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

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.

SUBMITTER: Park M

PROVIDER: S-EPMC7403347 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Park Mira M Hong Seok-Ho SH Park So Hee SH Kim Yeon Sun YS Yang Seung Chel SC Kim Hye-Ryun HR Noh Songmi S Na Sunghun S Lee Hyung Keun HK Lim Hyunjung J HJ Lyu Sang Woo SW Song Haengseok H

Molecular therapy : the journal of the American Society of Gene Therapy 20200520 8

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. H ...[more]

PMID: 32534604

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Project description:BackgroundThe human endometrium in premenopausal women is an active site of physiological angiogenesis, with regenerative cells present, suggesting that the endometrium contains adult angiogenic stem cells. In the context of cardiac repair after ischemic injury, angiogenesis is a crucial process to rescue cardiomyocytes. We therefore investigated whether human endometrium-derived stem cells (hEMSCs) can be used for cardiac repair after ischemic injury and their possible underlying mechanisms.MethodsComparisons were made between hEMSCs successfully isolated from 22 premenopausal women and human bone marrow mesenchymal stem cells (hBMSCs) derived from 25 age-matched patients. Cell proliferation, migration, differentiation, and angiogenesis were evaluated through in vitro experiments, while the ability of hEMSCs to restore cardiac function was examined by in vivo cell transplantation into the infarcted nude rat hearts.ResultsIn vitro data showed that hEMSCs had greater proliferative and migratory capacities, whereas hBMSCs had better adipogenic differentiation ability. Human umbilical cord vein endothelial cells, treated with conditioned medium from hEMSCs, had significantly higher tube formation than that from hBMSCs or control medium, indicating greater angiogenic potentials for hEMSCs. In vivo, hEMSC transplantation preserved cardiac function, decreased infarct size, and improved tissue repair post-injury. Cardiac metabolism, assessed by 18F-FDG uptake, showed that 18F-FDG uptake at the infarction area was significantly higher in both hBMSC and hEMSC groups, compared to the PBS control group, with hEMSCs having the highest uptake, suggesting hEMSC treatment improves cardiomyocyte metabolism and survival after injury. Mechanistic assessment of the angiogenic potential for hEMSCS revealed that angiogenesis-related factors angiopoietin 2, Fms-like tyrosine kinase 1, and FGF9 were significantly upregulated in hEMSC-implanted infarcted hearts, compared to the PBS control group.ConclusionhEMSCs, compared to hBMSCs, have greater capacity to induce angiogenesis, and improved cardiac function after ischemic injury.

Project description:BackgroundDisruptions of angiogenesis can have a significant effect on the healing of uterine scars. Human endometrial perivascular cells (CD146+PDGFRβ+) function as stem cells in the endometrium. Cysteine-rich angiogenic inducer 61 (CYR61) plays an important role in vascular development. The purpose of this study was to observe the effects of the transplantation of human endometrial perivascular cells (En-PSCs) overexpressing CYR61 on structural and functional regeneration in rat models of partial full-thickness uterine excision.MethodsWe first sorted human En-PSCs from endometrial single-cell suspensions by flow cytometry. Human En-PSCs expressing low or high levels of CYR61 were then generated via transfection with a CYR61-specific small interfering ribonucleic acid (si-CYR61) construct or overexpression plasmid. To establish a rat model of uterine injury, a subset of uterine wall was then resected from each uterine horn in experimental animals. Female rats were randomly assigned to five groups, including a sham-operated group and four repair groups that received either PBS loaded on a collagen scaffold (collagen/PBS), En-PSCs loaded on a collagen scaffold (collagen/En-PSCs), En-PSCs with low CYR61 expression loaded on a collagen scaffold (collagen/si-CYR61 En-PSCs), and En-PSCs overexpressing CYR61 loaded on a collagen scaffold (collagen/ov-CYR61 En-PSCs). These indicated constructs were sutured in the injured uterine area to replace the excised segment. On days 30 and 90 after transplantation, a subset of rats in each group was sacrificed, and uterine tissue was recovered and serially sectioned. Hematoxylin and eosin staining and immunohistochemical staining were then performed. Finally, the remaining rats of each group were mated with fertile male rats on day 90 for a 2-week period.ResultsSorted En-PSCs expressed all recognized markers of mesenchymal stem cells (MSCs), including CD10, CD13, CD44, CD73, CD90, and CD105, and exhibited differentiation potential toward adipocytes, osteoblasts, and neuron-like cells. Compared with En-PSCs and En-PSCs with low CYR61 expression, En-PSCs with elevated CYR61 expression enhanced angiogenesis by in vitro co-culture assays. At day 90 after transplantation, blood vessel density in the collagen/ov-CYR61 En-PSCs group (11.667 ± 1.287) was greater than that in the collagen/En-PSCs group (7.167 ± 0.672) (P < 0.05) and the collagen/si-CYR61 En-PSCs group (3.750 ± 0.906) (P < 0.0001). Pregnancy rates differed among groups, from 40% in the collagen/PBS group to 80% in the collagen/En-PSCs group, 12.5% in the collagen/si-CYR61 En-PSCs group, and 80% in the collagen/ov-CYR61 En-PSCs group. In addition, four embryos were evident in the injured uterine horns of the collagen/ov-CYR61 En-PSCs group, while no embryos were identified in the injured uterine horns of the collagen/PBS group.ConclusionsThe results showed that CYR61 plays an important role in angiogenesis. Collagen/ov-CYR61 En-PSCs promoted endometrial and myometrial regeneration and induced neovascular regeneration in injured rat uteri. The pregnancy rate of rats treated with transplantation of collagen/En-PSCs or collagen/ov-CYR61 En-PSCs was improved. Moreover, the number of embryos implantation on the injured area in uterus was increased after transplantation of collagen/ov-CYR61 En-PSCs.

Dataset Information

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

Publications

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

Similar Datasets

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