Tsujimoto Hiraku, Araoka Toshikazu, Nishi Yohei, Ohta Akira, Nakahata Tatsutoshi, Osafune Kenji
Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Biochem Biophys Res Commun. 2021 Jun 18;558:231-238. doi: 10.1016/j.bbrc.2020.02.130. Epub 2020 Feb 26.
Several groups have developed in vitro expansion cultures for mouse metanephric nephron progenitor cells (NPCs) using cocktails of small molecules and growth factors including BMP7. However, the detailed mechanisms by which BMP7 acts in the NPC expansion remain to be elucidated. Here, by performing chemical screening for BMP substitutes, we identified a small molecule, TCS21311, that can replace BMP7 and revealed a novel inhibitory role of BMP7 in JAK3-STAT3 signaling in NPC expansion culture. Further, we found that TCS21311 facilitates the proliferation of mouse embryonic NPCs and human induced pluripotent stem cell-derived NPCs when added to the expansion culture. These results will contribute to understanding the mechanisms of action of BMP7 in NPC proliferation in vitro and in vivo and to the stable supply of NPCs for regenerative therapy, disease modeling and drug discovery for kidney diseases.
几个研究小组利用包括BMP7在内的小分子和生长因子混合物，开发了用于小鼠后肾肾单位祖细胞（NPCs）的体外扩增培养方法。然而，BMP7在NPC扩增中发挥作用的详细机制仍有待阐明。在这里，通过对BMP替代物进行化学筛选，我们鉴定出一种小分子TCS21311，它可以替代BMP7，并揭示了BMP7在NPC扩增培养中对JAK3-STAT3信号传导的新抑制作用。此外，我们发现，将TCS21311添加到扩增培养中时，它能促进小鼠胚胎NPCs和人诱导多能干细胞衍生的NPCs的增殖。这些结果将有助于理解BMP7在体外和体内NPC增殖中的作用机制，并有助于为再生治疗、疾病建模和肾脏疾病药物发现稳定供应NPCs。
