Medical Scientist Training Program and Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Section of Infectious Disease, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Rep. 2020 Dec 22;33(12):108530. doi: 10.1016/j.celrep.2020.108530.
During chronic infection, the inflammatory cytokine interferon gamma (IFNγ) damages hematopoietic stem cells (HSCs) by disrupting quiescence and promoting excessive terminal differentiation. However, the mechanism by which IFNγ hinders HSC quiescence remains undefined. Using intravital 3-dimensional microscopy, we find that IFNγ disrupts the normally close interaction between HSCs and CXCL12-abundant reticular (CAR) cells in the HSC niche. IFNγ stimulation increases expression of the cell surface protein BST2, which we find is required for IFNγ-dependent HSC relocalization and activation. IFNγ stimulation of HSCs increases their E-selectin binding by BST2 and homing to the bone marrow, which depends on E-selectin binding. Upon chronic infection, HSCs from mice lacking BST2 are more quiescent and more resistant to depletion than HSCs from wild-type mice. Overall, this study defines a critical mechanism by which IFNγ promotes niche relocalization and activation in response to inflammatory stimulation and identifies BST2 as a key regulator of HSC quiescence. VIDEO ABSTRACT.
在慢性感染期间，炎症细胞因子干扰素 γ（IFNγ）通过破坏静止状态和促进过度终末分化来损伤造血干细胞（HSCs）。然而，IFNγ 阻碍 HSC 静止的机制仍未确定。我们使用活体三维显微镜发现，IFNγ 破坏了 HSC 龛中 HSCs 与 CXCL12 丰富的网状（CAR）细胞之间的正常紧密相互作用。IFNγ 刺激增加了细胞表面蛋白 BST2 的表达，我们发现这对于 IFNγ 依赖性 HSC 重定位和激活是必需的。IFNγ 刺激 HSCs 通过 BST2 增加其与 E-选择素的结合，并归巢到骨髓中，这取决于 E-选择素的结合。在慢性感染期间，缺乏 BST2 的小鼠的 HSCs 比野生型小鼠的 HSCs 更静止，并且更能抵抗耗竭。总的来说，这项研究定义了一个关键的机制，即 IFNγ 如何响应炎症刺激促进龛位的重定位和激活，并确定 BST2 是 HSC 静止的关键调节剂。视频摘要。
