Exosomal miR-9-5p derived from iPSC-MSCs ameliorates doxorubicin-induced cardiomyopathy by inhibiting cardiomyocyte senescence

Abstract

Doxorubicin (DOX) is a chemotherapeutic agent widely used for tumor treatment. Nonetheless its clinical application is heavily limited by its cardiotoxicity. There is accumulated evidence that transplantation of mesenchymal stem cell-derived exosomes (MSC-EXOs) can protect against Dox-induced cardiomyopathy (DIC). This study aimed to examine the cardioprotective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) against DIC and explore the potential mechanisms. EXOs were isolated from the cultural supernatant of human BM-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) by ultracentrifugation. A mouse model of DIC was induced by intraperitoneal injection of Dox followed by tail vein injection of PBS, BM-MSC-EXOs, or iPSC-MSC-EXOs. Cardiac function, cardiomyocyte senescence and mitochondrial dynamics in each group were assessed. In vitro, neonatal mouse cardiomyocytes (NMCMs) were subjected to Dox and treated with BM-MSC-EXOs or iPSC-MSC-EXOs. The mitochondrial morphology and cellular senescence of NMCMs were examined by Mitotracker staining and senescence-associated-β-galactosidase assay, respectively. Compared with BM-MSC-EXOs, mice treated with iPSC-MSC-EXOs displayed improved cardiac function and decreased cardiomyocyte mitochondrial fragmentation and senescence. In vitro, iPSC-MSC-EXOs were superior to BM-MSC-EXOs in attenuation of cardiomyocyte mitochondrial fragmentation and senescence caused by DOX. MicroRNA sequencing revealed a higher level of miR-9-5p in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, iPSC-MSC-EXOs transported miR-9-5p into DOX-treated cardiomyocytes, thereby suppressing cardiomyocyte mitochondrial fragmentation and senescence via regulation of the VPO1/ERK signal pathway. These protective effects and cardioprotection against DIC were largely reversed by knockdown of miR-9-5p in iPSC-MSC-EXOs. Our results showed that miR-9-5p transferred by iPSC-MSC-EXOs protected against DIC by alleviating cardiomyocyte senescence via inhibition of the VPO1/ERK pathway. This study offers new insight into the application of iPSC-MSC-EXOs as a novel therapeutic strategy for DIC treatment. Graphical Abstract

Emerging Strategies in Mesenchymal Stem Cell-Based Cardiovascular Therapeutics

“…Recent studies have highlighted the specific role of miRNAs in modulating the functions and therapeutic potential of MSCs. Zheng et al [78] found that exosomal miR-9-5p from iPSC-derived MSCs mitigates doxorubicin-induced cardiomyopathy by preventing cardiomyocyte senescence, primarily through the inhibition of the VPO1/ERK signaling pathway. Human umbilical cord-derived MSCs alleviated myocardial fibrosis and restored miRNA-133a expression in diabetic cardiomyopathy, which positively influenced fibrosis markers and inflammatory mediators in a diabetic mouse model [79].…”

Emerging Landscape of Mesenchymal Stem Cell Senescence Mechanisms and Implications on Therapeutic Strategies

“…Induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) offer a promising solution. − They provide an unlimited, reliable source for generating MSCs (referred to as iMSCs) from well-characterized, homogeneous cell lines − (see Figure ). These iMSCs can be cultured indefinitely without experiencing replicative senescence, and they exhibit well-defined functions and phenotypes, alleviating many of the technical and biological limitations associated with traditional MSCs.…”