GDF11 enhances therapeutic efficacy of mesenchymal stem cells for myocardial infarction via YME1L-mediated OPA1 processing
Open Access
- 1 October 2020
- journal article
- research article
- Published by Oxford University Press (OUP) in Stem Cells Translational Medicine
- Vol. 9 (10), 1257-1271
- https://doi.org/10.1002/sctm.20-0005
Abstract
Growth differentiation factor 11 (GDF11) has been shown to promote stem cell activity, but little is known about the effect of GDF11 on viability and therapeutic efficacy of cardiac mesenchymal stem cells (MSCs) for cardiac injury. To understand the roles of GDF11 in MSCs, mouse heart-derived MSCs were transduced with lentiviral vector carrying genes for both GDF11 and green fluorescent protein (GFP) (MSCsLV-GDF11) or cultured with recombinant GDF11 (MSCsrGDF11). Either MSCsrGDF11 or MSCs (LV-GDF11) displayed less cell apoptosis and better paracrine function, as well as preserved mitochondrial morphology and function under hypoxic condition as compared with control MSCs. GDF11 enhanced phosphorylation of Smad2/3, which upregulated expression of YME1L, a mitochondria protease that balances OPA1 processing. Inhibitors of TGF-beta receptor (SB431542) or Smad2/3 (SIS3) attenuated the effects of GDF11 on cell viability, mitochondrial function, and expression of YME1L. Transplantation of MSCsGDF11 into infarct heart resulted in improved cell survival and retention, leading to more angiogenesis, smaller scar size, and better cardiac function in comparison with control MSCs. GDF11 enhanced viability and therapeutic efficiency of MSCs by promoting mitochondrial fusion through TGF-beta receptor/Smad2/3/YME1L-OPA1 signaling pathway. This novel role of GDF11 may be used for a new approach of stem cell therapy for myocardial infarction.Funding Information
- youth program of national natural science foundation of china (81902002)
- National Natural Science Foundation of China (81970227, 81670257, 81528002, 81570251)
- National Natural Science Foundation of China (81970227, 81670257, 81528002, 81570251)
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