The maintenance of hematopoietic stem cells (HSCs) is a complex process involving numerous cell-extrinsic and -intrinsic regulators. The first member of the cyclin-dependent kinase family of inhibitors to be identified, p21, has been reported to perform a wide range of critical biological functions, including cell cycle regulation, transcription, differentiation, and so on. Given the previous inconsistent results regarding the functions of p21 in HSCs in a p21-knockout mouse model, we employed p21-tdTomato (tdT) mice to further elucidate its role in HSCs during homeostasis. The results showed that p21-tdT+ HSCs exhibited increased self-renewal capacity compared to p21-tdT- HSCs. Zbtb18, a transcriptional repressor, was upregulated in p21-tdT+ HSCs, and its knockdown significantly impaired the reconstitution capability of HSCs. Furthermore, p21 interacted with ZBTB18 to co-repress the expression of cKit in HSCs and thus regulated the self-renewal of HSCs. Our data provide novel insights into the physiological role and mechanisms of p21 in HSCs during homeostasis independent of its conventional role as a cell cycle inhibitor.

中文翻译：

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p21/Zbtb18 抑制 cKit 的表达以调节造血干细胞的自我更新。


造血干细胞 （HSC） 的维持是一个复杂的过程，涉及许多细胞外源性和内在调节因子。据报道，细胞周期蛋白依赖性激酶抑制剂家族中第一个被鉴定的成员 p21 具有广泛的关键生物学功能，包括细胞周期调节、转录、分化等。鉴于先前关于 p21 敲除小鼠模型中 p21 在 HSC 中功能的不一致结果，我们采用 p21-tdTomato （tdT） 小鼠进一步阐明其在稳态期间在 HSCs 中的作用。结果表明，与 p21-tdT-HSC 相比，p21-tdT+ HSCs 表现出更高的自我更新能力。Zbtb18 是一种转录抑制因子，在 p21-tdT+ HSC 中上调，其敲除显着损害了 HSC 的重建能力。此外，p21 与 ZBTB18 相互作用，共同抑制 HSC 中 cKit 的表达，从而调节 HSC 的自我更新。我们的数据为 p21 在稳态期间 HSC 中的生理作用和机制提供了新的见解，而这与其作为细胞周期抑制剂的常规作用无关。