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.

中文翻译：

---

精原干细胞移植后非消融受体小鼠生育能力的恢复

精原干细胞（SSC）移植是研究干细胞与生态位相互作用的重要工具。然而，传统方法需要去除内源性SSC，从而对生态位造成损害。在这里，我们引入了 WIN18,446，一种 ALDH1A2 抑制剂，可增强非消融受体中的 SSC 定植。移植前用 WIN18,446 治疗可诱导异常的密蛋白表达，该蛋白表达构成血睾屏障并阻碍 SSC 定植。因此，与未处理的宿主相比，WIN18,446 的定植效率提高了 4.6 倍。尽管停止使用WIN18,446，但经WIN18,446治疗的睾丸仍然很小，这表明其作用是不可逆的。使用捐赠者的精子通过显微授精出生后代。虽然 WIN18,446 对白消安治疗的小鼠是致命的，但环磷酰胺或放射治疗的动物在 WIN18,446 治疗后存活下来。尽管 WIN18,446 由于毒性而不适用于人类，但类似的 ALDH1A2 抑制剂可能可用于将 SSC 移植到未消融的睾丸中，揭示类维生素A代谢对 SSC-生态位相互作用的作用，并推进动物模型和人类中的 SSC 研究。