CCR2 Mediates Hematopoietic Stem and Progenitor Cell Trafficking to Inflammation Sites to Enhance Organ Repair.

Abstract 2547

Poster Board II-524

Hematopoietic stem cells (HSCs) are bone-marrow derived, self-renewing pluripotent cells that give rise to terminally differentiated circulating blood cells. Recent work has implicated HSCs in the repair of parenchymal tissue in the setting of inflammation. In response to the antagonist of the chemokine receptor CXCR4, HSCs and their progenitors migrate from bone marrow to the blood. However, little is known about the signals that mediate their trafficking from the blood into peripheral tissues. Recently, we showed that mice genetically deficient in chemokine receptor CCR2 (CCR2–/– mice) have a marked decrease in the number of circulating “inflammatory” (7/4+, Ly6c+) monocytes, but no decrease in myeloid progenitor cells in the bone marrow (Tsou et al, J Clin Invest, 2007, 902). These data indicated that although CCR2 is not necessary for HSCs to differentiate into mature monocytes, it does play a role in monocyte egress from bone marrow to blood. In the current study, we extend this work and investigate the expression of CCR2 on hematopoietic stem cells and progenitor cells (HSPCs), and tested the hypothesis that CCR2 is critical for the recruitment of circulating HSPCs to sites of inflammation. Here we report that the chemokine receptor CCR2 is expressed on subsets of primitive hematopoietic stem cells as well as some early myeloid progenitors but not on the progenitors dedicated to megakaryocyte and erythroid differentiation. CCR2 mediates the chemotaxis of c-Kit+Lin- bone marrow derived cells to MCP-1 (CCL2) and MCP-3 (CCL7), which are known CCR2 ligands. In unchallenged mice, CCR2 appears to play a minimal role in HSCs trafficking. However, following instillation of thioglycollate to cause aseptic inflammation HSPCs were actively recruited to the peritoneum, as demonstrated by both FACS and functional colony formation assays. That these cells were true HSCs was demonstrated by their engraftment into the bone marrow of irradiated recipients. In contrast, mice genetically deficient in CCR2 (CCR2−/−) were profoundly impaired in the recruitment of HSCs to the inflamed peritoneum. Furthermore, in human disease models of acetaminophen induced liver damages, hematopoietic stem and progenitors were increased dramatically at site of injury in WT mice but not in CCR2−/− mice. CCR2 recruited HSPC play a tissue protective role by increase the numbers of M2 macrophages in injured liver. Taken together, these findings document a novel role for CCR2 in the specific homing of primitive hematopoietic stem and progenitors to sites of inflammation and injury, and suggest a new role for chemokines in increasing the numbers of differentiated leukocytes at sites of inflammation. Recruited HSPCs hasten the resolution of the inflammatory response, and promote repair of injured tissue, at least partially due to locally increase the number of tissue reparative macrophages.