Journal
MOLECULAR THERAPY-NUCLEIC ACIDS
Volume 21, Issue -, Pages 37-50Publisher
CELL PRESS
DOI: 10.1016/j.omtn.2020.05.013
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Funding
- National Natural Science Foundation of China [81801515, 81801494]
- Suzhou Introduce Expert Team of Clinical Medicine [SZYJTD201708, SZYJTD201707]
- Suzhou Talent Training Program [GSWS2019005]
- Suzhou Science and Technology for People's Livelihood [SYS2018081]
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Human amniotic mesenchymal stem cells (hAMSCs) were previously shown to effectively rescue ovarian function in a premature ovarian insufficiency (POI) mouse model. The therapeutic mechanism of hAMSC-derived exosomes (hAMSC-Exos) is not fully understood. In this study, the therapeutic mechanism involved in exosomal microRNA-320a (miR-320a) and Sirtuin 4 (SIRT4) was investigated in POI mouse ovaries oocytes and human granulosa cells (hGCs) by fluorescence-activated cell sorting (FACS), hematoxylin and eosin (H&E) staining, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence experiments. hAMSC-Exos improved proliferation, inhibited apoptosis, and decreased the expression of SIRT4 and relative genes in POI hGCs and ovaries. hAMSC-Exos elevated ovarian function and prohibited SIRT4 expression in oogenesis. The therapeutic effects were attenuated when miR-320a was knocked down. hAMSC-Exos decreased the ROS levels in POI hGCs and oocytes and improved ovarian weight and litter size, except for the Exos(anti-miR-320a)/POI group. Finally, hAMSC-Exos reduced the SIRT4 and ROS levels in POI ovaries and hGCs. The downstream protein expression (ANT2, AMP-dependent kinase [AMPK], and L-OPA1) was downregulated in the hGCs-SIRT4(KD) group but disappeared in the Exos(anti-miR-320a)/POI group. Our study is the first to illustrate the therapeutic potential of hAMSC-Exos in POI. Exosomal miR-320 plays a key role in the hAMSC-Exos-mediated effects on ovarian function via SIRT4 signaling.
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