Asherman’s syndrome (AS) is caused by intrauterine adhesions and inactive endometrium from repeated curettage of the uterine endometrium. AS is a major cause of recurrent implantation failure and miscarriage and is very difficult to treat because of the poor recovery of endometrial basal cells. Platelet-rich plasma (PRP) has abundant growth factors that may induce angiogenesis and cell proliferation. Here, we demonstrate that human PRP (hPRP) significantly enhances angiogenesis to restore embryo implantation, leading to successful pregnancy in mice with AS. In mice with AS, hPRP treatment considerably reduced the expression of fibrosis markers and alleviated oligo/amenorrhea phenotypes. Mice with AS did not produce any pups, but the hPRP therapy restored their infertility. AS-induced abnormalities, such as aberrantly delayed embryo implantation and intrauterine growth retardation, were considerably eliminated by hPRP. Furthermore, hPRP significantly promoted not only the elevation of various angiogenic factors, but also the migration of endometrial stromal cells. It also increased the phosphorylation of STAT3, a critical mediator of wound healing, and the expression of tissue remodeling genes in a fibrotic uterus. PRP could be a promising therapeutic strategy to promote angiogenesis and reduce fibrosis in impaired uterine environments, leading to successful embryo implantation for better clinical outcomes in patients with AS.

Progesterone (P4) is required for the preparation of the endometrium for a successful pregnancy. P4 resistance is a leading cause of the pathogenesis of endometrial disorders like endometriosis, often leading to infertility; however, the underlying epigenetic cause remains unclear. Here we demonstrate that CFP1, a regulator of H3K4me3, is required for maintaining epigenetic landscapes of P4-progesterone receptor (PGR) signaling networks in the mouse uterus. Cfp1f/f;Pgr-Cre (Cfp1d/d) mice showed impaired P4 responses, leading to complete failure of embryo implantation. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 regulates uterine mRNA profiles not only in H3K4me3-dependent but also in H3K4me3-independent manners. CFP1 directly regulates important P4 response genes, including Gata2, Sox17, and Ihh, which activate smoothened signaling pathway in the uterus. In a mouse model of endometriosis, Cfp1d/d ectopic lesions showed P4 resistance, which was rescued by a smoothened agonist. In human endometriosis, CFP1 was significantly downregulated, and expression levels between CFP1 and these P4 targets are positively related regardless of PGR levels. In brief, our study provides that CFP1 intervenes in the P4-epigenome-transcriptome networks for uterine receptivity for embryo implantation and the pathogenesis of endometriosis.