Generation of Human PSC-Derived Kidney Organoids with Patterned Nephron Segments and a De Novo Vascular Network
Generation of Human PSC-Derived Kidney Organoids with Patterned Nephron Segments and a De Novo Vascular Network
复制标题
具有图案化肾单位片段和从头血管网络的人PSC衍生的肾类器官的产生
DOI：
10.1016/j.stem.2019.06.009
复制
发表时间：
2019-09-05
期刊：
影响因子：
23.9
通讯作者：
Xia, Yun
中科院分区：
文献类型：
--
作者：
Low, Jian Hui;Li, Pin;Xia, Yun
人类多能干细胞衍生的肾类器官概括了发育过程和组织结构，但固有的局限性，如缺乏血管和功能，极大地阻碍了它们的应用。在这里，我们建立了一种生成血管化三维（3D）肾类器官的通用方案。我们采用WNT信号的动态调节来控制近端和远端肾元段的相对比例，产生相关水平的血管内皮生长因子a （VEGFA）来定义一个常驻血管网络。单细胞RNA测序鉴定了肾元祖细胞亚群作为肾血管的潜在来源。这些肾类器官在植入后经历进一步的结构和功能成熟。利用该肾脏类器官平台，我们建立了常染色体隐性多囊肾病（ARPKD）的体外模型，通过基因校正或药物治疗可有效预防该病的囊性表型。我们的研究为研究人类肾脏发育、疾病发病机制建模和进行患者特异性药物验证提供了新的途径。
Human pluripotent stem cell-derived kidney organoids recapitulate developmental processes and tissue architecture, but intrinsic limitations, such as lack of vasculature and functionality, have greatly hampered their application. Here we establish a versatile protocol for generating vascularized three-dimensional (3D) kidney organoids. We employ dynamic modulation of WNT signaling to control the relative proportion of proximal versus distal nephron segments, producing a correlative level of vascular endothelial growth factor A (VEGFA) to define a resident vascular network. Single-cell RNA sequencing identifies a subset of nephron progenitor cells as a potential source of renal vasculature. These kidney organoids undergo further structural and functional maturation upon implantation. Using this kidney organoid platform, we establish an in vitro model of autosomal recessive polycystic kidney disease (ARPKD), the cystic phenotype of which can be effectively prevented by gene correction or drug treatment. Our studies provide new avenues for studying human kidney development, modeling disease pathogenesis, and performing patient-specific drug validation.