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

骨髓内环境因素对淋巴造血细胞行为的时空调节

基本信息

批准号：
17209019
负责人：
NAGASAWA Takashi
金额：
$ 32.86万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17209019/
关键词：
Chemokine Bone marrow niche Hematopoietic stem cell (HSCs)B cell Plasmacytoid dendritic cells (pDCs)

项目摘要

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.

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中细胞运输的能力。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B淋巴细胞的生成和包括造血干细胞(HSCs)在内的造血细胞在骨髓的定植是必不可少的。此外，我们还鉴定了一小部分高表达CXCL12的基质细胞，我们称之为成人骨髓中的CXCL12丰富网状细胞(CAR)。在这项研究中，我们已经证明，在成年小鼠中诱导CXCR4的缺失导致HSC数量的严重减少。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，并提示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，来自HSC，被认为在抗病毒免疫中发挥核心作用。接下来，我们发现在体内没有CXCR4的情况下，pDC及其最早的祖细胞的数量严重减少。此外，大多数PDDC与骨髓间隙中的CAR细胞接触。因此，我们将CXCL12确定为PDC发育的关键调控因子，为PDC的治疗控制提供了新的靶点。同时，这些结果为理解骨髓内环境因素对淋巴造血的时空调控提供了新的基础。