Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Bioresource Engineering Division, RIKEN BioResource Research Center, Ibaraki 305-0074, Japan.
Stem Cell Reports. 2024 Apr 9;19(4):443-455. doi: 10.1016/j.stemcr.2024.02.003. Epub 2024 Mar 7.
Spermatogonial stem cell (SSC) transplantation is a valuable tool for studying stem cell-niche interaction. However, the conventional approach requires the removal of endogenous SSCs, causing damage to the niche. Here we introduce WIN18,446, an ALDH1A2 inhibitor, to enhance SSC colonization in nonablated recipients. Pre-transplantation treatment with WIN18,446 induced abnormal claudin protein expression, which comprises the blood-testis barrier and impedes SSC colonization. Consequently, WIN18,446 increased colonization efficiency by 4.6-fold compared with untreated host. WIN18,446-treated testes remained small despite the cessation of WIN18,446, suggesting its irreversible effect. Offspring were born by microinsemination using donor-derived sperm. While WIN18,446 was lethal to busulfan-treated mice, cyclophosphamide- or radiation-treated animals survived after WIN18,446 treatment. Although WIN18,446 is not applicable to humans due to toxicity, similar ALDH1A2 inhibitors may be useful for SSC transplantation into nonablated testes, shedding light on the role of retinoid metabolism on SSC-niche interactions and advancing SSC research in animal models and humans.
精原干细胞 (SSC) 移植是研究干细胞-巢相互作用的一种有价值的工具。然而，传统方法需要去除内源性 SSC，从而对巢造成损伤。在这里，我们引入了 WIN18,446，一种 ALDH1A2 抑制剂，以增强非消融受体内的 SSC 定植。移植前用 WIN18,446 处理会诱导异常 Claudin 蛋白表达，这包括血睾屏障并阻碍 SSC 定植。因此，与未处理的宿主相比，WIN18,446 使定植效率提高了 4.6 倍。尽管停止了 WIN18,446 的使用，但 WIN18,446 处理的睾丸仍然很小，这表明其具有不可逆的作用。通过使用供体来源的精子进行微注射，产生了后代。虽然 WIN18,446 对白消安处理的小鼠是致命的，但环磷酰胺或辐射处理的动物在 WIN18,446 处理后存活下来。尽管由于毒性，WIN18,446 不适用于人类，但类似的 ALDH1A2 抑制剂可能对非消融睾丸中的 SSC 移植有用，这揭示了视黄醇代谢对 SSC-巢相互作用的作用，并推进了动物模型和人类中的 SSC 研究。
