Paracrine mechanisms of stem cell reparative and regenerative actions in the heart

Abstract

Stem cells play an important role in restoring cardiac function in the damaged heart. In order to mediate repair, stem cells need to replace injured tissue by differentiating into specialized cardiac cell lineages and/or manipulating the cell and molecular mechanisms governing repair. Despite early reports describing engraftment and successful regeneration of cardiac tissue in animal models of heart failure, these events appear to be infrequent and yield too few new cardiomyocytes to account for the degree of improved cardiac function observed. Instead, mounting evidence suggests that stem cell mediated repair takes place via the release of paracrine factors into the surrounding tissue that subsequently direct a number of restorative processes including myocardial protection, neovascularization, cardiac remodeling, and differentiation. The potential for diverse stem cell populations to moderate many of the same processes as well as key paracrine factors and molecular pathways involved in stem cell‐mediated cardiac repair will be discussed in this review. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".

Introduction

Myocardial infarction (MI) is one of the major causes of cardiovascular mortality and morbidity, especially congestive heart failure [1]. Despite major advances in drug and interventional therapies, surgical procedures and organ transplantation, restoration and regeneration of the damaged myocardium remains a tremendous challenge. Stem cell therapy has generated significant interest and to date preclinical research has documented its therapeutic potential. Clinical studies, still in early stages, have reported that this therapeutic modality may lead to an overall improvement of cardiac function [2], [3]. The precise underlying mechanisms of stem cell action are still under debate. There is a growing body of evidence supporting the hypothesis that stem cells can enhance endogenous repair and regenerative processes through the release and actions of paracrine factors.

Numerous studies have demonstrated that stem cells contribute to tissue repair and regeneration by releasing important paracrine factors in a dynamic spatial-temporal manner that can lead to cell survival, angiogenesis, tissue repair and remodeling, as well as cellular regeneration [4], [5], [6], [7]. Moreover it has been postulated that the cross-talk facilitated by stem cells in the cardiac microenvironment includes both direct autocrine communication as well as paracrine-mediated signaling with surrounding cells.

Various types of adult stem cells that have demonstrated therapeutic potential with potential paracrine activities can be broadly categorized as bone marrow-derived, circulating, and resident to the heart [7]. Studies that have claimed the use of bone marrow derived stem cells have included a broad range of cells from purified mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), to bone marrow-derived mononuclear cells (BM-MNCs), and unfractionated bone marrow cells (BMCs). Evidence supports the contribution of paracrine mediators to the actions of these cells [6], [7], [8], [9], [10]. The category of circulating stem/progenitor cells is represented principally by endothelial progenitor cells (EPCs) that can be isolated from circulation and have been reported to restore blood flow to ischemic myocardium via paracrine mechanisms [11]. Resident cardiac progenitor/stem cells (CPCs) are believed to represent self-renewing populations of cells confined to specific niches within the heart that may be stimulated to proliferate and differentiate as a result of paracrine effects [12]. While embryonic stem cells (ESCs) continue to hold promise for regenerative research, their role in paracrine-mediated cell therapy has not been extensively studied. Recent data suggest that multiple factors secreted by these cells may be important for their therapeutic effect [9], [10]. The recent discovery of induced pluripotent stem cells by Takahashi and Yamanaka circumvents ESC-related concerns [13] and holds much promise for cardiac regenerative medicine [14], [15]. Still, their contribution to paracrine-mediated stem cell therapy remains unknown at present.

The majority of studies relating to paracrine-mediated cardiac repair have utilized adult stem cells and therefore this review will primarily focus on the mediation of these cells in regulating the healing process in the heart via secretion of key regulatory molecules (Fig. 1).