Perivascular Stem Cell-Derived Cyclophilin A Improves Uterine Environment with Asherman’s Syndrome via HIF1α-Dependent Angiogenesis

作者：Mira Park, Seok‐Ho Hong, Sohee Park, Yeon Sun Kim, Seung Chel Yang, Hye Ryun Kim, Songmi Noh, Sunghun Na, Hyung Keun Lee, Hyunjung Jade Lim, Sang Woo Lyu, Haengseok Song · 发表于：Molecular Therapy · 年份：2020 · DOI：10.1016/j.ymthe.2020.05.015 · 被引用次数：31 · 研究领域：Gynecological conditions and treatments、Reproductive System and Pregnancy、Uterine Myomas and Treatments

Asherman's syndrome (AS) is characterized by intrauterine adhesions or fibrosis resulting from scarring inside the endometrium. AS is associated with infertility, recurrent miscarriage, and placental abnormalities. Although mesenchymal stem cells show therapeutic promise for the treatment of AS, the molecular mechanisms underlying its pathophysiology remain unclear. We ascertained that mice with AS, like human patients with AS, suffer from extensive fibrosis, oligo/amenorrhea, and infertility. Human perivascular stem cells (hPVSCs) from umbilical cords repaired uterine damage in mice with AS, regardless of their delivery routes. In mice with AS, embryo implantation is aberrantly deferred, which leads to intrauterine growth restriction followed by no delivery at term. hPVSC administration significantly improved implantation defects and subsequent poor pregnancy outcomes via hypoxia inducible factor 1α (HIF1α)-dependent angiogenesis in a dose-dependent manner. Pharmacologic inhibition of HIF1α activity hindered hPVSC actions on pregnancy outcomes, whereas stabilization of HIF1α activity facilitated such actions. Furthermore, therapeutic effects of hPVSCs were not observed in uterine-specific HIF1α-knockout mice with AS. Secretome analyses of hPVSCs identified cyclophilin-A as the major paracrine factor for hPVSC therapy via HIF1α-dependent angiogenesis. Collectively, we demonstrate that hPVSCs-derived cyclophilin-A facilitates HIF1α-dependent angiogenesis to ameliorate compromi...