title: Potent Paracrine Effects of human induced Pluripotent Stem Cell-derived Mesenchymal Stem Cells Attenuate Doxorubicin-induced Cardiomyopathy.
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.
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Songyan
authors.initials: S
authors.lastname: Liao
authors.affiliation: Department of Biochemistry, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Weixin
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Junwen
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Yingmin
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Ophthalmology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Ophthalmology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Mo
authors.initials: M
authors.lastname: Yang
authors.affiliation: Otorhinolaryngology Hospital, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Qingling
authors.initials: Q
authors.lastname: Fu
authors.affiliation: 1] Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong [2] Shenzhen Institutes of Research and Innovation, the University of Hong Kong, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Yuet-Hung
authors.initials: YH
authors.lastname: Chai
authors.affiliation: Department of Ophthalmology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors.forename: Jia
authors.initials: J
authors.lastname: He
authors.affiliation: 1] Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong [2] Shenzhen Institutes of Research and Innovation, the University of Hong Kong, China.
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
authors.affiliation: 1] Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong [2] Department of Ophthalmology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong [3] Shenzhen Institutes of Research and Innovation, the University of Hong Kong, China.
authors.forename: Qizhou
authors.initials: Q
authors.lastname: Lian
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000517:prevention & control*; D017077:Culture Media, Conditioned; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D039904:Pluripotent Stem Cells / Q000166:cytology*
chemical_list: D000903:Antibiotics, Antineoplastic; D017077:Culture Media, Conditioned; D004317:Doxorubicin