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Transcriptional profiling of human cardiomyocytes and endothelial cells derived from NOTCH1 knockout induced pluripotent stem cells (iPSCs)

ABSTRACT: Pathogenic NOTCH1 mutations are linked to congenital heart defects. To pinpoint how NOTCH1 deficiency affects cardiac development, we generated homozygous NOTCH1 knockout (N1KO) human induced pluripotent stem cells (iPSCs). We then performed high-throughput RNA-seq to profile differential gene expression in cardiomyocytes (iPSC-CMs) and endothelial cells (iPSC-ECs) derived from wild type (WT) and N1KO iPSCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE195559 | GEO | 2023/01/26

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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Transcriptional profiling of human cardiomyocytes and endothelial cells derived from NOTCH1 knockout induced pluripotent stem cells (iPSCs)

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