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World J Stem Cells. Jan 26, 2017; 9(1): 9-25
Published online Jan 26, 2017. doi: 10.4252/wjsc.v9.i1.9
Optimizing stem cells for cardiac repair: Current status and new frontiers in regenerative cardiology
Shant Der Sarkissian, Thierry Lévesque, Nicolas Noiseux
Shant Der Sarkissian, Nicolas Noiseux, Department of Surgery, Faculté de Médecine, Université de Montréal, Montreal, QC H3C 3J7, Canada
Thierry Lévesque, Faculté de Médecine, Université de Montréal, Montreal, QC H3C 3J7, Canada
Author contributions: All authors contributed to this paper with conception, literature review, editing, references and final approval.
Conflict-of-interest statement: No potential conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Nicolas Noiseux, MD, FRCS(C), MSc (Molecular Biology), BSc (Biochemistry), Cardiac Surgeon, Full Professor of Surgery, Director of Research Cardiac Surgery, Department of Surgery, Faculté de Médecine, Université de Montréal, Pavillon Hôtel-Dieu 3840, Saint-Urbain St., Local 2-420, Montreal, QC H3C 3J7, Canada. noiseuxn@videotron.ca
Telephone: +1-514-8908131 Fax: +1-514-4127231
Received: July 1, 2016
Peer-review started: July 3, 2016
First decision: September 5, 2016
Revised: September 29, 2016
Accepted: October 22, 2016
Article in press: October 24, 2016
Published online: January 26, 2017
Processing time: 200 Days and 22.2 Hours
Abstract

Cell therapy has the potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These controversies are believed to arise by the lack of uniformity of the clinical trial methodologies, uncertainty regarding the underlying reparative mechanisms of stem cells, questions concerning the most appropriate cell population to use, the proper delivery method and timing in relation to the moment of infarction, as well as the poor stem cell survival and engraftment especially in a diseased microenvironment which is collectively acknowledged as a major hindrance to any form of cell therapy. Indeed, the microenvironment of the failing heart exhibits pathological hypoxic, oxidative and inflammatory stressors impairing the survival of transplanted cells. Therefore, in order to observe any significant therapeutic benefit there is a need to increase resilience of stem cells to death in the transplant microenvironment while preserving or better yet improving their reparative functionality. Although stem cell differentiation into cardiomyocytes has been observed in some instance, the prevailing reparative benefits are afforded through paracrine mechanisms that promote angiogenesis, cell survival, transdifferentiate host cells and modulate immune responses. Therefore, to maximize their reparative functionality, ex vivo manipulation of stem cells through physical, genetic and pharmacological means have shown promise to enable cells to thrive in the post-ischemic transplant microenvironment. In the present work, we will overview the current status of stem cell therapy for ischemic heart disease, discuss the most recurring cell populations employed, the mechanisms by which stem cells deliver a therapeutic benefit and strategies that have been used to optimize and increase survival and functionality of stem cells including ex vivo preconditioning with drugs and a novel “pharmaco-optimizer” as well as genetic modifications.

Keywords: Stem cell; Regenerative medicine; Cellular cardiomyoplasty; Preconditioning; Myocardial infarction; Heart failure; Viability; Paracrine activity; Transplantation; Pharmaco-optimizer

Core tip: Cell therapy has the potential to improve healing of the ischemic heart, to repopulate injured myocardium and restore cardiac function in ischemic and non-ischemic cardiomyopathy. However, one of the biggest impediments lessening clinical effectiveness of cell therapy is the poor viability, retention and functionality of transplanted cells. This review looks as various stem cell ex vivo preconditioning and reprogramming methods aimed at enhancing the therapeutic potential of stem cells for heart failure treatment.