Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan.
Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan.
Biochem Biophys Res Commun. 2023 Jun 25;662:18-25. doi: 10.1016/j.bbrc.2023.04.052. Epub 2023 Apr 18.
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.
全世界终末期肾衰竭患者的数量正在逐年增加，而肾移植供体短缺的问题更加严重。在我们之前的研究中，我们已经证明将肾祖细胞移植到异源胎肾的肾发生区可以诱导肾单位的发育。我们还开发了一种转基因小鼠，通过药物可以去除特定的肾祖细胞。通过将这两种技术结合起来，我们成功地在胎鼠中生成了人鼠嵌合肾。我们希望将这些技术应用于再生医学。从人多能干细胞中分离得到的肾单位祖细胞（NPCs）的质量对于嵌合肾的生成非常重要，但目前还没有用于评估人 NPC 嵌合潜能的简单评价体系。在这项研究中，我们关注的是这样一个事实，即即使将小鼠肾祖细胞重新聚集到单个细胞中，也可以用于肾单位的形成。首先，我们研究了在重新聚集过程中，哪些条件可能导致肾单位的形成。接下来，为了提高多能干细胞来源的人 NPC 的分化潜能，我们使用整合素亚基α 8（ITGA8）对 NPC 进行分选。最后，我们在最佳条件下，将纯化的、经选择性诱导的人 NPC 与小鼠细胞混合，证明了不同物种之间的嵌合体形成。我们在不同的时间点观察这些嵌合类器官，以了解这些人鼠嵌合结构在肾发育的不同阶段的情况。我们发现，嵌合体形成的速率受到人 NPC 的纯度和所用细胞比例的影响。我们证明，即使在不同的物种之间，也可以使用简单的模型生成嵌合肾单位。我们相信，这种人源和鼠源肾祖细胞的混合物是一种很有前途的技术，有可能用于评估 NPC 的嵌合体形成能力。
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