Contributions of BMPR2 Mutations and Extrinsic Factors to Cellular Phenotypes of Pulmonary Arterial Hypertension Revealed by Induced Pluripotent Stem Cell Modeling.

Abstract

Reduced bone morphogenetic protein receptor 2 (BMPR2) signaling is central to the pathobiology of pulmonary arterial hypertension (PAH). However, the reduced penetrance of BMPR2 mutations in families suggests that other factors are required to establish disease (1). To date, it has proved difficult to elucidate these factors due to a lack of appropriate models. Sa et al. (2017) developed an iPSC-EC model of PAH that recapitulated some of the previously described phenotypes of patient-derived PAECs, as well as appropriate responsiveness to Elafin and FK506 (2). This demonstrated a potential utility of iPSCs in modeling PAECs in PAH. However, other phenotypes such as inner mitochondrial membrane (IMM) hyperpolarization, could not be recapitulated. Therefore, there is a need to better understand the contribution of BMPR2 mutations to PAH-associated phenotypes and the requirement for other factors in this process. Two advantages of iPSCs in disease modeling are their amenability to genome editing and their differentiation into specific cell types under serum-free, chemically-defined conditions. This allows the assessment of the impact of a BMPR2 mutation without the confounding effects of genetic differences between cell lines, and to determine the impact of controlled exposure to extrinsic factors that may influence the acquisition of a diseased state. In addition, no iPSC-smooth muscle cell (SMC) model of PAH has yet been described. We have addressed these issues.