Mouse Cancer Genetics Program, Center for Cancer Research, NCI, Frederick, MD 21702, USA.
Mouse Cancer Genetics Program, Center for Cancer Research, NCI, Frederick, MD 21702, USA; Basic Science Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
Cell Rep. 2020 Apr 28;31(4):107572. doi: 10.1016/j.celrep.2020.107572.
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, Id1Id3 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. Id1Id3 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.
研究调节内皮细胞（EC）生长和存活的机制对于理解 EC 的稳态以及 EC 如何维持干细胞龛至关重要。我们在这里报告，成年 EC 中 Id 基因的靶向缺失导致扩张、渗漏的窦状隙和炎症状态，随着时间的推移而加重。窦状隙完整性的破坏导致造血干细胞（HSC）增殖、分化、迁移和耗竭增加。在机制上，由于 Id 基因缺失后 Bcl2 家族基因表达减少，窦状 EC（SEC）显示出凋亡增加。此外，Id1Id3 SEC 和上游类型 H 血管显示出细胞周期蛋白依赖性激酶抑制剂 p21 和 p27 的表达增加，增殖能力受损，通过降低 E2-2 的表达可以得到挽救。Id1Id3 小鼠由于血管再生和造血功能衰竭而无法在亚致死剂量照射下存活。因此，Id 基因对于 BM SEC 在稳态和应激期间的存活和再生以及维持 HSC 发育是必需的。
