Novel Cell Replacement Strategies for Heart Failure Treatment
Received Date: Nov 09, 2015 / Accepted Date: Dec 03, 2015 / Published Date: Dec 10, 2015
Heart failure treatment
Myocardial infarction (MI), or heart attack, is caused by the blockage of blood flow in the heart, which reduces oxygen levels, damages tissues (ischemia) and kills close to one billion cardiomyocytes (infarction) . Fibroblasts then migrate into the infarcted area where they proliferate to create a cardiomyocytedepleted scar that cannot contribute to the electrophysiologicallydriven contractions of the heart. This often causes HF leading to fatigue, peripheral edema, or even death. To find more effective therapies for HF, we need to improve our understanding of its pathophysiology and develop new approaches to treating it.
Cell-replacement therapy has emerged as a novel approach to treat HF. This approach relies on the theory that after MI or in HF, lost cardiomyocytes can be replaced by adding either new cardiomyocytes or a potential source of cardiomyocytes such as stem cells. To find the most effective approach, researchers have tested several types of stem cells including skeletal myoblasts , cardiac progenitor cells , and mesenchymal stem cells from bone marrow . However, they have only been modestly successful because the beneficial effects are mainly mediated by indirect paracrine mechanisms: stem cells do not transdifferentiate into cardiomyocytes in-vivo and the number of stem cells retained in the heart after delivery is disappointingly low . Fortunately, cell-replacement therapy for HF using pluripotent stemcell- derived cardiomyocytes showed more promising results in rodents and non-human primates because they integrate and electrically couple with the healthy myocardium [6-8]. However, technologies involving stem-cell-derived cardiomyocytes must be further optimized before they can effectively treat HF. Specifically, we need to find methods that improve the efficiency and consistency of cardiomyocyte differentiation in large scale, their survival in disease conditions, their integration into cardiac tissue, and their resistance to autoimmune rejection.
Recently, Srivastava laboratory and others demonstrated an alternative approach-transdifferentiation of resident cardiac fibroblasts (CFs) into cardiomyocytes, called direct cardiac reprogramming. They initially illustrated that CFs transdifferentiate into a more cardiac-like state both in-vitro and in-vivo when treated with a combination of three transcription factors associated with cardiogenesis-Gata4, Mef2c, and Tbx5 (GMT) . Building on this technology, subsequent reports have shown that various combinations of transcription factors, and microRNAs and other combinations [10-13]. However, the efficiency of reprogramming and extent of cardiac-specific gene expression and morphology, such as sarcomere organization, have been consistently better in-vivo than in-vitro [14,15].
In fact, reprogramming CFs in-vivo improved cardiac function after injury (e.g., ejection fraction, cardiac output, and stroke volume) [14, 15]. While reprogramming the pool of endogenous cardiac fibroblasts into cardiomyocyte-like cells is a promising approach for cardiac regeneration, the methods must be refined to enhance the efficiency and quality of their reprogramming. Thus, we must understand the mechanism by which the reprogramming factors fundamentally alter the cell state. This work is currently conducted by various groups around the world to identify the barriers for cell transdifferentiation.
- Burridge PW, Keller G, Gold JD, Wu JC (2012) Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell 10: 16-28.
- Menasché P, Hagège AA, Vilquin JT, Desnos M, Abergel E, et al. (2003) Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am CollCardiol 41: 1078-1083.
- Chugh AR, Beache GM, Loughran JH, Mewton N, Elmore JB, et al. (2012) Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial: surgical aspects and interim analysis of myocardial function and viability by magnetic resonance. Circulation 126: S54-64.
- Assmus B, Schächinger V, Teupe C, Britten M, Lehmann R, et al. (2002) Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation 106: 3009-3017.
- Malliaras K, Marbán E (2011) Cardiac cell therapy: where we've been, where we are, and where we should be headed. Br Med Bull 98: 161-185.
- Chong JJ, Yang X, Don CW, Minami E, Liu YW, et al. (2014) Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510: 273-277.
- Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, et al. (2007) Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 25: 1015-1024.
- Shiba Y, Fernandes S, Zhu WZ, Filice D, Muskheli V, et al. (2012) Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature 489: 322-325.
- Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, et al. (2010) Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142: 375-386.
- Song K, Nam YJ, Luo X, Qi X, Tan W, et al. (2012) Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 485: 599-604.
- Protze S, Khattak S, Poulet C, Lindemann D, Tanaka EM, et al. (2012) A new approach to transcription factor screening for reprogramming of fibroblasts to cardiomyocyte-like cells. J Mol Cell Cardiol 53: 323-332.
- Christoforou N, Chellappan M, Adler AF, Kirkton RD, Wu T, et al. (2013) Transcription factors MYOCD, SRF, Mesp1 and SMARCD3 enhance the cardio-inducing effect of GATA4, TBX5, and MEF2C during direct cellular reprogramming. PLoS One 8: e63577.
- Addis RC, Ifkovits JL, Pinto F, Kellam LD, Esteso P, et al. (2013) Optimization of direct fibroblast reprogramming to cardiomyocytes using calcium activity as a functional measure of success. J Mol Cell Cardiol 60: 97-106.
- Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, et al. (2012) In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 485: 593-598.
- Jayawardena TM, Egemnazarov B, Finch EA, Zhang L, Payne JA, et al. (2012) MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res 110: 1465-1473.
Citation: Mohamed TMA (2015) Novel Cell Replacement Strategies for Heart Failure Treatment. Atheroscler open access 1: 102.
Copyright: © 2015 Mohamed TM. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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