Abstract

Niche, also known as cesarean scar defect, is a long-term complication of cesarean sections (CS), and its pathogenesis remains incompletely understood. Here, we profile 135,793 individual cells from adjacent myometrium tissue of niche (Adjacent, n  = 48,587), well-healed cesarean scar tissue (Control, n  = 47,653), and niche tissue (Niche, n  = 39,553) using single-cell RNA sequencing. We identify a deficiency in LRP1 within a specific subgroup of fibroblasts in niche tissue, which correlate with a reduced ability to synthesize extracellular matrix (ECM). Through in vitro experiments, we demonstrate that LRP1 deficiency inhibited CTGF from effectively activating both the ERK and WNT signaling pathways in fibroblasts, thereby impairing their function. Tissue staining (30 non-healing vs 30 healing groups) validates our findings, showing decreased expression of LRP1 in non-healing groups. In a rat uterine scar model, treatment with recombinant human CTGF (rhCTGF) promoted myometrial regeneration and enhanced collagen production in uterine fibroblasts. Our analysis provides deep insights into the defective healing microenvironment of CS incisions and identifies critical cell types and signaling pathways involved in the formation of the niche. These results may inform novel prognostic approaches for predicting and treating niches. Niche, also known as cesarean scar defect, is a long-term complication of cesarean sections (CS). Here the authors use single-cell RNA sequencing of niche, adjacent myometrium and well-healed cesarean scar tissue controls together with in vitro and vivo models to identify the connective tissue growth factor (CTGF)–low density lipoprotein receptor-related protein 1 (LRP1) axis as a regulator of CS niche healing.