In vitro generation of a ureteral organoid from pluripotent stem cells

The ureter is the outlet for urine produced by the kidney. Recent advances in stem cell biology have enabled the in vitro generation of kidney organoids from pluripotent stem cells (PSCs), but they lack the ureter, which hinders the smooth drainage of urine. By mimicking the in vivo developmental process of ureteral stromal progenitors (SPs) from the posterior intermediate mesoderm, we report here in vitro induction protocols for ureteral SPs from mouse and human PSCs. When the induced SPs were combined with ureteral epithelia derived from mouse embryos, the elongated, multilayered ureteral structure was reconstituted, exhibiting peristaltic constriction. The ureter-like spherical organoids entirely derived from mouse PSCs can also be generated by combining the induced SPs and the epithelial progenitor, the ureteric bud. Furthermore, ureteral SPs induced from TBX18-deficient human PSCs recapitulate the disease state of a congenital anomaly of the urinary tract. Therefore, our induction protocols for ureteral SPs will be useful for the elucidation of ureteral development and disease, and will be an important step towards functional kidney organoids with urine flow. Kidney mRNA profiles of embryonic day E11.5, E13.5, E15.5, E17.5, postnatal day 0 and day7 at single cell resolution. mRNA profiles of Induced stromal progenitors from mouse ESCs and cultured ureters at single cell resolution

输尿管是肾脏生成尿液的排出通路。近年来干细胞生物学领域的进展已实现从多能干细胞（pluripotent stem cells, PSCs）体外构建肾脏类器官，但此类类器官均缺失输尿管结构，这会阻碍尿液的顺畅引流。本研究通过模拟输尿管间质祖细胞（ureteral stromal progenitors, SPs）从后中间中胚层的体内发育过程，报道了从小鼠与人类多能干细胞体外诱导输尿管间质祖细胞的实验方案。将诱导获得的SPs与小鼠胚胎来源的输尿管上皮共培养后，可重建出细长的多层输尿管结构，该结构呈现蠕动收缩特性。完全由小鼠多能干细胞衍生的输尿管样球形类器官，也可通过将诱导得到的SPs与上皮祖细胞——输尿管芽（ureteric bud）——联合培养而生成。此外，从TBX18缺陷型人类多能干细胞诱导得到的输尿管SPs，能够复现先天性尿路异常的疾病表型。综上，本研究建立的输尿管SPs诱导方案将有助于阐明输尿管发育与疾病的相关机制，同时也是构建具备尿液流通功能的功能性肾脏类器官的重要一步。本数据集包含两部分：一是单细胞分辨率下，小鼠胚胎第E11.5、E13.5、E15.5、E17.5天以及出生后第0天、第7天的肾脏mRNA表达谱；二是单细胞分辨率下，小鼠胚胎干细胞诱导间质祖细胞与体外培养输尿管的mRNA表达谱。