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MSC-derived Exosomal miRNA as a Novel Therapy for Fertility-impacting Condition?

Review of “Exosomal miRNA ‐17‐5p derived from human umbilical cord mesenchymal stem cells improves ovarian function in premature ovarian insufficiency by regulating SIRT7” from STEM CELLS by Stuart P. Atkinson

As hormone replacement therapy for premature ovarian insufficiency (POI), a fertility-impacting condition that affects around 1% of women worldwide by the age of 40 [1], can increase the risk of cancer and post‐treatment recurrence [2], alternative treatment approaches are much sought after. Recent studies from the laboratories of Boxian Huang and Hong Li (Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China) have added to the growing body of research that supports the therapeutic application of mesenchymal stem cells (MSCs) in POI patients [3, 4]. In particular, the authors highlighted a mediating role for extracellular vesicles (EVs) known as exosomes, which carry a cargo composed of proteins, DNA, and RNA species such as microRNA (miRNA). 

Now, in their new STEM CELLS article [5], Ding et al. suggest a critical role for exosomal miR‐17‐5P and its downstream target mRNA (NAD-dependent deacetylase sirtuin 7 - SIRT7) in the amelioration of symptoms in an in vitro model of POI following the transplantation of human umbilical cord-derived MSCs.

The mouse model of POI employed in this new study comprised the damage of human granulosa cells, which support the developing oocyte, by cyclophosphamide treatment before their transplantation into the mouse ovaries. In vitro analysis first demonstrated that MSC‐derived exosomes improved the proliferation and suppressed the apoptosis of cyclophosphamide‐damaged human granulosa cells in a dose‐dependent manner. Additionally, MSC‐derived exosomes also inhibited the expression of SIRT7 and its candidate downstream target genes (γH2AX, PARP1, and XRCC6). Subsequent in vivo analysis in the POI mouse model revealed that the injection of MSC‐derived exosomes also enhanced cell proliferation and inhibited apoptosis, SIRT7 expression, and reactive oxygen species levels, thereby confirming the overall efficacy of MSC‐derived exosomes in POI.

The study then employed small RNA sequencing to evaluate the miRNA content of MSC‐derived exosomes; this highlighted the overexpression of miR‐17‐5P, a critical regulator of the G1/S phase cell cycle transition [6] and a suppressor of ovarian cancer cell apoptosis [7]. Interestingly, computational prediction analysis suggested that miR‐17‐5P can bind to the 3′ untranslated region of SIRT7 mRNA to inhibit SIRT7 expression, and this prompted the authors to evaluate the therapeutic effect of MSC-derived exosomes lacking miR‐17‐5P. Fascinatingly, the loss of this miRNA significantly reduced any therapeutic effect from MSC-derived exosome treatment and prompted an increase in both SIRT7 and reactive oxygen species levels following injection into the ovaries of the POI model mice.

While this exciting new study demonstrates just how MSC-derived exosome treatment can reduce the symptoms of POI in a mouse model, it also underscores the enormous potential of miRNA‐based therapies.

For more on MSCs, exosomes, microRNA, and more, stay tuned to the Stem Cells Portal!

References

  1. Jiao X, Ke H, Qin Y, et al., Molecular Genetics of Premature Ovarian Insufficiency. Trends in Endocrinology & Metabolism 2018;29:795-807.
  2. van Kasteren YM and Schoemaker J, Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Human Reproduction Update 1999;5:483-492.
  3. Ding C, Zou Q, Wang F, et al., Human amniotic mesenchymal stem cells improve ovarian function in natural aging through secreting hepatocyte growth factor and epidermal growth factor. Stem Cell Research & Therapy 2018;9:55.
  4. Huang B, Lu J, Ding C, et al., Exosomes derived from human adipose mesenchymal stem cells improve ovary function of premature ovarian insufficiency by targeting SMAD. Stem Cell Research & Therapy 2018;9:216.
  5. Ding C, Zhu L, Shen H, et al., Exosomal miRNA-17-5p derived from human umbilical cord mesenchymal stem cells improves ovarian function in premature ovarian insufficiency by regulating SIRT7. STEM CELLS 2020;38:1137-1148.
  6. Cloonan N, Brown MK, Steptoe AL, et al., The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition. Genome Biology 2008;9:R127.
  7. Fang Y, Xu C, and Fu Y, MicroRNA-17-5p induces drug resistance and invasion of ovarian carcinoma cells by targeting PTEN signaling. Journal of Biological Research-Thessaloniki 2015;22:12.