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Pathophysiology of androgen-associated endothelial cell dysfunction in phenotype A polycystic ovarian syndrome revealed by iPSCs modeling

ABSTRACT: Abundant evidence suggests that women with polycystic ovary syndrome (PCOS) have increased metabolic aberrations and cardiovascular risks and present with signs of endothelial cell (EC) dysfunction. However, whether and how androgen is involved in the pathogenesis of EC dysfunction in PCOS remains unclear. Induced pluripotent stem cells (iPSCs) were established in two PCOS patients and two control participants and further differentiated into ECs via monoculture under chemically defined conditions. Both PCOS patients were phenotype A (present with oligomenorrhea, hyperandrogenism, and polycystic ovarian morphology) and were diagnosed with metabolic syndrome. Single-cell transcriptomic analysis of the iPSC-derived ECs revealed functional differences involving the cell cycle process, vascular endothelial growth factor (VEGF) signaling and apoptosis between the PCOS and control groups. Decreased expression of cell proliferation and cell cycle related genes were noted in the PCOS iPSC-derived ECs. Dihydrotestosterone (DHT) treatment significantly enhanced cell proliferation and angiogenic function in the control iPSC-derived ECs. In contrast, significantly deteriorated cell proliferation accompanied with diminished expression of androgen receptor/cyclin-dependent kinase 1/VEGF signaling pathway was shown in the PCOS iPSC-derived ECs after DHT treatment, alongside with impaired angiogenesis demonstrated by the tube formation and wound healing assay. In conclusion, disease-specific iPSCs were successfully established in phenotype A PCOS patients with metabolic syndrome and served as an effective platform for disease modeling in this specific subgroup. Both intrinsic and androgen-induced cellular proliferation and angiogenesis were significantly impaired in the PCOS iPSC-derived ECs, providing new pathogenic evidence for androgen-mediated EC dysfunction and possibly further cardiovascular consequences.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246456 | GEO | 2023/11/01

REPOSITORIES: GEO

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Project description:Background:Port wine birthmark (PWB) is a congenital vascular malformation resulting from developmentally defective endothelial cells (ECs). Developing clinically relevant disease models for PWB studies is currently an unmet need. Objective: Our study aims to generate PWB-derived induced pluripotent stem cells (iPSCs) and iPSC-derived ECs that preserve disease-related phenotypes. Methods: PWB iPSCs were generated by reprogramming lesional dermal fibroblasts and differentiated into ECs. RNA-seq was performed to identify differentially expressed genes (DEGs) and enriched pathways. The functional phenotypes of iPSC-derived ECs were characterized by capillary-like structure (CLS) formation in vitro and Geltrex plug-in assay in vivo. Results: Human PWB and control iPSC lines were generated through reprogramming of dermal fibroblasts by introducing the “Yamanaka factors” (Oct3/4, Sox2, Klf4, c-Myc) into them; the iPSCs were successfully differentiated into ECs. These iPSCs and their derived ECs were validated by expression of a series of stem cell and EC biomarkers, respectively. PWB iPSC-derived ECs showed impaired CLS in vitro with larger perimeters and thicker branches as compared to control iPSC-derived ECs. In the plug-in assay, perfused human vasculature formed by PWB iPSC-derived ECs showed bigger perimeters and greater densities than those formed by control iPSC-derived ECs in severe combined immune deficient (SCID) mice. The transcriptome analysis showed that dysregulated pathways of stem cell differentiation, Hippo, Wnt, and focal adhesion persisted through differentiation of PWB iPSCs to ECs. Functional enrichment analysis showed that Hippo and Wnt pathway-related PWB DEGs are enriched for vasculature development, tube morphology, endothelium development, and EC differentiation. Further, members of the zinc finger (ZNF) gene family were overrepresented among the DEGs in PWB iPSCs. ZNF DEGs confer significant functions in transcriptional regulation, chromatin remodeling, protein ubiquitination, and retinoic acid receptor signaling. Furthermore, NF-kappa B, TNF, MAPK, and cholesterol metabolism pathways were dysregulated in PWB ECs as readouts of impaired differentiation. Conclusions: PWB iPSC-derived ECs render a novel and clinically-relevant disease model by retaining pathological phenotypes. Our data demonstrate multiple pathways, such as Hippo and Wnt, NF-kappa B, TNF, MAPK, and cholesterol metabolism, are dysregulated, which may contribute to the development of differentiation-defective ECs in PWB.

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Pathophysiology of androgen-associated endothelial cell dysfunction in phenotype A polycystic ovarian syndrome revealed by iPSCs modeling

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