Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Cells. 2022 Nov 29;11(23):3823. doi: 10.3390/cells11233823.
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary vascular resistance (PVR), causing right ventricular hypertrophy and ultimately death from right heart failure. Heterozygous mutations in the bone morphogenetic protein receptor type 2 () are linked to approximately 80% of hereditary, and 20% of idiopathic PAH cases, respectively. While patients carrying a gene mutation are more prone to develop PAH than non-carriers, only 20% will develop the disease, whereas the majority will remain asymptomatic. PAH is characterized by extreme vascular remodeling that causes pulmonary arterial endothelial cell (PAEC) dysfunction, impaired apoptosis, and uncontrolled proliferation of the pulmonary arterial smooth muscle cells (PASMCs). To date, progress in understanding the pathophysiology of PAH has been hampered by limited access to human tissue samples and inadequacy of animal models to accurately mimic the pathogenesis of human disease. Along with the advent of induced pluripotent stem cell (iPSC) technology, there has been an increasing interest in using this tool to develop patient-specific cellular models that precisely replicate the pathogenesis of PAH. In this review, we summarize the currently available approaches in iPSC-based PAH disease modeling and explore how this technology could be harnessed for drug discovery and to widen our understanding of the pathophysiology of PAH.
肺动脉高压（PAH）是一种进行性疾病，其特征为肺血管阻力（PVR）增加，导致右心室肥厚，并最终因右心衰竭而死亡。骨形态发生蛋白受体 2 型（BMPR2）的杂合突变分别与约 80%的遗传性和 20%的特发性 PAH 病例相关。虽然携带 BMPR2 基因突变的患者比非携带者更容易患上 PAH，但只有 20%的患者会发展为该疾病，而大多数患者仍无症状。PAH 的特征是极度血管重构，导致肺动脉内皮细胞（PAEC）功能障碍、凋亡受损以及肺动脉平滑肌细胞（PASMC）不受控制的增殖。迄今为止，对 PAH 病理生理学的理解进展受到人类组织样本获取有限以及动物模型不能准确模拟人类疾病发病机制的限制。随着诱导多能干细胞（iPSC）技术的出现，人们越来越有兴趣利用该工具开发精确复制 PAH 发病机制的患者特异性细胞模型。在这篇综述中，我们总结了目前基于 iPSC 的 PAH 疾病建模的方法，并探讨了如何利用这项技术进行药物发现，并加深对 PAH 病理生理学的理解。
