Med23调控造血干细胞自我更新与分化间稳态维持的机制

Hematopoietic stem cells (HSCs) harbor the capacity of both self-renewal and differentiation to sustain life-long hematopoiesis. While differentiation is responsible for producing all functional blood cells, self-renewal is critical for maintaining the HSC pool size. In order to maintain the homeostasis of the whole hematopoietic system, HSCs precisely adjusts the balance between self-renewal and differentiation, which are actively regulated by multiple key factors. Thus, exploring the key regulatory factors that sustain the balance between self-renewal and differentiation of HSCs has been a central issue in HSC biology. .As a key subunit of the transcriptional mediator complex, Med23 plays an important role in orchestrating the transcriptional profiles in various cell types. Our primary data show that Med23 deficiency leads to serious reduction of the HSC compartments and the common lymphoid progenitors during steady-state hematopoiesis. Moreover, Med23-deficient HSCs display aberrant self-renewal capacity and myeloid-biased differentiation pattern. These data suggest that Med23 may regulate both self-renewal and differentiation of HSCs as well as the balance between them. .In the present program, we first explore the function of Med23 in regulating self-renewal and differentiation of HSCs, followed by eclucidating the molecular mechanism by which Med23 maintains their balance. Finanlly, the relationship between HSC homeostasis and hematopoietic diseases will be revealed based on the Med23 defiecient mouse model. This program aims to provide new insight into the underlying mechanisms that sustain the homeostasis of HSCs, as well as proposing new therapeutic methods of related diseases.

造血干细胞具有自我更新以及分化产生所有血细胞的能力，是维持整个生命周期造血所必须的。造血干细胞自我更新、分化及两者间稳态的维持是一个多因子参与的复杂生理过程，其在造血系统稳态维持中发挥着重要作用，因此参与该过程的关键调控因子受到了广泛的研究。作为转录中介体复合物的一个重要组成亚基，Med23在转录组整体水平的调控中起着不可或缺的作用。我们的初步研究表明：Med23缺失小鼠骨髓中的造血干细胞、多功能前体细胞以及淋系前体细胞的比例及数量均显著下降，进一步分析表明Med23的缺失将导致造血干细胞自我更新能力缺陷及分化潜能异常。鉴于此，本项目将通过系统分析Med23在造血干细胞自我更新及分化中的功能，来研究Med23调控造血干细胞自我更新及分化间稳态维持的分子机制，并进一步探索其在造血系统疾病和肿瘤发生发展中的作用，为阐明造血干细胞稳态维持的机理机制提供线索，并为治疗相关造血系统疾病提供新的思路。

造血干细胞通过调节自我更新和分化来维持造血系统的稳态。在应急情况下，处于静息状态的造血干细胞能够快速激活，分化产生所需要的各种血液细胞，这一过程是如何调控的并不清楚。本研究揭示了转录中介体亚基Med23在造血干细胞髓系分化潜能方面发挥至关重要的调控作用。造血系统特异性敲除Med23小鼠的外周血血常规指标异常，具体表现为淋巴细胞、血细胞以及血红蛋白的降低。对造血干细胞和造血前体细胞的分析结果表明，Med23敲除后造血干细胞自我更新功能受损，髓系前体细胞增加而淋系前体细胞减少，表明缺失Med23的造血干细胞偏向于髓系分化而降低了自我更新能力。转录组分析结果揭示Med23敲除的造血干细胞提前表达了髓系特征性基因而抑制了干性相关基因和淋系特征性基因表达。单细胞转录组分析结果进一步表明，Med23敲除小鼠的髓系偏好性造血干细胞明显增多，而淋系偏好性造血干细胞明显减少。对小鼠进行连续的5-FU髓系清除处理，Med23敲除的小鼠能够更快地分化产生髓系细胞进而能更好抵抗这种应急情况。该工作揭示了Med23调控造血干细胞髓系分化潜能的分子机制，阐明了Med23介导的转录调控、造血干细胞的活化以及髓系分化潜能之间的关系。该研究为治疗相关造血系统疾病以及实现急性造血提供了新的思路。