Using patient-specific induced pluripotent stem cells to understand and treat pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is characterized by endothelial cell (EC) dysfunction, loss of peripheral pulmonary arterial (PA) microvessels, and proliferation of vascular cells in proximal PAs, leading to occlusion of the lumen. Loss of function mutations in bone morphogenetic protein receptor (BMPR)2 occur in over 70% of heritable form of PAH (HPAH) patients. Intriguingly, only 20% of the mutation carriers develop clinical symptoms, suggesting that genetic variation may provide modifiers that alleviate the disease. Induced pluripotent stem cell (iPSC)-derived vascular cells provide a new opportunity to further understand the disease mechanisms in a personalized manner. In our study, we demonstrated that iPSC-derived endothelial cell (iPSC-EC) recapitulates the functional and gene expression abnormalities in native PAEC from the same PAH patients compared with healthy controls. Interestingly, PAH PAEC and iPSC-EC also respond similarly to potential PAH therapies elafin and FK506 in terms of improved angiogenesis. We then used iPSC-ECs to further understand the reduced penetrance of the BMPR2 mutation. iPSC-EC was generated from three families with unaffected mutation carriers (UMC), HPAH patients, and gender-matched controls. We identified patient-specific features of preserved function in UMC iPSC-EC attributed to the regulators of BMPR2 signaling or to cell survival gene revealed by RNA-Seq analyses. Our findings therefore highlight protective modifiers for HPAH that could help inform development of future treatment strategies. Despite the site of disease in the lung and the particular vulnerability of the PA vasculature, iPSC-EC is a good surrogate for PAH modeling and drug testing.