Local activation of cardiac stem cells for post-myocardial infarction cardiac repair

Abstract

The prognosis of patients with myocardial infarction (MI) and resultant chronic heart failure remains extremely poor despite continuous advancements in optimal medical therapy and interventional procedures. Animal experiments and clinical trials using adult stem cell therapy following MI have shown a global improvement of myocardial function. The emergence of stem cell transplantation approaches has recently represented promising alternatives to stimulate myocardial regeneration. Regarding their tissue-specific properties, cardiac stem cells (CSCs) residing within the heart have advantages over other stem cell types to be the best cell source for cell transplantation. However, time-consuming and costly procedures to expanse cells prior to cell transplantation and the reliability of cell culture and expansion may both be major obstacles in the clinical application of CSC-based transplantation therapy after MI. The recognition that the adult heart possesses endogenous CSCs that can regenerate cardiomyocytes and vascular cells has raised the unique therapeutic strategy to reconstitute dead myocardium via activating these cells post-MI. Several strategies, such as growth factors, mircoRNAs and drugs, may be implemented to potentiate endogenous CSCs to repair infarcted heart without cell transplantation. Most molecular and cellular mechanism involved in the process of CSC-based endogenous regeneration after MI is far from understanding. This article reviews current knowledge opening up the possibilities of cardiac repair through CSCs activation in situ in the setting of MI.

Fig. 1

Resident cardiac stem cells activation after MI can lead to endogenous cardiac repair through multiple differentiation, paracrine/autocrine effects and other potential effects. Several proposed modulators, such as growth factors, physical activations, pharmacological approaches, mircoRNAs, stem cell transplantation and supporting non-stem cell stimulation, may enhance and maintain these beneficial effects (see text for details).

Fig. 2

Proposed modulators of growth factors and receptor systems coupled by downstream signallings that may be used as important therapeutic targets to activate resident cardiac stem cells (CSCs) to repair infarct heart. These modulators can activate CSCs in situ via different mechanisms of action, such as prosurvival, migration, proliferation and differentiation, resulting in cardiac repair following MI (see text for details). IGF-1, insulin-like growth factor 1; HGF, hepatocyte growth factor; VEGF, vascular endothelial growth factor; PI3K, phosphatidylinositol-3-kinase; GSK-3, glycogen synthase kinase-3; SDF, stromal cell-derived factor; CXCR-4, CXC chemokine receptor 4; HIF-1alpha, hypoxia-inducible factor 1alpha; bFGF, basic fibroblast growth factor; SCF, stem cell factor; MAPK, mitogen-activated protein kinase; NF, nuclear factor; VCAM/VLA-4, vascular cell adhesion molecule/very late antigen-4; ERK, extracellular signal-regulated kinase; LIF, leukaemia inhibitory factor; STAT-3, signal transducer and activator of transcription 3; FGF-2, fibroblast growth factor 2; EGF, epidermal growth factor; G-CSF, granulocyte colonystimulating factor; TGF-1beta, transforming growth factor-1beta; HMGB-1, high-mobility group box 1.