ArticleStem cell research & therapy2026
hAECs restore follicular development in premature ovarian insufficiency via IGFBP2/IGF1R-mediated intercellular communication.
Article in Stem cell research & therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundPremature ovarian insufficiency (POI) is defined by ovarian dysfunction and consequent decreased fertility. While follicular depletion is an acknowledged factor, dynamic changes in follicular subpopulations and single-cell-level niche remodeling remains largely unexplored. Human amniotic epithelial cells (hAECs) represent a promising regenerative approach for restoring ovarian function; however, the underlying mechanism in promoting follicular development remains unclear.
methodsWe established a chemotherapy-induced POI mouse model and conducted single-nucleus RNA sequencing (snRNA-seq) to systematically characterize ovarian cellular heterogeneity, residual follicular development, and ovarian microenvironmental alteration. A human-derived cell projection model was established to track the distribution of transplanted hAECs. Furthermore, the functional role of IGF1R signaling in granulosa cells was validated using both in vitro culture assays and in vivo interventions.
resultsWe identified eight distinct ovarian cell types and uncovered stage-specific injury patterns: acute chemotherapy exposure induced massive loss of granulosa cells and oocytes, while the chronic phase was characterized by fibrotic accumulation and immune infiltration. Furthermore, residual follicles exhibited aberrant development trajectories and compromised progression, primarily due to disrupted granulosa cells -oocytes communication. Notably, hAEC transplantation significantly enhanced follicle survival, partially attenuated fibrosis and promoted ovarian structural restoration. Mechanistically, hAECs-derived IGFBP2 regulated IGF1R expression in granulosa cells, thereby reactivating the Akt/FoxO3A signaling pathway and downregulating the senescence marker P21.
conclusionsThis study presents a time-resolved snRNA-seq atlas capturing both acute and chronic injury phases in a chemotherapy-induced POI model, combined with a human-mouse projection approach to track transplanted hAECs in damaged ovaries. Our study establishes a novel cell-based therapeutic strategy for partial ovarian functional recovery, in which hAEC-derived IGFBP2 restores granulosa cell function and intercellular communication by regulating the IGF1R/Akt/mTOR signaling axis.
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