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

• Published in: Stem cell research & therapy Vol. 14; no. 1; p. 336
• Main Authors: Peng, Kexin, Xie, Wanqin, Wang, Tingting, Li, Yamei, de Dieu Habimana, Jean, Amissah, Obed Boadi, Huang, Jufang, Chen, Yong, Ni, Bin, Li, Zhiyuan
• Format: Journal Article
• Language: English
• Published: England BioMed Central 19.11.2023; BMC
• Subjects: Angiogenesis; Antibodies; Caspase-3; Cell survival; Cisplatin; Drug screening; Endothelial Cells; Endothelium; Gene expression; HIF-1α; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-inducible factor 1a; Induced Pluripotent Stem Cells; Kidney; Kidney organoid; Kidneys; Maternal & child health; Microscopy; Organoids; Plasmids; Pluripotency; Progenitor cells; Reagents; Stem cells; Transfection; Vascular endothelial growth factor receptors; Vascularization; Japan; HIF-1α; Kidney organoid; Cisplatin; Vascularization
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-023-03528-9

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 α (HIF-1α) serves as a critical regulator in vascularization and cell survival under hypoxia environment. Less is known about the role of HIF-1α in kidney organoids in this regard. This study tried to investigate the effect of HIF-1α in kidney organoid vascularization and related disease modeling. For the vascularization study, kidney organoids were generated from human induced pluripotent stem cells. We overexpressed HIF-1α via plasmid transfection or treated DMOG (Dimethyloxallyl Glycine, an agent for HIF-1α 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-1α transfection. HIF-1α overexpression elicited kidney organoid vascularization. The endothelial cells and angiotool analysis parameters were increased in HIF-1α 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-1α through the upregulation of CD31 and SOD2. We demonstrated that HIF-1α elicited the process of kidney organoid vascularization and protected against cisplatin-induced kidney organoid injury in hypoxia environment.