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

趋化因子是一类结构相关的小分子，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（CXCL12/SDF-1/PBSF）及其主要生理受体CXCR4对于造血细胞（包括造血干细胞（hsc））的B淋巴生成和骨髓定植至关重要。此外，我们在成人骨髓中发现了少量表达大量CXCL12的基质细胞，我们称之为富含CXCL12的网状（CAR）细胞。在这项研究中，我们发现在成年小鼠中诱导删除CXCR4导致HSC数量严重减少。这些发现表明，CXCL12-CXCR4信号在维持静止的HSC池中起着至关重要的作用，并表明CAR细胞似乎是HSC生态位的关键组成部分。浆细胞样树突状细胞（pDCs），也被称为I型干扰素（IFN）产生细胞，起源于造血干细胞，被认为在抗病毒免疫中发挥核心作用。我们接下来的研究表明，在体内缺乏CXCR4的情况下，pDCs及其早期祖细胞的数量严重减少。此外，大多数pDCs与骨髓内腔的CAR细胞接触。因此，我们确定了CXCL12是细胞壁龛产生pDC的关键调控因子，为pDC的治疗控制提供了新的靶点。总之，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.