Dataset Information

IPSC-MSCs with High Intrinsic MIRO1 and Sensitivity to TNF-? 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 TNF?IP2 expression, iPSC-MSCs are more responsive to tumor necrosis factor alpha (TNF-?)-induced tunneling nanotube (TNT) formation for mitochondrial transfer to CMs, which is regulated via the TNF-?/NF-?B/TNF?IP2 signaling pathway. Inhibition of TNF?IP2 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-?-induced nanotube formation, effectively attenuates anthracycline-induced CM damage.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5063626 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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iPSC-MSCs with High Intrinsic MIRO1 and Sensitivity to TNF-α Yield Efficacious Mitochondrial Transfer to Rescue Anthracycline-Induced Cardiomyopathy.

Zhang Yuelin Y Yu Zhendong Z Jiang Dan D Liang Xiaoting X Liao Songyan S Zhang Zhao Z Yue Wensheng W Li Xiang X Chiu Sin-Ming SM Chai Yuet-Hung YH Liang Yingmin Y Chow Yenyen Y Han Shuo S Xu Aimin A Tse Hung-Fat HF Lian Qizhou Q

Stem cell reports 20160915 4

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 ...[more]

PMID: 27641650

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Project description:BackgroundMice with deletion of complex I subunit Ndufs4 develop mitochondrial encephalomyopathy resembling Leigh syndrome (LS). The metabolic derangement and underlying mechanisms of cardio-encephalomyopathy in LS remains incompletely understood.MethodsWe performed echocardiography, electrophysiology, confocal microscopy, metabolic and molecular/morphometric analysis of the mice lacking Ndufs4. HEK293 cells, human iPS cells-derived cardiomyocytes and neurons were used to determine the mechanistic role of mitochondrial complex I deficiency.ResultsLS mice develop severe cardiac bradyarrhythmia and diastolic dysfunction. Human-induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) with Ndufs4 deletion recapitulate LS cardiomyopathy. Mechanistically, we demonstrate a direct link between complex I deficiency, decreased intracellular (nicotinamide adenine dinucleotide) NAD+ /NADH and bradyarrhythmia, mediated by hyperacetylation of the cardiac sodium channel NaV 1.5, particularly at K1479 site. Neuronal apoptosis in the cerebellar and midbrain regions in LS mice was associated with hyperacetylation of p53 and activation of microglia. Targeted metabolomics revealed increases in several amino acids and citric acid cycle intermediates, likely due to impairment of NAD+ -dependent dehydrogenases, and a substantial decrease in reduced Glutathione (GSH). Metabolic rescue by nicotinamide riboside (NR) supplementation increased intracellular NAD+ / NADH, restored metabolic derangement, reversed protein hyperacetylation through NAD+ -dependent Sirtuin deacetylase, and ameliorated cardiomyopathic phenotypes, concomitant with improvement of NaV 1.5 current and SERCA2a function measured by Ca2+ -transients. NR also attenuated neuronal apoptosis and microglial activation in the LS brain and human iPS-derived neurons with Ndufs4 deletion.ConclusionsOur study reveals direct mechanistic explanations of the observed cardiac bradyarrhythmia, diastolic dysfunction and neuronal apoptosis in mouse and human induced pluripotent stem cells (iPSC) models of LS.

Project description:BACKGROUND:Primary mesenchymal stem cells (MSCs) are fraught with aging-related shortfalls. Human-induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) have been shown to be a useful clinically relevant source of MSCs that circumvent these aging-associated drawbacks. To date, the extent of the retention of aging-hallmarks in iMSCs differentiated from iPSCs derived from elderly donors remains unclear. METHODS:Fetal femur-derived MSCs (fMSCs) and adult bone marrow MSCs (aMSCs) were isolated, corresponding iPSCs were generated, and iMSCs were differentiated from fMSC-iPSCs, from aMSC-iPSCs, and from human embryonic stem cells (ESCs) H1. In addition, typical MSC characterization such as cell surface marker expression, differentiation capacity, secretome profile, and trancriptome analysis were conducted for the three distinct iMSC preparations-fMSC-iMSCs, aMSC-iMSCs, and ESC-iMSCs. To verify these results, previously published data sets were used, and also, additional aMSCs and iMSCs were analyzed. RESULTS:fMSCs and aMSCs both express the typical MSC cell surface markers and can be differentiated into osteogenic, adipogenic, and chondrogenic lineages in vitro. However, the transcriptome analysis revealed overlapping and distinct gene expression patterns and showed that fMSCs express more genes in common with ESCs than with aMSCs. fMSC-iMSCs, aMSC-iMSCs, and ESC-iMSCs met the criteria set out for MSCs. Dendrogram analyses confirmed that the transcriptomes of all iMSCs clustered together with the parental MSCs and separated from the MSC-iPSCs and ESCs. iMSCs irrespective of donor age and cell type acquired a rejuvenation-associated gene signature, specifically, the expression of INHBE, DNMT3B, POU5F1P1, CDKN1C, and GCNT2 which are also expressed in pluripotent stem cells (iPSCs and ESC) but not in the parental aMSCs. iMSCs expressed more genes in common with fMSCs than with aMSCs. Independent real-time PCR comparing aMSCs, fMSCs, and iMSCs confirmed the differential expression of the rejuvenation (COX7A, EZA2, and TMEM119) and aging (CXADR and IGSF3) signatures. Importantly, in terms of regenerative medicine, iMSCs acquired a secretome (e.g., angiogenin, DKK-1, IL-8, PDGF-AA, osteopontin, SERPINE1, and VEGF) similar to that of fMSCs and aMSCs, thus highlighting their ability to act via paracrine signaling. CONCLUSIONS:iMSCs irrespective of donor age and cell source acquire a rejuvenation gene signature. The iMSC concept could allow circumventing the drawbacks associated with the use of adult MSCs und thus provide a promising tool for use in various clinical settings in the future.

Dataset Information

IPSC-MSCs with High Intrinsic MIRO1 and Sensitivity to TNF-? Yield Efficacious Mitochondrial Transfer to Rescue Anthracycline-Induced Cardiomyopathy.

Publications

iPSC-MSCs with High Intrinsic MIRO1 and Sensitivity to TNF-α Yield Efficacious Mitochondrial Transfer to Rescue Anthracycline-Induced Cardiomyopathy.

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