Department of Immunobiology and Hematology
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 embryonic viability, development of B lymphocytes, colonization of bone marrow by hematopoietic cells, colonization of the gonads by primordial germ cells (PGCs) and cardiovascular formation during ontogeny (Nagasawa et al. Nature 382, 635-638 (1996); Tachibana et al. Nature 393, 591-594 (1998); Egawa et al. Immunity 15, 323-334 (2001)).
On the other hand, we have found that a small population of stromal cells expressing high amounts of CXCL12, which we call CXCL12-abundant reticular (CAR) cells are scattered throughout bone marrow. Most of multipotent hematopoietic progenitors, pre-pro-B cells and the end-stage B lymphocytes plasma cells were attached to CAR cells, suggesting that CAR cells function as the special microenvironments niches for primitive hematopoietic progenitors and B lymphocytes (Tokoyoda et al. Immunity 20, 707-718(2004)).
In recent years, we have studied the role of CXCL12 in HSCs in adult bone marrow and their interaction with CAR cells. In adult bone marrow, the special niches are thought to nurture a pool of HSCs, which give rise to all types of blood cells including lymphocytes and myeloid cells. It has been shown previously that many HSCs reside near the vasculature and some are found near bone surfaces but the molecular regulatory mechanism of niches for HSC maintenance remains unclear. We have shown that the induced deletion of CXCR4 in adult mice, resulted in severe reduction of HSC numbers and increased sensitivity to myelotoxic injury, although it did not impair expansion of the more mature progenitors. Most HSCs were found in contact with CAR cells, which surrounded sinusoidal endothelial cells or were located near the endosteum. 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, including both vascular and endosteal niches in adult bone marrow.
This study revealed for the first time the environmental factor essential for maintaining the HSC pool and produced by bone marrow stromal cell niches, including vascular niches, where many HSCs might reside. Considering that CXCL12 also acts on other organ-specific stem cells including PGCs, our findings provide a novel basis for probing the molecular mechanisms that control maintenance of the stem cell pool within microenvironmental niches in mammals.