During development, nephron structures are derived from a SIX2+ stem cell population. After 36 weeks of gestation, these cells are exhausted, and no new nephrons are formed. We have previously described a non-invasive strategy to isolate and expand the native SIX2+ kidney stem cells from the urine of preterm neonates, named neonatal kidney stem/progenitor cells (nKSPC). Here, we investigated the safety and feasibility of administering nKSPC into human kidneys discarded for transplantation during normothermic machine perfusion (NMP) and evaluated the regenerative and immunomodulatory potential of nKSPC treatment. We found that nKSPC administration during NMP is safe and feasible. Interestingly, nKSPC induced the de novo expression of SIX2 in proximal tubular cells of the donor kidneys and upregulated regenerative markers such as SOX9 and VEGF. This is the first time that SIX2 re-expression is observed in adult human kidneys. Moreover, nKSPC administration significantly lowered levels of kidney injury biomarkers and reduced inflammatory cytokine levels via the tryptophan-IDO-kynurenine pathway. In conclusion, nKSPC is a novel cell type to be applied in kidney-targeted cell therapy, with the potential to induce an endogenous regenerative process and immunomodulation.

中文翻译：

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用新生儿肾脏干/祖细胞处理的人肾脏中的从头 SIX2 激活

在开发过程中，肾单位结构源自 SIX2+ 干细胞群。妊娠 36 周后，这些细胞已耗尽，不再形成新的肾单位。我们之前已经描述了一种非侵入性策略，用于从早产新生儿的尿液中分离和扩增天然 SIX2+ 肾干细胞，命名为新生儿肾干/祖细胞 (nKSPC)。在这里，我们研究了在常温机器灌注 (NMP) 期间将 nKSPC 用于移植丢弃的人类肾脏的安全性和可行性，并评估了 nKSPC 治疗的再生和免疫调节潜力。我们发现在 NMP 期间管理 nKSPC 是安全可行的。有趣的是，nKSPC 在供体肾脏的近端肾小管细胞中诱导了 SIX2 的从头表达，并上调了再生标志物，例如SOX9和血管内皮生长因子。这是首次在成人肾脏中观察到 SIX2 重新表达。此外，nKSPC 给药显着降低了肾损伤生物标志物的水平，并通过色氨酸-IDO-犬尿氨酸途径降低了炎症细胞因子水平。总之，nKSPC 是一种应用于肾脏靶向细胞治疗的新型细胞类型，具有诱导内源性再生过程和免疫调节的潜力。