Mesenchymal Stem Cell Therapy for Doxorubicin-Induced Cardiomyopathy: Potential Mechanisms, Governing Factors, and Implications of the Heart Stem Cell Debate

Abstract

Over the past decades, researchers have reported several mechanisms for doxorubicin (DOX)-induced cardiomyopathy, including oxidative stress, inflammation, and apoptosis. Another mechanism that has been suggested is that DOX interferes with the cell cycle and induces oxidative stress in C-kit+ cells (commonly known as cardiac progenitor cells), reducing their regenerative capacity. Cardiac regeneration through enhancing the regenerative capacity of these cells or administration of other stem cells types has been the axis of several studies over the past 20 years. Several experiments revealed that local or systemic injections with mesenchymal stem cells (MSCs) were associated with significantly improved cardiac function, ameliorated inflammatory response, and reduced myocardial fibrosis. They also showed that several factors can affect the outcome of MSC treatment for DOX cardiomyopathy, including the MSC type, dose, route, and timing of administration. However, there is growing evidence that the C-kit+ cells do not have a cardiac regenerative potential in the adult mammalian heart. Similarly, the protective mechanisms of MSCs against DOX-induced cardiomyopathy are not likely to include direct differentiation into cardiomyocytes and probably occur through paracrine secretion, antioxidant and anti-inflammatory effects. Better understanding of the involved mechanisms and the factors governing the outcomes of MSCs therapy are essential before moving to clinical application in patients with DOX-induced cardiomyopathy.

Keywords: anthracyclines; cardiac progenitor cells; cardiomyopathy; doxorubicin; mesenchymal stem cells.

Figure 1

The commonly investigated mechanisms of doxorubicin-induced cardiotoxicity. This figure was adapted from a previous publication by the authors (Abushouk et al., 2017) and an adequate permission for reproduction was obtained from the publisher (Elsevier).

Figure 2

The mechanisms of action of stem-cell-based treatment in ameliorating doxorubicin-induced cardiotoxicity. ADSCs, adipose-derived stem cells; BMMSCs, bone-marrow mesenchymal stem cells; HGF, hepatocyte growth factor; hUCB-MSCs, human umbilical cord blood mesenchymal stem cells; IDO, indoleamine 2,3-dioxygenase; IGF-1, insulin-like growth factor-1; Il, interleukin; MMP, matrix metallopeptidase; PDGF, platelet-derived growth factor; PGE, prostaglandin E; ROS, reactive oxygen species; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor.