Patient-specific iPSC-derived endothelial cells reveal aberrant p38 MAPK signaling in atypical hemolytic uremic syndrome. Homo sapiens

Atypical hemolytic uremic syndrome (aHUS) is a rare disease associated with high morbidity and mortality. Existing evidence suggested that the central pathogenesis to aHUS might be endothelial cell damage due to uncontrolled activation of an alternative pathway to the complement system. Nevertheless, the role of endothelial cell alterations in aHUS has not been well characterized and the underlying mechanisms remain unclear. Three pediatric patients with anti-complement factor H (CFH) autoantibody-associated aHUS and two age- and gender-matched healthy control subjects were recruited in this study. Induced pluripotent stem cells (iPSCs) were generated from skin fibroblasts using non-integrated Sendai virus. All iPSCs were differentiated into endothelial cells (iPSC-ECs) using a monolayer-based differentiation protocol. aHUS iPSC-ECs exhibited intrinsic defect in endothelial functions, including decreased migration, decreased tube formation capacity and impaired cell proliferation. Stimulation using aHUS patient-specific serums exacerbated endothelial dysfunctions, leading to cell apoptosis in iPSC-ECs, whereas anti-CFH autoantibodies alone had no effect on endothelial cell death. Importantly, we demonstrated a differential transcriptomic profile in aHUS iPSC-ECs and identified p38 MAPK as a novel signaling pathway contributing to endothelial dysfunctions in anti-CFH autoantibody-associated aHUS. These results illustrate that iPSC-ECs can be a reliable model to recapitulate EC pathological features, thus providing a unique platform for gaining mechanistic insights of EC injury in aHUS. Our findings highlight that the p38 MAPK signaling pathway can be a therapeutic target for treatment of anti-CFH-associated aHUS.