HucMSC-mediated stromal metabolic reprogramming in reactivating aged ovaries: a single-cell transcriptomic...

Area of Science:

• Reproductive biology
• Stem cell therapy
• Aging research

Background:

• Ovarian aging leads to decreased function and oocyte quality, contributing to female infertility.
• Mechanisms of human umbilical cord-derived mesenchymal stem cell (HucMSC)-mediated ovarian rejuvenation are not fully understood.

Purpose of the Study:

• To investigate how HucMSCs restore ovarian function and oocyte quality in aged mice.
• To elucidate the molecular pathways involved in HucMSC-induced ovarian rejuvenation.

Main Methods:

• Aged mice received HucMSC ovarian injections.
• Ovarian function and fertility were assessed.
• Low-input RNA-seq and single-cell RNA sequencing (scRNA-seq) analyzed transcriptomic changes in oocytes and somatic cells.
• HucMSC-primed stromal cells were transplanted to assess their functional roles.

Main Results:

• HucMSC treatment improved follicular development, increased antral follicle numbers, and partially restored fertility.
• Oocyte transcriptomes shifted towards youthful patterns, with improved mitochondrial function.
• Granulosa cells showed increased transcription and glycolysis; stromal cells were redirected from fibrosis to steroidogenesis and folliculogenesis.
• Transplantation of HucMSC-primed stromal cells replicated these benefits, mediated by enhanced pregnenolone synthesis.

Conclusions:

• HucMSCs reactivate aged ovaries through metabolic reprogramming of oocytes and somatic cells.
• Enhanced mitochondrial function in oocytes and stromal cell redirection to steroidogenic/folliculogenic pathways are key mechanisms.
• Stromal cell functional modulation is critical for counteracting ovarian aging and represents a therapeutic target.