hUCMSCs restore ovarian function via angiopoietin 1/2 rebalance in POI rats.

BACKGROUND: Premature ovarian insufficiency (POI) is often iatrogenic and the therapeutic potential of human umbilical cord derived mesenchymal stem cells (hUCMSCs) remain incompletely defined. This study aimed to evaluate the effects and underlying mechanism of hUCMSCs on ovarian function in a rat model of POI. METHODS: hUCMSCs were characterized by morphology, flow cytometry, and multi-lineage differentiation assays. POI was induced in rats using cyclophosphamide (CTX), followed by intravenous administration of hUCMSCs. Therapeutic outcomes were assessed through cell homing analysis, ovarian histopathology, and serum hormone measurements. Bioinformatic analysis identified Angiopoietin 1 (Angpt1) as a key angiogenic regulator, which was validated by western blot and qRT-PCR. Rat ovarian microvascular endothelial cells (ROMECs) were isolated and functionally assessed under CTX and hUCMSCs treatment using wound healing, tube formation, and evaluation of the Angpt1 and Angpt2 balance. RESULTS: In vivo, hUCMSCs preferentially homed to the ovarian theca layer and restored ovarian function. The Angpt1/Angpt2 ratio was markedly reduced in POI rats but significantly increased after hUCMSCs treatment, and the ratio positively correlated with CD31 expression. In vitro, CTX impaired ROMECs migration and angiogenic capacity, whereas coculture with hUCMSCs rescued these functions and restored the Angpt1/Angpt2 ratio. CONCLUSION: hUCMSCs ameliorate ovarian dysfunction in POI by modulating the Angpt1/Angpt2 axis, thereby enhancing vascular homeostasis and angiogenesis within the ovarian microenvironment. These findings provided mechanistic insights supporting the clinical translation of hUCMSCs-based therapies for POI. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13048-025-01856-3.