State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
School of Life Sciences, Hebei University, No. 180 Wusi Dong Road, Lian Chi District, Baoding City, Hebei Province, 071000, China.
Adv Sci (Weinh). 2022 Feb;9(5):e2103838. doi: 10.1002/advs.202103838. Epub 2021 Dec 19.
Hematopoietic stem and progenitor cells (HSPCs) possess the remarkable ability to regenerate the whole blood system in response to ablated stress demands. Delineating the mechanisms that maintain HSPCs during regenerative stresses is increasingly important. Here, it is shown that Hemgn is significantly induced by hematopoietic stresses including irradiation and bone marrow transplantation (BMT). Hemgn deficiency does not disturb steady-state hematopoiesis in young mice. Hemgn HSPCs display defective engraftment activity during BMT with reduced homing and survival and increased apoptosis. Transcriptome profiling analysis reveals that upregulated genes in transplanted Hemgn HSPCs are enriched for gene sets related to interferon gamma (IFN-γ) signaling. Hemgn HSPCs show enhanced responses to IFN-γ treatment and increased aging over time. Blocking IFN-γ signaling in irradiated recipients either pharmacologically or genetically rescues Hemgn HSPCs engraftment defect. Mechanistical studies reveal that Hemgn deficiency sustain nuclear Stat1 tyrosine phosphorylation via suppressing T-cell protein tyrosine phosphatase TC45 activity. Spermidine, a selective activator of TC45, rescues exacerbated phenotype of HSPCs in IFN-γ-treated Hemgn mice. Collectively, these results identify that Hemgn is a critical regulator for successful engraftment and reconstitution of HSPCs in mice through negatively regulating IFN-γ signaling. Targeted Hemgn may be used to improve conditioning regimens and engraftment during HSPCs transplantation.
造血干细胞和祖细胞（HSPCs）具有响应消融应激需求再生整个血液系统的非凡能力。阐明在再生应激期间维持 HSPCs 的机制变得越来越重要。在这里，研究表明 Hemgn 被造血应激（包括辐照和骨髓移植（BMT））显著诱导。Hemgn 缺陷不会干扰年轻小鼠的稳态造血。Hemgn HSPCs 在 BMT 期间表现出植入活性缺陷，归巢和存活减少，凋亡增加。转录组谱分析显示，移植的 Hemgn HSPCs 中上调的基因富集与干扰素γ（IFN-γ）信号相关的基因集。Hemgn HSPCs 对 IFN-γ治疗的反应增强，并且随着时间的推移老化增加。通过药理学或遗传方法阻断辐照受者中的 IFN-γ信号可挽救 Hemgn HSPCs 的植入缺陷。机制研究表明，Hemgn 缺乏通过抑制 T 细胞蛋白酪氨酸磷酸酶 TC45 的活性来维持核 Stat1 酪氨酸磷酸化。亚精胺是 TC45 的选择性激活剂，可挽救 IFN-γ处理的 Hemgn 小鼠中 HSPCs 的恶化表型。总之，这些结果表明，Hemgn 通过负调控 IFN-γ信号，是小鼠 HSPCs 成功植入和重建的关键调节剂。靶向 Hemgn 可能用于改善 HSPCs 移植期间的调理方案和植入。
