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

类有机物 诱导多能干细胞 干细胞 生物 血管生成 缺氧诱导因子 细胞生物学 祖细胞 癌症研究 内分泌学 胚胎干细胞 生物化学 基因
作者
Kexin Peng,Wei Xie,Tingting Wang,Yamei Li,Jean de Dieu Habimana,Obed Boadi Amissah,Jufang Huang,Yong Chen,Bin Ni,Zhiyuan Li
出处
期刊:Stem Cell Research & Therapy [BioMed Central]
卷期号:14 (1)
标识
DOI:10.1186/s13287-023-03528-9
摘要

Abstract 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 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. Methods 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. Result 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. Conclusion We demonstrated that HIF-1α elicited the process of kidney organoid vascularization and protected against cisplatin-induced kidney organoid injury in hypoxia environment.

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