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Transcriptomic Analysis of Nicotine on the Cardiovascular System Using a Diverse Population of Human Induced Pluripotent Stem Cell-derived Endothelial Cells

ABSTRACT: Nicotine, the primary addictive component of tobacco, is linked to major adverse cardiovascular events (MACE) and increased mortality. The impact of nicotine across diverse populations is challenging to investigate in clinical studies due to individual variations in environmental exposures, the presence of other compounds in cigarettes and e-cigarettes, and differences in nicotine dosage and frequency. While animal models offer control over these variables, translating findings to human physiology remains complex. Induced pluripotent stem cells (iPSCs) present a promising alternative, leveraging each patient's unique genetic profile. In this study, we utilized iPSCs to explore the effects of nicotine on the cardiovascular system in a genetically diverse population. We derived endothelial cells (iPSC-ECs) from iPSCs of 20 healthy donors from diverse ancestries, including African, Caucasian, East Asian, and Hispanic, and exposed them to 1 µM nicotine for 48 hours. RNA sequencing analysis revealed significant interindividual variation in gene expression, while the nicotine-induced transcriptomic signature was consistent across individuals. A total of 399 differentially expressed genes (DEGs) were identified, with 303 downregulated and 96 upregulated genes. Pathway analysis indicated that upregulated genes were associated with cardiovascular diseases and nicotine addiction, whereas downregulated genes were linked to type 2 diabetes and respiratory disorders. Further analysis highlighted nicotine's effect on pathways related to atherosclerosis and type 2 diabetes. Notably, genes such as HMOX1 and HSPA6 were significantly downregulated upon nicotine exposure, findings validated by quantitative real-time PCR. This study underscores the utility of iPSC-ECs in modeling nicotine's direct impact on the endothelium, providing insights into its role in disease pathogenesis and offering potential avenues for the development of diagnostic markers and therapeutic interventions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274506 | GEO | 2025/07/31

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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Transcriptomic Analysis of Nicotine on the Cardiovascular System Using a Diverse Population of Human Induced Pluripotent Stem Cell-derived Endothelial Cells

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