Endometrial injury (EI) is a primary cause of refractory infertility characterized by defective glandular regeneration and impaired receptivity, for which effective regenerative therapies remain limited. Here, we identify the depletion of stromal-derived RSPO1 as a conserved molecular defect driving the loss of glandular stemness in both murine models and patient samples. We further demonstrate that this regeneration failure is rooted in the disruption of the spatial organization within the peri-glandular niche. Mechanistically, injured glandular epithelia act as spatial regulators by activating a paracrine IL10-IL10R-CD26 signaling cascade that enzymatically shapes a localized CXCL12 gradient. This chemokine-guided mechanism governs the selective recruitment of CXCR4⁺ mesenchymal stromal cells (MSCs) to peri-glandular domains. Crucially, we reveal that MSC-mediated repair operates via a spatially restricted mechanism of action, where therapeutic efficacy hinges on precise niche targeting. Upon niche localization, MSC-delivered RSPO1 reconstitutes WNT-driven glandular regeneration and implantation competence. Leveraging this endogenous spatial guidance, we engineered CXCR4/RSPO1 dual-enhanced MSCs to overcome delivery constraints, significantly improving homing efficiency and functional recovery in refractory EI models. Validation in patient-derived biopsies and organoids confirms the translational relevance of the IL10-CXCL12-RSPO1 regenerative axis. Collectively, these findings establish spatially targeted cell delivery as a precision pharmacotherapy, providing a mechanistic foundation for treating refractory infertility. • Stromal RSPO1 depletion drives regenerative failure in endometrial injury. • IL10-CXCL12 signaling guides the spatial recruitment of MSCs to injured niches. • CXCR4/RSPO1-engineered MSCs enhance niche-directed repair and restore fertility.
Liu et al. (Fri,) studied this question.