HIF-1α promotes kidney organoid vascularization and applications in disease modeling

Background Kidney organoids derived from human pluripotent stem cells (HiPSCs) hold huge applications for drug screening, disease modeling, and cell transplanting therapy. However, these applications are limited since kidney organoid cannot maintain complete morphology and function like human kidney. Kidney organoids are not well differentiated since the core of the organoid lacked oxygen, nutrition, and vasculature, which creates essential niches. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) serves as a critical regulator in vascularization and cell survival under hypoxia environment. Less is known about the role of HIF-1 alpha in kidney organoids in this regard. This study tried to investigate the effect of HIF-1 alpha in kidney organoid vascularization and related disease modeling.Methods For the vascularization study, kidney organoids were generated from human induced pluripotent stem cells. We overexpressed HIF-1 alpha via plasmid transfection or treated DMOG (Dimethyloxallyl Glycine, an agent for HIF-1 alpha stabilization and accumulation) in kidney progenitor cells to detect the endothelium. For the disease modeling study, we treated kidney organoid with cisplatin under hypoxia environment, with additional HIF-1 alpha transfection.Result HIF-1 alpha overexpression elicited kidney organoid vascularization. The endothelial cells and angiotool analysis parameters were increased in HIF-1 alpha plasmid-transfected and DMOG-treated organoids. These angiogenesis processes were partially blocked by VEGFR inhibitors, semaxanib or axitinib. Cisplatin-induced kidney injury (Cleaved caspase 3) was protected by HIF-1 alpha through the upregulation of CD31 and SOD2.Conclusion We demonstrated that HIF-1 alpha elicited the process of kidney organoid vascularization and protected against cisplatin-induced kidney organoid injury in hypoxia environment.