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

Authors
 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 
Citation
 MOLECULAR THERAPY, Vol.28(8) : 1818-1832, 2020-08 
Journal Title
MOLECULAR THERAPY
ISSN
 1525-0016 
Issue Date
2020-08
Keywords
Asherman's syndrome ; MSCs ; MSCs-derived secretome(s) ; angiogenesis ; cyclophilin A ; endometrium ; tissue regeneration
Abstract
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.
Full Text
https://www.sciencedirect.com/science/article/pii/S1525001620302495
DOI
10.1016/j.ymthe.2020.05.015
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Hyung Keun(이형근) ORCID logo https://orcid.org/0000-0002-1123-2136
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/184963
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