Spatial and temporal single cell multi-omics in mice reveals macrophage-SFRP4+ stroma interactions promoting endometrial regeneration via TNF-α.

Repair and regeneration disorder after endometrial injury is the core cause of endometrial diseases. Using a mouse full-thickness endometrial injury model and human endometrial datasets, we performed time-series single-cell and spatial omics to explore the cellular and molecular dynamics of mouse endometrial regeneration. In the early inflammatory stage (0-4 dpi), macrophages rapidly infiltrate and are indispensable for regeneration. During the middle regenerative stage (4-14 dpi), SFRP4+ stromal cells expand and undergo developmental reprogramming, a conserved mechanism in human normal endometrium but reduced in regenerative defect diseases. Macrophages promote this reprogramming via tumor necrosis factor-alpha (TNF-α), and TNF-α-induced SFRP4+ stromal cells effectively enhance regeneration after transplantation. This study provides a valuable multi-omics resource for understanding endometrial regeneration, with the understanding that further validation is required for clinical applicability.