Potent Paracrine Effects of human induced Pluripotent Stem Cell-derived Mesenchymal Stem Cells Attenuate Doxorubicin-induced Cardiomyopathy

• Published in: Scientific reports Vol. 5; no. 1; p. 11235
• Main Authors: Zhang, Yuelin, Liang, Xiaoting, Liao, Songyan, Wang, Weixin, Wang, Junwen, Li, Xiang, Ding, Yue, Liang, Yingmin, Gao, Fei, Yang, Mo, Fu, Qingling, Xu, Aimin, Chai, Yuet-Hung, He, Jia, Tse, Hung-Fat, Lian, Qizhou
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.06.2015; Nature Publishing Group
• Subjects: 13/1; 13/21; 14/34; 14/63; 45/100; 64/60; 692/308/2171; 692/699/75/74; Anthracycline; Antibiotics, Antineoplastic - pharmacology; Apoptosis; Bone marrow; Bone marrow transplantation; Cardiomyocytes; Cardiomyopathies - chemically induced; Cardiomyopathies - prevention & control; Cardiomyopathy; Culture Media, Conditioned; Cytokines; Doxorubicin; Doxorubicin - pharmacology; Fibrosis; Heart diseases; Humanities and Social Sciences; Humans; Injection; Leukocyte migration; Macrophage migration inhibitory factor; Macrophages; Mesenchymal Stem Cell Transplantation; Mesenchymal stem cells; Mesenchymal Stromal Cells - cytology; Mesenchyme; multidisciplinary; Neonates; Oxidative stress; Paracrine signalling; Pluripotency; Pluripotent Stem Cells - cytology; Science; Stem cell transplantation; Stem cells; Transplantation; Ventricle
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep11235

Transplantation of bone marrow mesenchymal stem cells (BM-MSCs) can protect cardiomyocytes against anthracycline-induced cardiomyopathy (AIC) through paracrine effects. Nonetheless the paracrine effects of human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) on AIC are poorly understood. In vitro studies reveal that doxorubicin (Dox)-induced reactive oxidative stress (ROS) generation and cell apoptosis in neonatal rat cardiomyocytes (NRCMs) are significantly reduced when treated with conditioned medium harvested from BM-MSCs (BM-MSCs-CdM) or iPSC-MSCs (iPSC-MSCs-CdM). Compared with BM-MSCs-CdM, NRCMs treated with iPSC-MSCs-CdM exhibit significantly less ROS and cell apoptosis in a dose-dependent manner. Transplantation of BM-MSCs-CdM or iPSC-MSCs-CdM into mice with AIC remarkably attenuated left ventricular (LV) dysfunction and dilatation. Compared with BM-MSCs-CdM, iPSC-MSCs-CdM treatment showed better alleviation of heart failure, less cardiomyocyte apoptosis and fibrosis. Analysis of common and distinct cytokines revealed that macrophage migration inhibitory factor (MIF) and growth differentiation factor-15 (GDF-15) were uniquely overpresented in iPSC-MSC-CdM. Immunodepletion of MIF and GDF-15 in iPSC-MSCs-CdM dramatically decreased cardioprotection. Injection of GDF-15/MIF cytokines could partially reverse Dox-induced heart dysfunction. We suggest that the potent paracrine effects of iPSC-MSCs provide novel “cell-free” therapeutic cardioprotection against AIC and that MIF and GDF-15 in iPSC-MSCs-CdM are critical for these enhanced cardioprotective effects.