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Introduction
The kidney is a vital organ in the human body responsible for maintaining homeostasis. It fulfills a variety of functions, including the regulation of water volume and ion balance, the excretion of waste products, hematopoiesis, and bone metabolism. For the kidney to perform its function, it requires not only the kidney itself, but also the ureter, which is the outlet for the urine produced by the kidney. Recent advances in stem cell biology have enabled the generation of kidney organoids from pluripotent stem cells (PSCs)1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11–12. However, no kidney organoids with ureters or even ureteral organoids have been generated, which is one of the hurdles to overcome for the future application of organoids in transplant treatment.
The ureter is a straight tube that allows efficient transport of urine from the kidney to the bladder by unidirectional peristalsis. The ureter is composed of two distinct tissue compartments: the ureteral epithelium and the surrounding ureteral mesenchyme. The ureteral epithelium, also known as the urothelium, is a specialized epithelium that is highly extensible and forms a tight seal around the lumen. It is further divided into three cell layers, from the inside to the outside: superficial cells, intermediate cells, and basal cells13, 14–15 (Supplementary Fig. 1a). The ureteral mesenchyme also consists of three cell layers: the inner lamina propria, the tunica muscularis with contractile smooth muscle cells (SMCs), and the outer tunica adventitia that anchors the ureter to the body wall16,17 (Supplementary Fig. 1a). Given that the ureter develops as a result of the interaction between the epithelium and the surrounding mesenchyme16,18, a logical approach to generate the ureter from PSCs would be to induce the progenitors of these tissues and combine them to elicit the interactions necessary for ureter development. While induction protocols for the progenitor of the ureteral epithelium, ureteric buds (UBs), have been established6, 7, 8–9,11,12, the progenitor of the ureteral mesenchyme has yet to be induced from PSCs. Stromal progenitors (SPs) of the mouse ureter surround the distal UB stalk at embryonic day (E) 11.5 and around the ureter from E12.5 onwards, and differentiate through interactions with the adjacent ureteral epithelia19,20. In the E11.5...