Generation of the organotypic kidney by integrating pluripotent stem cell-derived renal stroma

Organs consist of not only parenchyma but also stroma, the latter of which coordinates generation of organotypic structures. Despite recent advances in organoid technology, induction of organ-specific stroma and recapitulating the complex organ configurations from pluripotent stem cells (PSCs) has remained challenging. For the kidney, the stromal progenitor coordinates differentiation of the two parenchymal progenitors: nephron progenitor and ureteric bud. By identifying the origin and dorsoventral patterning of the renal stromal progenitor, we established its induction protocol from mouse PSCs. When the three types of progenitors were differentially induced from PSCs and assembled, the all PSC-derived organoids reproduced the complex kidney structures, with multiple types of stromal cells distributed around differentiating nephrons and branching ureteric buds. Thus, integration of PSC-derived stroma into the conventional organoids enables recapitulation of organotypic architecture. Kidney mRNA profiles of embryonic day 9.5, E11.5, E15.5, E13.5, E17.5, postnatal day 0 mice and mouse ES cells-derived kidney organoids at single cell resolution.

器官不仅由实质组织（parenchyma）与间质（stroma）共同组成，其中间质可协调器官特异性结构的生成。尽管类器官（organoid）技术近年来取得了长足进展，但从多能干细胞（PSCs）中诱导获得器官特异性间质，并重现复杂的器官构型，仍是一项颇具挑战性的研究课题。以肾脏为例，间质祖细胞（stromal progenitor）可调控两类实质祖细胞的分化：肾单位祖细胞与输尿管芽。本研究通过明确肾间质祖细胞的起源与背腹模式化（dorsoventral patterning）机制，建立了从小鼠多能干细胞中诱导其分化的标准化方案。当三类祖细胞从小鼠多能干细胞中被差异化诱导并体外组装后，所有多能干细胞来源的类器官均可重现复杂的肾脏结构，多种间质细胞精准分布于正在分化的肾单位与分支状输尿管芽周围。由此可见，将多能干细胞来源的间质整合至传统类器官中，即可实现器官特异性结构的完整重现。本数据集包含胚胎发育第9.5天、E11.5、E15.5、E13.5、E17.5、出生后第0天的小鼠肾脏，以及小鼠胚胎干细胞（ES cells）来源的肾脏类器官的单细胞分辨率（single cell resolution）mRNA表达谱。