The spatiotemporal regulation of cell behavior in lymphohe matopoiesis by environmental factors within bone marrow

趋化因子是一个结构相关的小分子家族，最初被认为具有调节炎症细胞运输的能力。我们已经证明趋化因子CXC趋化因子配体12/基质细胞衍生因子/前B细胞生长刺激因子（CXCL 12/SDF-1/PBSF）及其主要生理受体CXCR 4对于B淋巴细胞生成和造血细胞（包括造血干细胞（HSC））在骨髓中的定殖是必需的。此外，我们已经确定了一小群基质细胞表达大量的CXCL 12，我们称之为CXCL 12丰富的网状（CAR）细胞在成人骨髓。在这项研究中，我们已经表明，诱导删除CXCR 4在成年小鼠中导致严重减少HSC的数量。这些发现表明CXCL 12-CXCR 4信号在维持静止HSC池中起着重要作用，并且表明CAR细胞似乎是HSC niches.Plasmacytoid树突状细胞（pDC）的关键组分，也称为I型干扰素（IFN）产生细胞，其产生自HSC，并且被认为在抗病毒免疫中起核心作用。我们接下来已经表明，在体内不存在CXCR 4的情况下，pDC及其最早祖细胞的数量严重减少。此外，大多数pDC与骨髓间隙中的CAR细胞接触。因此，我们确定了CXCL 12作为细胞小生境产生的pDC发育的关键调节因子，为pDC治疗控制提供了新的靶点，这些结果为理解骨髓内环境因素对淋巴造血的时空调节提供了新的基础。

Chemokines are a family of small structurally related molecules that were recognized originally for their ability to regulate cell trafficking in inflammation. We have shown that a chemokine, CXC chemokine ligand 12/stromal cell-derived factor/pre-B-cell growth stimulating factor (CXCL12/SDF-1/PBSF) and its primary physiologic receptor CXCR4 are essential for B lymphopoiesis and colonization of bone marrow by hematopoietic cells including hematopoietic stem cells (HSCs). In addition, we have identified a small population of stromal cells expressing high amounts of CXCL12, which we call CXCL12-abundant reticular (CAR) cells in adult bone marrow. In this study, we have shown that the induced deletion of CXCR4 in adult mice resulted in severe reduction of HSC numbers. These findings indicate that CXCL12-CXCR4 signaling plays an essential role in maintaining the quiescent HSC pool, and suggest that CAR cells appear to be a key component of HSC niches.Plasmacytoid dendritic cells (pDCs), also known as type I interferon (IFN)-producing cells arise from HSCs and are thought to play central roles in antiviral immunity. We have next shown that the numbers of pDCs and their earliest progenitors were severely decreased in the absence of CXCR4 in vivo. In addition, most pDCs are in contact with CAR cells in the intersinal space of bone marrow. Thus we identified CXCL12 as a key regulator of pDC development produced by cellular niches, providing new targets for pDC therapeutic control.Together, these results provide a novel basis for understanding the spatiotemporal regulation of lymphohematopoiesis by environmental factors within bone marrow.