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.

IGF-1 enhances BMSC viability, migration, and anti-apoptosis in myocardial infarction via secreted frizzled-related protein 2 pathway

“…Impressively, BMSCs-IGF1-1 showed protective effects on H9C2 under hypoxia through a mechanism that was independent of cell-to-cell connections, indicating that the mediator was likely to be soluble paracrine factors. These results further supported the notion that the effects of BMSCs on treatment for AMI may be largely mediated by their paracrine effects [27]. Our in vivo results further confirmed the protective effects of BMSCs-IGF-1 in AMI hearts.…”

Phoenix dactyliferaProtects against Doxorubicin-Induced Cardiotoxicity and Nephrotoxicity

“…Pathogenesis of DOX-induced cardiomyopathy is implicated by multiple mechanisms including oxidative stress, downregulation of functional cardiac muscle-specific and mitochondrial proteins, inhibition and activation of enzymatic pathways, and exaggerated immune response. All these pathological events lead to altered molecular signaling and activation of apoptotic cascade resulting in the destruction of nucleic acid, sarcomere disruption, and myofibril loss [8]. However, the elevated mitochondria-to-cardiomyocyte ratio makes cardiomyocytes more susceptible to oxidative stress and has been proposed a key factor in pathogenesis compared with the aforementioned mechanisms.…”

“…On the contrary, DOX inhibits the activities of endogenous enzymatic and nonenzymatic antioxidants. So, an imbalance between ROS generation and neutralization leads to oxidative stress and has a greater damaging effect on heart compared with other organs such as the kidney and liver [8][9][10].…”

Functional Blockade of E-Selectin in Tumor-Associated Vessels Enhances Anti-Tumor Effect of Doxorubicin in Breast Cancer

“…ESTA was neither cytotoxic by itself nor an enhancer of DOX cytotoxicity, rather, administration of ESTA allowed an approximately five-fold reduction in dose of DOX to achieve equal therapeutic effect perhaps through the indirect effect of suppressing the DOX treatment-associated T H 2 shift. Anthracycline-induced cardiomyopathy, including oxidative stress [23][24][25], IL-1-mediated inflammation [23,[26][27][28], and cardiac apoptosis [23,24], limits the allowable cumulative lifetime dose; thus, reduction of DOX dosage while maintaining efficacy is an attractive therapeutic strategy. ESTA blocked de novo infiltration of CD45 + cells and the T H 2 shift in the DOX-treated tumors; however, the effect of DOX/ESTA on other ogans remains unaddressed.…”

“…stimulating factor receptor (CSF1R[25]) have been successfully targeted by monoclonal antibodies271 for impediment of immune cell infiltration into tumors or other tissues. These antibodies, in 272 Schematic working model of ESTA's mechanism of action.…”