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

Yuelin Zhang, Xiaoting Liang, Songyan Liao, Weixin Wang, Junwen Wang, Xiang Li, Yue Ding, Yingmin Liang, Fei Gao, Mo Yang, Qingling Fu, Aimin Xu, Yuet Hung Chai, Jia He, Hung Fat Tse, Qizhou Lian

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article number11235
JournalScientific Reports
Volume5
DOIs
StatePublished - Jun 9 2015
Externally publishedYes

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Induced Pluripotent Stem Cells
Mesenchymal Stromal Cells
Cardiomyopathies
Doxorubicin
Growth Differentiation Factor 15
Anthracyclines
Cardiac Myocytes
Bone Marrow
Apoptosis
Bone Marrow Transplantation
Oxidative Stress
Cytokines
Macrophage Migration-Inhibitory Factors
Left Ventricular Dysfunction
Conditioned Culture Medium
Dilatation
Fibrosis
Heart Failure

ASJC Scopus subject areas

  • General

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

In: Scientific Reports, Vol. 5, 11235, 09.06.2015.

Research output: Contribution to journalArticle

Zhang, Y, Liang, X, Liao, S, Wang, W, Wang, J, Li, X, Ding, Y, Liang, Y, Gao, F, Yang, M, Fu, Q, Xu, A, Chai, YH, He, J, Tse, HF & Lian, Q 2015, 'Potent Paracrine Effects of human induced Pluripotent Stem Cell-derived Mesenchymal Stem Cells Attenuate Doxorubicin-induced Cardiomyopathy', Scientific Reports, vol. 5, 11235. https://doi.org/10.1038/srep11235
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. / Potent Paracrine Effects of human induced Pluripotent Stem Cell-derived Mesenchymal Stem Cells Attenuate Doxorubicin-induced Cardiomyopathy. In: Scientific Reports. 2015 ; Vol. 5.
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AU - Wang, Junwen

AU - Li, Xiang

AU - Ding, Yue

AU - Liang, Yingmin

AU - Gao, Fei

AU - Yang, Mo

AU - Fu, Qingling

AU - Xu, Aimin

AU - Chai, Yuet Hung

AU - He, Jia

AU - Tse, Hung Fat

AU - Lian, Qizhou

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