Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
Laboratory Animal Center, Wakayama Medical University, Wakayama, 641-8509, Japan.
Nat Commun. 2019 Aug 2;10(1):3496. doi: 10.1038/s41467-019-11386-4.
The timely mobilization of hematopoietic stem and progenitor cells (HSPCs) is essential for maintaining hematopoietic and tissue leukocyte homeostasis. Understanding how HSPCs migrate between bone marrow (BM) and peripheral tissues is of great significance in the clinical setting, where therapeutic strategies for modulating their migration capacity determine the clinical outcome. Here, we identify an epigenetic regulator, Phc2, as a critical modulator of HSPC trafficking. The genetic ablation of Phc2 in mice causes a severe defect in HSPC mobilization through the derepression of Vcam1 in bone marrow stromal cells (BMSCs), ultimately leading to a systemic immunodeficiency. Moreover, the pharmacological inhibition of VCAM-1 in Phc2-deficient mice reverses the symptoms. We further determine that Phc2-dependent Vcam1 repression in BMSCs is mediated by the epigenetic regulation of H3K27me3 and H2AK119ub. Together, our data demonstrate a cell-extrinsic role for Phc2 in controlling the mobilization of HSPCs by finely tuning their bone marrow niche.
造血干细胞和祖细胞（HSPCs）的及时动员对于维持造血和组织白细胞稳态至关重要。了解 HSPCs 如何在骨髓（BM）和外周组织之间迁移，对于临床治疗策略具有重要意义，因为这些策略可以调节其迁移能力，从而决定临床治疗效果。在这里，我们鉴定出一种表观遗传调节剂 Phc2，它是 HSPC 迁移的关键调节剂。Phc2 在小鼠中的基因缺失会导致 HSPC 动员严重缺陷，这是通过骨髓基质细胞（BMSCs）中 Vcam1 的去抑制引起的，最终导致全身性免疫缺陷。此外，在 Phc2 缺陷小鼠中抑制 VCAM-1 的药物治疗可逆转症状。我们进一步确定，BMSCs 中 Phc2 依赖性 Vcam1 抑制是由 H3K27me3 和 H2AK119ub 的表观遗传调控介导的。总之，我们的数据表明 Phc2 通过精细调节其骨髓龛，在控制 HSPC 动员方面发挥细胞外在作用。
