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Id1 and Id3 Maintain Steady-State Hematopoiesis by Promoting Sinusoidal Endothelial Cell Survival and Regeneration

机译:ID1和ID3通过促进正弦内皮细胞存活和再生来维持稳态血液血液

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摘要

Summary: Investigating mechanisms that regulate endothelial cell (EC) growth and survival is important for understanding EC homeostasis and how ECs maintain stem cell niches. We report here that targeted loss of Id genes in adult ECs results in dilated, leaky sinusoids and a pro-inflammatory state that increases in severity over time. Disruption in sinusoidal integrity leads to increased hematopoietic stem cell (HSC) proliferation, differentiation, migration, and exhaustion. Mechanistically, sinusoidal ECs (SECs) show increased apoptosis because of reduced Bcl2-family gene expression following Id gene ablation. Furthermore, Id1−/−Id3−/− SECs and upstream type H vessels show increased expression of cyclin-dependent kinase inhibitors p21 and p27 and impaired ability to proliferate, which is rescued by reducing E2-2 expression. Id1−/−Id3−/− mice do not survive sublethal irradiation because of impaired vessel regeneration and hematopoietic failure. Thus, Id genes are required for the survival and regeneration of BM SECs during homeostasis and stress to maintain HSC development. : Gadomski et al. show that Id genes are critical regulators of bone marrow endothelial cell proliferation and survival. Selective loss of Id genes in endothelial cells promotes vessel dilation, apoptosis, and increased permeability, leading to the functional decline of hematopoietic stem cells under steady-state and stress conditions. Keywords: endothelial cells, ID proteins, hematopoietic stem cells, hematopoietic microenvironment, instructive niche, transcription factors, tissue regeneration, progenitor cells, proliferation, bone marrow
机译:发明内容:调查调节内皮细胞(EC)生长和存活的机制对于了解EC稳态和ECS如何维持干细胞效力是重要的。我们在此报告的是,成人ECS中的ID基因损失导致扩张,泄漏的正弦曲线和促炎状态随着时间的推移而增加。中断正弦完整性导致造血干细胞(HSC)增殖,分化,迁移和疲劳增加。机械上,正弦EC(秒)显示出增加的细胞凋亡,因为在ID基因消融后的BCL2-族基因表达减少。此外,ID1 - / - ID3 - / - 秒和上游型H血管显示了细胞周期蛋白依赖性激酶抑制剂P21和P27的表达,并通过减少E2-2表达来抵抗损伤的能力。 ID1 - / - ID3 - / - 小鼠由于血管再生和造血故障受损而不存在止逆辐照。因此,在稳态和胁迫下,BM SEC的存活和再生需要ID基因,以维持HSC发育。 :Gadomski等人。表明ID基因是骨髓内皮细胞增殖和存活的关键调节因素。内皮细胞中ID基因的选择性丧失促进血管扩张,细胞凋亡和增加的渗透性,导致稳态和应力条件下造血干细胞的功能下降。关键词:内皮细胞,ID蛋白,造血干细胞,造血微环境,指导性利基,转录因子,组织再生,祖细胞,增殖,骨髓

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