Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis
Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis
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DOI：
10.1038/nature15695
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发表时间：
2015-10-22
期刊：
影响因子：
64.8
通讯作者：
Little, Melissa H.
中科院分区：
文献类型：
--
作者：
Takasato, Minoru;Er, Pei X.;Little, Melissa H.
人类肾脏含有多达200万个负责血液过滤的上皮性肾单位。再生肾脏需要诱导排泄所需的20多种不同类型的细胞，并调节pH，以及电解质和液体平衡。我们之前已经描述了通过人类多能干细胞的定向分化同时诱导集合管和肾单位的祖细胞(1)。矛盾的是，虽然两者都起源于中胚层，但集合管和肾单位有不同的时空起源。在这里，我们确定了调控集合管相对于肾间充质祖细胞优先诱导的发育机制。利用这一知识，我们已经产生了含有肾单位的肾脏器官，这些肾单位与由肾间质和内皮细胞包围的集合管网络有关。在这些器官体内，单个肾单位分为远端和近端小管、Henle早期环和含有足细胞的肾小球，足细胞负责足突和血管形成。当将肾脏类器官的转录谱与人胎儿组织进行比较时，它们与妊娠早期的人肾显示出最高的同源性。此外，近端小管内吞右旋糖苷和差异性凋零对肾毒性药物顺铂的反应。这些肾脏有机化合物代表了未来应用的强大的人体器官模型，包括肾毒性筛查、疾病建模和作为治疗细胞的来源。
The human kidney contains up to 2 million epithelial nephrons responsible for blood filtration. Regenerating the kidney requires the induction of the more than 20 distinct cell types required for excretion and the regulation of pH, and electrolyte and fluid balance. We have previously described the simultaneous induction of progenitors for both collecting duct and nephrons via the directed differentiation of human pluripotent stem cells(1). Paradoxically, although both are of intermediate mesoderm in origin, collecting duct and nephrons have distinct temporospatial origins. Here we identify the developmental mechanism regulating the preferential induction of collecting duct versus kidney mesenchyme progenitors. Using this knowledge, we have generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. When transcription profiles of kidney organoids were compared to human fetal tissues, they showed highest congruence with first trimester human kidney. Furthermore, the proximal tubules endocytose dextran and differentially apoptose in response to cisplatin, a nephrotoxicant. Such kidney organoids represent powerful models of the human organ for future applications, including nephrotoxicity screening, disease modelling and as a source of cells for therapy.