Cardiac stem cell therapy: Checkered past, promising future? John J. Squiers, BSE, Kelley A. Hutcheson, MD, Jeffrey E. Thatcher, PhD, J. Michael DiMaio, MD  The Journal of Thoracic and Cardiovascular Surgery  Volume 148, Issue 6, Pages 3188-3193 (December 2014) DOI: 10.1016/j.jtcvs.2014.10.077 Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 Proposed mechanisms for cardiac regeneration. Therapeutic effects of stem cells likely promote some or all of these innate pathways in the treatment of cardiac disease. (1) Paracrine factors promote proliferation of cardiomyocytes. (2) Progenitor cells activate and differentiate into cardiomyocytes. (3) Mature cardiomyocytes dedifferentiate to reenter the cell cycle and proliferate into new cardiomyocytes. (4) Activated epicardium stimulates angiogenesis and/or proliferation of cardiomyocytes. (Figure adapted from Cell Stem Cell, Vol. 12, Garbern JC, Lee RT, Cardiac stem cell therapy and the promise of heart regeneration, p. 692, Copyright 2013, with permission from Elsevier.18) The Journal of Thoracic and Cardiovascular Surgery 2014 148, 3188-3193DOI: (10.1016/j.jtcvs.2014.10.077) Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Approaches to cardiac regeneration in heart disease. In addition to (1) stem cell delivery, several other related methods may prove to be effective therapies. (2) Tissue engineering combines cells with mechanical support and adjunctive biomaterials that promote survival. (3) Paracrine factors may be isolated from stem cell cultures and delivered as small molecules to promote repair and regeneration. (4) Noncardiomyocytes may be reprogrammed via the delivery of viruses, small molecules, or microRNAs. All of these mechanisms may promote one or more of the pathways for cardiac regeneration described in Figure 1. (Figure adapted with permission.18) The Journal of Thoracic and Cardiovascular Surgery 2014 148, 3188-3193DOI: (10.1016/j.jtcvs.2014.10.077) Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions