| Budget Amount *help |
¥51,350,000 (Direct Cost: ¥39,500,000、Indirect Cost: ¥11,850,000)
Fiscal Year 2007: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000)
Fiscal Year 2006: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000)
Fiscal Year 2005: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000)
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| Research Abstract |
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.
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