CCR2 mediates hematopoietic stem and progenitor cell trafficking to sites of inflammation in mice
Yue Si, Chia-Lin Tsou, Kelsey Croft, Israel F. Charo
Yue Si, Chia-Lin Tsou, Kelsey Croft, Israel F. Charo
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Research Article Inflammation

CCR2 mediates hematopoietic stem and progenitor cell trafficking to sites of inflammation in mice

Abstract

HSCs are BM-derived, self-renewing multipotent cells that develop into circulating blood cells. They have been implicated in the repair of inflamed parenchymal tissue, but the signals that regulate their trafficking to sites of inflammation are unknown. As monocytes are recruited to sites of inflammation via chemoattractants that activate CCR2 on their surface, we investigated whether HSCs are also recruited to sites of inflammation through CCR2. Initial analysis indicated that in mice, CCR2 was expressed on subsets of HSCs and hematopoietic progenitor cells (HPCs) and that freshly isolated primitive hematopoietic cells (Lin–c-Kit+ cells) responded to CCR2 ligands in vitro. In vivo analysis indicated that after instillation of thioglycollate to cause aseptic inflammation and after administration of acetaminophen to induce liver damage, endogenous HSCs/HPCs were actively recruited to the peritoneum and liver, respectively, in WT but not Ccr2–/– mice. HSCs/HPCs recovered from the peritoneum successfully engrafted into the BM of irradiated primary and secondary recipients, confirming their self renewal and multipotency. Importantly, administration of exogenous WT, but not Ccr2–/–, HSCs/HPCs accelerated resolution of acetaminophen-induced liver damage and triggered the expression of genes characteristic of the macrophage M2 or repair phenotype. These findings reveal what we believe to be a novel role for CCR2 in the homing of HSCs/HPCs to sites of inflammation and suggest new functions for chemokines in promoting tissue repair and regeneration.

Authors

Yue Si, Chia-Lin Tsou, Kelsey Croft, Israel F. Charo

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Figure 5

BM engraftment and long-term reconstitution of myeloid and lymphoid lineages with peritoneum-derived HSCs.

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BM engraftment and long-term reconstitution of myeloid and lymphoid line...
(A) Peritoneal Lin– leukocytes from 12 thioglycollate-injected WT CD45.2 mice or Ccr2–/– mice were collected, mixed with 1 × 105 WT CD45.1 BM cells, and injected intravenously into lethally irradiated WT CD45.1 primary recipients. After 16 weeks, BM from the primary recipients was injected into lethally irradiated CD45.2 WT secondary recipients. (B) FACS plots show the percentage of CD45.2+ cells in the peripheral blood of the primary recipients at 8 and 16 weeks after transplantation and a secondary recipient at 16 weeks after transplantation. No engraftment was identified in mice injected with Ccr2–/–Lin– peritoneal cells (data not shown). At 16 weeks, the mean percentage (±SD) of donor chimerism from primary and secondary recipients was 9 ± 3.6 and 2 ± 0.9. Shown are representative FACS plots. (C) Lineage analysis of donor CD45.2 cells in the blood of primary recipients 16 weeks after transplantation. Numbers in the upper right quadrant are percentages of CD45.2+ peripheral blood cells expressing the respective markers. Shown are representative FACS plots.