promise in cardiac potential.[11] This cell line, however, is also less than ideal in that this cell type has been unable to mature into a homogeneous cell culture, making it immunogenic and teratogenic.[12] A third cell line that shows great promise and has no known safety concerns is the adult stem cell derived from bone marrow or from cardiac tissue explants. It has been shown in several studies that adult stem cells do have cardiogenic potential.[13][14][15]

Future direction

Presently, the success of adult stem cells in regenerating human myocardium is just a fraction of what it could be. Three major challenges have been observed. Adult stem cells exhibit a minimal[clarification needed] commitment to engraft into the damaged myocardium, they have low survival rates and they have limited proliferation.[16] The positive effects observed in clinical trials today are a result of the work of donated stem cells that persist in the damaged myocardium for just days to weeks after delivery. Clearly, if cell survival is prolonged, these effects could be greatly enhanced. This is where a majority of research is being done today and several methodologies hold great promise.[17] [18]

References

  1. Murry CE (2005). "Cell-Based Cardiac Repair: Reflections at the 10-Year Point". Circulation 112 (20): 3174–83. doi:10.1161/CIRCULATIONAHA.105.546218. PMID 16286608. 
  2. Traverse, JH; Ellis (Nov 2011). "Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial.". JAMA 306 (19): 2110–9. doi:10.1001/jama.2011.1670. PMID 22084195. 
  3. Bolli, R; Chugh (Nov 2011). "Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.". Lancet 378 (9806): 1847–57. doi:10.1016/S0140-6736(11)61590-0. PMID 22088800. 
  4. 4.0 4.1 Abbott, A (May 2014). "Doubts over heart stem-cell therapy.". Nature 509 (7498): 15–16. doi:10.1038/509015a. PMID 24784193. Bibcode2014Natur.509...15A. 
  5. "Lancet Editors Raise More Questions About Prominent Harvard Stem Cell Researcher". https://www.forbes.com/sites/larryhusten/2014/04/11/lancet-editors-raises-more-questions-about-prominent-harvard-stem-cell-researcher/. 
  6. The Lancet editors (April 2014). "Expression of concern: the SCIPIO trial.". Lancet 383 (9925): 1279. doi:10.1016/S0140-6736(14)60608-5. PMID 24725564. 
  7. van Berlo, J (2014). "c-kit+ cells minimally contribute cardiomyocytes to the heart.". Nature 509 (7500): 337–341. doi:10.1038/nature13309. PMID 24805242. Bibcode2014Natur.509..337V. 
  8. 8.0 8.1 "Preclinical Study Casts Doubt on Regenerative Ability of Special Cardiac Stem Cells - Journal News - TCTMD". http://www.tctmd.com/show.aspx?id=124193#. 
  9. Yang, L; Adler (May 2008). "Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population.". Nature 453 (7194): 524–528. doi:10.1038/nature06894. PMID 18432194. Bibcode2008Natur.453..524Y. 
  10. Asano, T; Sasaki (2006). In vivo tumor formation from primate embryonic stem cells. Methods in Molecular Biology. 329. pp. 459–467. doi:10.1385/1-59745-037-5:459. ISBN 978-1-59745-037-9. 
  11. Shiba, Y; Laflamme (2009). "Cardiac applications for human pluripotent stem cells.". Current Pharmaceutical Design 15 (24): 2791–806. doi:10.2174/138161209788923804. PMID 19689350. 
  12. Wu, SM; Hochedlinger, K. (June 2011). "Harnessing the potential of induced pluripotent stem cells for regenerative medicine.". Nature Cell Biology 13 (6): 497–505. doi:10.1038/ncb0511-497. PMID 21540845. 
  13. Beltrami, AP et al. (September 2003). "Adult cardiac stem cells are multipotent and support myocardial regeneration.". Cell 114 (6): 763–776. doi:10.1016/S0092-8674(03)00687-1. PMID 14505575. 
  14. Smits, AM et al. (2009). "Human cardiomyocyte progenitor cells differentiate into functional mature cardiomyocytes: an in vitro model for studying human cardiac physiology and pathophysiology.". Nature Protocols 4 (2): 232–243. doi:10.1038/nprot.2008.229. PMID 19197267. 
  15. Fischer, KM; Cottage CT; Wu W; Din S; Gude NA; Avitabil D; Quijada P; Collins BL et al. (Nov 2009). "Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase.". Circulation 120 (21): 2077–2087. doi:10.1161/CIRCULATIONAHA.109.884403. PMID 19901187. 
  16. Mohsin, Sadia; Siddiqu S; Collins B; Sussman M (December 2011). "Empowering adult stem cells for myocardial regeneration.". Circulation Research 109 (12): 1415–1428. doi:10.1161/CIRCRESAHA.111.243071. PMID 22158649. 
  17. Pagani, Francis D; DerSimonian, Harout; Zawadzka, Agatha; Wetzel, Kristie; Edge, Albert SB; Jacoby, Douglas B; Dinsmore, Jonathan H; Wright, Susan et al. (2003). "Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans". Journal of the American College of Cardiology 41 (5): 879–888. doi:10.1016/S0735-1097(03)00081-0. ISSN 0735-1097. PMID 12628737. 
  18. Muller-Ehmsen, J; Whittaker P; Kloner RA; Dow JS; Sakoda T; Long TI; Laird PW; Kedes L. (Feb 2002). "Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium.". J Mol Cell Cardiol 34 (2): 107–116. doi:10.1006/jmcc.2001.1491. PMID 11851351.