Decidualization-empowered ECM hydrogel integrating sustained Tβ4 release drives endometrial regeneration in intrauterine adhesions

TL;DR

A new hydrogel that mimics the body's natural healing process helps regenerate the uterine lining and restore fertility in a mouse model of intrauterine adhesions.

Contribution

A decidualization-empowered hydrogel combining DEndo-UdECM and sustained Tβ4 release is introduced for endometrial regeneration.

Findings

The hydrogel restores endometrial architecture and resolves fibrosis in a murine IUA model.

It leads to near-complete recovery of fertility after a single administration.

The hydrogel reprograms macrophages and inhibits fibrotic pathways.

Abstract

Intrauterine adhesions (IUA), a leading cause of female infertility, result from a pathological switch in the uterine injury response from regeneration to fibrotic scarring. Current treatments are often inadequate as they fail to address this fundamental shift. Here, we report a “decidualization-empowered” hydrogel that reverses this pathology by synergistically combining a bioactive extracellular matrix from decidualized endometrium (DEndo-UdECM) with the sustained release of the anti-fibrotic peptide Thymosin β4 (Tβ4). In a murine IUA model, a single administration of the hydrogel restores endometrial architecture, resolves fibrosis, and, most critically, leads to a near-complete recovery of fertility. Mechanistically, the hydrogel orchestrates a pro-regenerative niche by reprogramming macrophages to an M2 phenotype while dually inhibiting pyroptosis-driven inflammation and the canonical TGF-β/Smad3 fibrotic cascade. Together, these findings demonstrate that mimicking the biological intelligence of a physiological niche can resolve complex fibrotic diseases and restore organ function.

Intrauterine adhesions (IUA) are a leading cause of female infertility. Here, authors engineer a Tβ4-releasing ECM hydrogel that mimics decidualization to promote endometrial regeneration as a therapeutic strategy for treatment of IUA.

Figures