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

 Mira Park  ;  Seok-Ho Hong  ;  So Hee Park  ;  Yeon Sun Kim  ;  Seung Chel Yang  ;  Hye-Ryun Kim  ;  Songmi Noh  ;  Sunghun Na  ;  Hyung Keun Lee  ;  Hyunjung J Lim  ;  Sang Woo Lyu  ;  Haengseok Song 
 MOLECULAR THERAPY, Vol.28(8) : 1818-1832, 2020-08 
Journal Title
Issue Date
Asherman's syndrome ; MSCs ; MSCs-derived secretome(s) ; angiogenesis ; cyclophilin A ; endometrium ; tissue regeneration
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 compromised uterine environments in mice with AS, representing the major pathophysiologic features of humans with AS.
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1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
Yonsei Authors
Park, Min Soo(박민수) ORCID logo https://orcid.org/0000-0002-4395-9938
Park, Joon Sik(박준식) ORCID logo https://orcid.org/0000-0002-4902-4770
Baek, Seung Hwan(백승환)
Shin, Jeong Eun(신정은) ORCID logo https://orcid.org/0000-0002-4376-8541
Oh, Ji Young(오지영) ORCID logo https://orcid.org/0000-0003-3552-8465
Yu, Rita(유리타미영)
Eun, Ho Seon(은호선) ORCID logo https://orcid.org/0000-0001-7212-0341
Lee, Hyung Keun(이형근) ORCID logo https://orcid.org/0000-0002-1123-2136
Han, Jung Ho(한정호) ORCID logo https://orcid.org/0000-0001-6661-8127
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