Stem cell death and survival in heart regeneration and repair

Abstract

Cardiovascular diseases are major causes of mortality and morbidity. Cardiomyocyte apoptosis disrupts cardiac function and leads to cardiac decompensation and terminal heart failure. Delineating the regulatory signaling pathways that orchestrate cell survival in the heart has significant therapeutic implications. Cardiac tissue has limited capacity to regenerate and repair. Stem cell therapy is a successful approach for repairing and regenerating ischemic cardiac tissue; however, transplanted cells display very high death percentage, a problem that affects success of tissue regeneration. Stem cells display multipotency or pluripotency and undergo self-renewal, however these events are negatively influenced by upregulation of cell death machinery that induces the significant decrease in survival and differentiation signals upon cardiovascular injury. While efforts to identify cell types and molecular pathways that promote cardiac tissue regeneration have been productive, studies that focus on blocking the extensive cell death after transplantation are limited. The control of cell death includes multiple networks rather than one crucial pathway, which underlies the challenge of identifying the interaction between various cellular and biochemical components. This review is aimed at exploiting the molecular mechanisms by which stem cells resist death signals to develop into mature and healthy cardiac cells. Specifically, we focus on a number of factors that control death and survival of stem cells upon transplantation and ultimately affect cardiac regeneration. We also discuss potential survival enhancing strategies and how they could be meaningful in the design of targeted therapies that improve cardiac function.

Keywords: Apoptosis; Cell death; Heart; Regeneration; Stem cells; Therapy.

Fig. 1

Illustration showing effects of improved (a–e) vs current (f–j) stem cell therapeutic strategies on cell survival and cardiac regeneration. Under improved biological conditions, less numbers of stem cells: (a) are required and are expected to undergo efficient proliferation (b), exhibit less numbers of dying cells (c arrow), differentiate into cardiomyocytes (d arrow), maintain good contact with the ECM as well as with the healthy cardiomyocytes (d) and ultimately provide successful cardiac tissue regeneration (e). On the contrary, current strategies of stem cell therapy in the heart suffer from inefficient transplantation of large numbers of cells (f) that face harsh microenvironments which arrest their proliferation (g), force most of them to die (h arrows), partly due to lack of contact with the ECM as well as with cardiomyocytes (i), and this leads to failure of proper cardiac repair (j). ECM extracellular matrix, CM cardiomyocyte, DT damaged tissue. Asterisks indicate lack of stem cell contact with the ECM

Fig. 2

Schematic representation summarizes major factors affecting stem cell death, survival, differentiation and successful cardiac regeneration. Left desired conditions required for stem cell survival and proper cardiac regeneration. Right obstacles affecting viability of cells and failure to improve cardiac repair. ECM extracellular matrix, SAPK stress-activated protein kinases (such as P38 and JNK), MHC major histocompatibility complex. Other abbreviations are explained in text