Concise review: heart regeneration and the role of cardiac stem cells

Abstract

Acute myocardial infarction leads to irreversible loss of cardiac myocytes, thereby diminishing the pump function of the heart. As a result, the strenuous workload imposed on the remaining cardiac myocytes often gives rise to subsequent cell loss until the vicious circle ends in chronic heart failure (CHF). Thus, we are in need of a therapy that could ameliorate or even reverse the disease progression of CHF. Endogenous regeneration of the mammalian heart has been shown in the neonatal heart, and the discovery that it may still persist in adulthood sparked hope for novel cardioregenerative therapies. As the basis for cardiomyocyte renewal, multipotent cardiac stem/progenitor cells (CSCs) that reside in the heart have been shown to differentiate into cardiac myocytes, smooth muscle cells, and vascular endothelial cells. These CSCs do have the potential to actively regenerate the heart but clearly fail to do so after abundant and segmental loss of cells, such as what occurs with myocardial infarction. Therefore, it is vital to continue research for the most optimal therapy based on the use or in situ stimulation of these CSCs. In this review, we discuss the current status of the cardioregenerative field. In particular, we summarize the current knowledge of CSCs as the regenerative substrate in the adult heart and their use in preclinical and clinical studies to repair the injured myocardium.

Keywords: Adult stem cells; Cardiac stem/progenitor cell; Self-renewal.

Figure 1.

Cardiac stem/progenitor cell-based regeneration in the adult mammalian heart. The proposed mechanism of cardiac regeneration mediated by endogenous CSCs present in the heart is shown. This mechanism is based on the observation that cardiac stem/progenitor cells (CSCs) are multipotent (A), self-renewing (B), and clonogenic (C). In their undifferentiated state, CSCs express low levels of pluripotency markers such as OCT3/4, Sox2, and Nanog (see inset). The majority of CSCs also express key regulators such as BMI-1 that controls cell cycle inhibitors P19 and P21 to maintain and regulate their ability to proliferate. Once activated, CSCs can re-enter the cell cycle and subsequently can give rise to progeny that both maintain their own pool of undifferentiated stem cells and mature into three different lineages (see functional differentiation) under the influence of various lineage-specific transcription factors.

Figure 2.

Preclinical studies on the efficacy of exogenous CSC delivery in myocardial infarction in rodents. Shown is a Forrest plot showing the pooled results of the mean difference on left ventricular ejection fraction (LVEF) at follow-up (21–28 days) compared with the baseline of exogenous CSC delivery in rodent models of acute myocardial infarction. Different CSC therapy led to a roughly equal improvement in LVEF for c-kit^pos CSCs (+10.88%; [95% CI: 8.83–12.94]), Sca-1^pos CSCs (+9.88%; [95% CI: 8.49–11.27]), or CDCs (+14.00%; [95% CI: 8.6–19.40]) at follow-up. Abbreviations: CI, confidence interval; CSC, cardiac stem/progenitor cell; IV, inverse variance; Fixed, fixed effects analysis.

Figure 3.

Novel strategies for CSC-based myocardial repair. Schematic overviews of current strategies used to make use of CSCs for myocardial repair are shown. Strategy 1 is based on activation of endogenous CSCs by various means, e.g., growth factors (A), noncardiac stem cells (B), or gene therapy (C). Upon activation, resident endogenous CSCs can proliferate and mature into newly formed cardiac myocytes (green cardiac myocytes). Strategy 2 is based on the delivery of autologous CSCs that have been isolated from small myocardial biopsies and scaled up outside the patient to sufficient numbers. Exogenous CSCs are also shown to be capable of activating the local endogenous CSC compartment. In addition, exogenously delivered CSCs are hypothesized to mature and differentiate into functional cardiac myocytes (yellow cardiac myocytes) that are electromechanically coupled with the pre-existing cardiac myocytes (orange cardiac myocytes) [31]. Abbreviation: CSC, cardiac stem/progenitor cell.