Araoka Toshikazu, Toyohara Kosuke, Ryosaka Makoto, Inui Chihiro, Matsuura Maasa, Ma Cheng, Watahiki Jun, Li Zhongwei, Iwasaki Mio, Watanabe Akira, Yokokawa Ryuji, Tabata Yasuhiko, Izpisua Belmonte Juan Carlos, Osafune Kenji
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
Department of Micro Engineering, Kyoto University, Kyoto 615-8540, Japan.
Sci Transl Med. 2025 Apr 2;17(792):eadt5553. doi: 10.1126/scitranslmed.adt5553.
The number of patients requiring dialysis therapy continues to increase worldwide because of the lack of effective treatments for chronic kidney disease (CKD). Furthermore, no curative treatments for acute kidney injury (AKI) have been established. The therapeutic effects of human induced pluripotent stem cell-derived nephron progenitor cells (hiPSC-NPCs) on AKI have been reported in mice but not clinically confirmed. There are also no reports examining the therapeutic potential of hiPSC-NPCs on CKD. Although large numbers of uniform hiPSC-NPCs are required for cell therapies for AKI and CKD, effective expansion cultures remain to be developed. Here, we established a culture medium for cells that enabled more than 100-fold proliferation of hiPSC-NPCs from multiple hiPSC lines in two passages. We demonstrated that hiPSC-NPCs expanded by our medium named CFY or by their conditioned medium alone attenuated kidney injury and improved survival in cisplatin-induced AKI mice. We also observed that hiPSC-NPCs prevented kidney functional decline, interstitial fibrosis, and senescence in aristolochic acid-induced CKD mice. In addition, we found c-MET to be a specific cell surface marker for hiPSC-NPCs and confirmed that purified c-MET hiPSC-NPCs had therapeutic effects on AKI and CKD mice. Furthermore, we found that hiPSC-NPCs exerted their therapeutic effects in AKI and CKD mice by secreting vascular endothelial growth factor A. Expanded hiPSC-NPCs may be useful cell therapies for AKI and CKD and may open avenues for treating kidney diseases.
由于缺乏针对慢性肾脏病（CKD）的有效治疗方法，全球范围内需要透析治疗的患者数量持续增加。此外，急性肾损伤（AKI）的治愈性治疗方法尚未确立。人诱导多能干细胞来源的肾祖细胞（hiPSC-NPCs）对AKI的治疗效果已在小鼠中得到报道，但尚未得到临床证实。也没有关于hiPSC-NPCs对CKD治疗潜力的研究报告。尽管AKI和CKD的细胞治疗需要大量均匀的hiPSC-NPCs，但有效的扩增培养方法仍有待开发。在此，我们建立了一种细胞培养基，能使来自多个hiPSC系的hiPSC-NPCs在两代培养中增殖超过100倍。我们证明，通过我们命名为CFY的培养基或单独通过其条件培养基扩增的hiPSC-NPCs可减轻顺铂诱导的AKI小鼠的肾损伤并提高存活率。我们还观察到，hiPSC-NPCs可预防马兜铃酸诱导的CKD小鼠的肾功能下降、间质纤维化和衰老。此外，我们发现c-MET是hiPSC-NPCs的一种特异性细胞表面标志物，并证实纯化的c-MET hiPSC-NPCs对AKI和CKD小鼠具有治疗作用。此外，我们发现hiPSC-NPCs通过分泌血管内皮生长因子A在AKI和CKD小鼠中发挥治疗作用。扩增的hiPSC-NPCs可能是治疗AKI和CKD的有用细胞疗法，并可能为治疗肾脏疾病开辟新途径。
