全球晚期肾衰竭患者数量每年都在增加，而肾移植供体短缺使问题更加严重。在我们先前的研究中，我们已经证明将肾前体细胞移植到异种胎儿的肾发生区可以诱导肾单位的发育。我们还开发了一种可以通过药物移除特定肾前体细胞的转基因小鼠。通过结合这两项技术，我们成功地在胎儿小鼠中生成了人-小鼠嵌合肾。我们希望将这些技术应用于再生医学。来自人类多能干细胞的肾前体细胞（NPCs）的质量对于嵌合肾的生成非常重要，但目前还没有简单的评估体系用于评估人类NPC的嵌合潜力。在这项研究中，我们专注于鼠肾前体细胞的重新聚集可以促进肾单位形成的事实，即使它们合并成单个细胞。首先，我们研究了再聚集过程中小鼠发生肾单位的可能性。接下来，为了提高从多能干细胞分化出的人类NPCs的分化潜力，我们使用整合素亚单位α8（ITGA8）进行了NPCs分类。最后，在最佳条件下混合小鼠细胞和纯化的、有选择地诱导的人类NPCs，我们展示了不同物种之间的嵌合体形成。我们观察了这些嵌合体的不同时间点，以了解这些人-小鼠嵌合结构在肾发育的各个阶段的情况。我们发现，嵌合体形成速率受到人类NPCs的纯度和细胞比例的影响。我们证明了即使在远离的物种之间也可以使用简单模型生成嵌合肾单位。我们相信这种混合人类和小鼠肾前体细胞的技术具有评估NPCs嵌合形成能力的潜在应用。Copyright © 2023 Elsevier Inc. All rights reserved.

The number of patients with end-stage renal failure is increasing annually worldwide and the problem is compounded by a shortage of renal transplantation donors. In our previous research, we have shown that transplantation of renal progenitor cells into the nephrogenic region of heterologous fetuses can induce the development of nephrons. We have also developed transgenic mice in which specific renal progenitor cells can be removed by drugs. By combining these two technologies, we have succeeded in generating human-mouse chimeric kidneys in fetal mice. We hope to apply these technologies to regenerative medicine. The quality of nephron progenitor cells (NPCs) derived from human pluripotent stem cells is important for the generation of chimeric kidneys, but there is currently no simple evaluation system for the chimerogenic potential of human NPCs. In this study, we focused on the fact that the re-aggregation of mouse renal progenitor cells can be used for nephron formation, even when merged into single cells. First, we examined the conditions under which nephron formation is likely to occur in mice during re-aggregation. Next, to improve the differentiation potential of human NPCs derived from pluripotent stem cells, NPCs were sorted using Integrin subunit alpha 8 (ITGA8). Finally, we demonstrated chimera formation between different species by mixing mouse cells with purified, selectively-induced human NPCs under optimum conditions. We observed these chimeric organoids at different time points to learn about these human-mouse chimeric structures at various stages of renal development. We found that the rate of chimera formation was affected by the purity of the human NPCs and the cell ratios used. We demonstrated that chimeric nephrons can be generated using a simple model, even between distant species. We believe that this admixture of human and mouse renal progenitor cells is a promising technology with potential application for the evaluation of the chimera formation abilities of NPCs.Copyright © 2023 Elsevier Inc. All rights reserved.