Cell-intrinsic in vivo requirement for the E47-p21 pathway in long-term hematopoietic stem cells.
Cell-intrinsic in vivo requirement for the E47-p21 pathway in long-term hematopoietic stem cells.
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DOI：
10.4049/jimmunol.1302502
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发表时间：
2014-01-01
期刊：
影响因子：
--
通讯作者：
Borghesi L
中科院分区：
文献类型：
--
作者：
Santos PM;Ding Y;Borghesi L
长期造血干细胞（LT-HSC）自我更新和增殖的主要调节因子已被确定，但缺乏关于其在体内线性途径相互作用的知识。在这里，我们显示了一个直接的遗传联系之间的转录因子E47和主要的细胞周期调节因子p21在控制LT-HSC的完整性在体内再生压力。许多研究表明，E47激活p21转录造血亚群在体外，我们现在揭示了E47-p21通路的体内相关性，通过减少基因剂量的每个因素单独（E47 het或p21 het）与串联（E47 hetp 21 het）。与野生型或单倍不足对照相比，E47 hetp 21 het LT-HSC和下游短期HSC（ST-HSC）表现出过度增殖和对丝裂毒素的优先易感性。在严格挑战自我更新的连续过继转移中，E47-p21 het LT-HSC显著且进行性地下降，表明细胞内在E47-p21在应激下保存LT-HSC中的重要性。下游ST-HSC的瞬时数量恢复使得能够产生功能上有能力的髓样细胞而不是淋巴样细胞，因为常见的淋巴样祖细胞（CLP）减少并且外周淋巴细胞几乎被消融。因此，我们证明了E47-p21通路在体内造血重建应激下维持LT-HSC、B和T细胞的发育隔室特异性和谱系特异性要求。
Major regulators of long-term hematopoietic stem cell (LT-HSC) self-renewal and proliferation have been identified but knowledge of their in vivo interaction in a linear pathway is lacking. Here, we show a direct genetic link between the transcription factor E47 and the major cell cycle regulator p21 in controlling LT-HSC integrity in vivo under repopulation stress. Numerous studies have shown that E47 activates p21 transcription in hematopoietic subsets in vitro and we now reveal the in vivo relevance of the E47-p21 pathway by reducing the gene dose of each factor individually (E47het or p21het) versus in tandem (E47hetp21het). E47hetp21het LT-HSCs and downstream short-term HSCs (ST-HSCs) exhibit hyperproliferation and preferential susceptibility to mitotoxin compared to wild-type or single haploinsufficient controls. In serial adoptive transfers that rigorously challenge self-renewal, E47hetp21het LT-HSCs dramatically and progressively decline, indicating importance of cell-intrinsic E47-p21 in preserving LT-HSCs under stress. Transient numeric recovery of downstream ST-HSCs enabled the production of functionally competent myeloid but not lymphoid cells as common lymphoid progenitors (CLPs) were decreased and peripheral lymphocytes virtually ablated. Thus, we demonstrate developmental compartment-specific and lineage-specific requirement for the E47-p21 pathway in maintaining LT-HSC, B and T cells under hematopoietic repopulation stress in vivo.
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