Mesenchymal Stem Cell-Derived Exosomes Laden Scaffold for Promoting Endometrium Regeneration and Fertility Restoration Through Macrophage Immunomodulation

Endometrial traumas caused by recurrent curettage, caesarean section and myomectomy always result in intrauterine adhesions (IUAs) and infertility. Umbilical cord-derived mesenchymal stem cell (MSC)-based therapies have shown some promise achievements in the treatment of IUAs for their easy collection, high proliferation and low immunogenicity. However, the potential tumorigenicity, low infusion and low retention of MSCs are still controversial and the clinical application of MSCs is limited. In contrast, MSC-derived exosomes exhibit a similar function to their source cells and are expected to overcome these limitations. Therefore, a novel and viable cell-free therapeutic strategy by MSC-derived exosomes was proposed in this study. Here, we designed a construct of exosomes and a collagen scaffold (CS/Exos) for endometrium regeneration, and investigated the regeneration mechanism through macrophage immunomodulation. The CS/Exos transplantation potently induced (i) endometrium regeneration, (ii) collagen remodeling, (iii) increased the expression of the estrogen receptor-alpha /progesterone receptor, and (iv) restored fertility. Mechanistically, CS/Exos facilitated CD163+ M2 macrophage polarization, reduced inflammation, and increased anti-inflammatory responses in vivo and in vitro. By RNA-seq, miRNAs enriched in exosomes were the main mediator for exosomes-induced macrophage polarization. Overall, we demonstrated that CS/Exos treatment facilitated endometrium regeneration and fertility restoration by immunomodulatory functions of miRNAs. Our research highlights the therapeutic prospects of CS/Exos for the management of IUAs.