Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Molecular and Computational Biology, Division of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
Dev Cell. 2019 Jul 1;50(1):102-116.e6. doi: 10.1016/j.devcel.2019.06.001.
The renal corpuscle of the kidney comprises a glomerular vasculature embraced by podocytes and supported by mesangial myofibroblasts, which ensure plasma filtration at the podocyte-generated slit diaphragm. With a spectrum of podocyte-expressed gene mutations causing chronic disease, an enhanced understanding of podocyte development and function to create relevant in vitro podocyte models is a clinical imperative. To characterize podocyte development, scRNA-seq was performed on human fetal kidneys, identifying distinct transcriptional signatures accompanying the differentiation of functional podocytes from progenitors. Interestingly, organoid-generated podocytes exhibited highly similar, progressive transcriptional profiles despite an absence of the vasculature, although abnormal gene expression was pinpointed in late podocytes. On transplantation into mice, organoid-derived podocytes recruited the host vasculature and partially corrected transcriptional profiles. Thus, human podocyte development is mostly intrinsically regulated and vascular interactions refine maturation. These studies support the application of organoid-derived podocytes to model disease and to restore or replace normal kidney functions.
肾脏的肾小球由被足细胞包围的肾小球血管系统和由系膜肌成纤维细胞支撑的肾小球组成，这些细胞确保了足细胞产生的裂孔隔膜处的血浆过滤。由于一系列导致慢性疾病的足细胞表达基因突变，因此深入了解足细胞的发育和功能，以创建相关的体外足细胞模型是临床的当务之急。为了描述足细胞的发育，对人胎儿肾脏进行了单细胞 RNA 测序，确定了伴随功能性足细胞从祖细胞分化而来的独特转录特征。有趣的是，尽管没有血管系统，类器官生成的足细胞表现出高度相似的、渐进的转录特征，但在晚期足细胞中发现了异常的基因表达。在移植到小鼠中后，类器官衍生的足细胞募集了宿主的血管系统，并部分纠正了转录特征。因此，人类足细胞的发育主要是内在调节的，血管相互作用则可以促进其成熟。这些研究支持应用类器官衍生的足细胞来模拟疾病，并恢复或替代正常的肾脏功能。
