State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
Center for Translational Medicine, Ministry of Education Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, 610041, Chengdu, Sichuan, China.
Nat Commun. 2018 Sep 14;9(1):3746. doi: 10.1038/s41467-018-06282-2.
In response to myeloablative stresses, HSCs are rapidly activated to replenish myeloid progenitors, while maintaining full potential of self-renewal to ensure life-long hematopoiesis. However, the key factors that orchestrate HSC activities during physiological stresses remain largely unknown. Here we report that Med23 controls the myeloid potential of activated HSCs. Ablation of Med23 in hematopoietic system leads to lymphocytopenia. Med23-deficient HSCs undergo myeloid-biased differentiation and lose the self-renewal capacity. Interestingly, Med23-deficient HSCs are much easier to be activated in response to physiological stresses. Mechanistically, Med23 plays essential roles in maintaining stemness genes expression and suppressing myeloid lineage genes expression. Med23 is downregulated in HSCs and Med23 deletion results in better survival under myeloablative stress. Altogether, our findings identify Med23 as a gatekeeper of myeloid potential of HSCs, thus providing unique insights into the relationship among Med23-mediated transcriptional regulations, the myeloid potential of HSCs and HSC activation upon stresses.
在应对骨髓清除性应激时，造血干细胞（HSCs）被迅速激活以补充髓系祖细胞，同时保持自我更新的全部潜能，以确保终生造血。然而，调节 HSCs 活性的关键因素在很大程度上仍然未知。在这里，我们报告 Med23 控制激活的 HSCs 的髓系潜能。造血系统中 Med23 的缺失导致淋巴细胞减少症。Med23 缺陷的 HSCs 经历偏向髓系的分化，并失去自我更新能力。有趣的是，Med23 缺陷的 HSCs 更容易在生理应激下被激活。在机制上，Med23 在维持干性基因表达和抑制髓系谱系基因表达方面发挥着重要作用。Med23 在 HSCs 中下调，Med23 缺失导致在骨髓清除性应激下更好的生存。总之，我们的研究结果确定 Med23 是 HSCs 髓系潜能的守门员，从而为 Med23 介导的转录调控、HSCs 的髓系潜能以及应激下 HSC 激活之间的关系提供了独特的见解。
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