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

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.Supported by funding from the British Heart Foundation (BHF) (project grant PG/14/31/30786 and programme grant RG/13/4/30107), the Cambridge National Institute for Health Research Biomedical Research Centre, the Dinosaur Trust, Fondation Leducq, the Medical Research Council (MRC Experimental Challenge Award – MR/KO20919/1), Pulmonary Hypertension Association UK, Fight for Sight and the Robert McAlpine Foundation. NWM was supported by a BHF Chair Award (CH/09/001/25945) and FNK was supported by a BHF PhD studentship (FS/13/51/30636) and a travel grant from St Catharine’s College Cambridge. AAR and NWM would also like to acknowledge support from the BHF Centre of Regenerative Medicine, Oxford and Cambridge (RM/13/3/30159), the BHF Centre for Research Excellence (RE/13/6/30180), the BHF IPAH cohort grant (SP/12/12/29836), Selwyn and St Catharine’s Colleges, Cambridge, and a Pfizer European Young Researcher of the Year award to AAR