title: iPSC-MSCs with High Intrinsic MIRO1 and Sensitivity to TNF-α Yield Efficacious Mitochondrial Transfer to Rescue Anthracycline-Induced Cardiomyopathy.
abstract: Mesenchymal stem cells (MSCs) can donate mitochondria and rescue anthracycline-induced cardiomyocyte (CM) damage, although the underlying mechanisms remain elusive. We determined that the superior efficiency of mitochondrial transfer by human induced-pluripotent-stem-cell-derived MSCs (iPSC-MSCs) compared with bone marrow-derived MSCs (BM-MSCs) is due to high expression of intrinsic Rho GTPase 1 (MIRO1). Further, due to a higher level of TNFαIP2 expression, iPSC-MSCs are more responsive to tumor necrosis factor alpha (TNF-α)-induced tunneling nanotube (TNT) formation for mitochondrial transfer to CMs, which is regulated via the TNF-α/NF-κB/TNFαIP2 signaling pathway. Inhibition of TNFαIP2 or MIRO1 in iPSC-MSCs reduced the efficiency of mitochondrial transfer and decreased CMs protection. Compared with BM-MSCs, transplantation of iPSC-MSCs into a mouse model of anthracycline-induced cardiomyopathy resulted in more human mitochondrial retention and bioenergetic preservation in heart tissue. Efficacious transfer of mitochondria from iPSC-MSCs to CMs, due to higher MIRO1 expression and responsiveness to TNF-α-induced nanotube formation, effectively attenuates anthracycline-induced CM damage.
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Central Laboratory, Peking University Shenzhen Hospital, Shenzhen 518000, China.
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Ophthalmology, The University of Hong Kong, Hong Kong, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Liang
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Songyan
authors.initials: S
authors.lastname: Liao
authors.affiliation: Department of Ophthalmology, The University of Hong Kong, Hong Kong, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Yue
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Sin-Ming
authors.initials: SM
authors.lastname: Chiu
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China; Research Centre of Heart, Brain, Hormone, and Healthy Aging, The University of Hong Kong, Hong Kong, China.
authors.forename: Yuet-Hung
authors.initials: YH
authors.lastname: Chai
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Yingmin
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Yenyen
authors.initials: Y
authors.lastname: Chow
authors.affiliation: Department of Ophthalmology, The University of Hong Kong, Hong Kong, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Han
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China; Research Centre of Heart, Brain, Hormone, and Healthy Aging, The University of Hong Kong, Hong Kong, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China; Research Centre of Heart, Brain, Hormone, and Healthy Aging, The University of Hong Kong, Hong Kong, China; Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, The University of Hong Kong, Hong Kong, China. Electronic address: hftse@hku.hk.
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China; Department of Ophthalmology, The University of Hong Kong, Hong Kong, China; Research Centre of Heart, Brain, Hormone, and Healthy Aging, The University of Hong Kong, Hong Kong, China; Shenzhen Institutes of Research and Innovation, The University of Hong Kong, Shenzhen 518000, China. Electronic address: qzlian@hku.hk.
authors.forename: Qizhou
authors.initials: Q
authors.lastname: Lian
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000009:adverse effects; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019899:Paracrine Communication / Q000187:drug effects; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D020741:rho GTP-Binding Proteins
chemical_list: D018943:Anthracyclines; D016207:Cytokines; D024101:Mitochondrial Proteins; D016328:NF-kappa B; C085839:TNFAIP2 protein, human; D014409:Tumor Necrosis Factor-alpha; C473124:RHOT1 protein, human; D020741:rho GTP-Binding Proteins
keywords: anthracyclines; cardiomyopathy; induced pluripotent stem cells; mesenchymal stem cells