Department of Medicine, Division of Regenerative Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, NJ, 07110, USA.
Nat Commun. 2020 Feb 3;11(1):666. doi: 10.1038/s41467-020-14478-8.
Inflammatory signals arising from the microenvironment have emerged as critical regulators of hematopoietic stem cell (HSC) function during diverse processes including embryonic development, infectious diseases, and myelosuppressive injuries caused by irradiation and chemotherapy. However, the contributions of cellular subsets within the microenvironment that elicit niche-driven inflammation remain poorly understood. Here, we identify endothelial cells as a crucial component in driving bone marrow (BM) inflammation and HSC dysfunction observed following myelosuppression. We demonstrate that sustained activation of endothelial MAPK causes NF-κB-dependent inflammatory stress response within the BM, leading to significant HSC dysfunction including loss of engraftment ability and a myeloid-biased output. These phenotypes are resolved upon inhibition of endothelial NF-κB signaling. We identify SCGF as a niche-derived factor that suppresses BM inflammation and enhances hematopoietic recovery following myelosuppression. Our findings demonstrate that chronic endothelial inflammation adversely impacts niche activity and HSC function which is reversible upon suppression of inflammation.
炎症信号源于微环境，在包括胚胎发育、传染病以及辐射和化疗引起的骨髓抑制损伤等多种过程中，已成为造血干细胞（HSC）功能的关键调节因子。然而，微环境中引发龛位驱动炎症的细胞亚群的贡献仍知之甚少。在这里，我们确定内皮细胞是骨髓（BM）炎症和骨髓抑制后观察到的 HSC 功能障碍的关键组成部分。我们证明，内皮细胞 MAPK 的持续激活导致 BM 中 NF-κB 依赖性炎症应激反应，导致 HSC 功能显著障碍，包括植入能力丧失和偏向髓系的输出。这些表型在抑制内皮细胞 NF-κB 信号后得到解决。我们确定 SCGF 是一种龛位衍生因子，可抑制 BM 炎症并增强骨髓抑制后的造血恢复。我们的研究结果表明，慢性内皮炎症对龛位活性和 HSC 功能产生不利影响，炎症抑制后可恢复其功能。
