CCR2 mediates hematopoietic stem and progenitor cell trafficking to sites of inflammation in mice
Yue Si, … , Kelsey Croft, Israel F. Charo
Yue Si, … , Kelsey Croft, Israel F. Charo
Published March 15, 2010
Citation Information: J Clin Invest. 2010;120(4):1192-1203. https://doi.org/10.1172/JCI40310.
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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 8

CCR2+Lin– BM cells differentiate into M2 macrophages in APAP-injured liver.

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CCR2+Lin– BM cells differentiate into M2 macrophages in APAP-injured liv...
(A–C) Identification of donor-derived CD45.2 cells in APAP-treated liver. At 48 hours after transfer of CD45.2+ WT or Ccr2–/– Lin– BM cells into APAP-treated CD45.1 mice, liver nonhepatocytes were isolated and stained for CD45.2 (A and B). Representative FACS plots are shown. (C) Number of donor-derived CD45.2+ cells per 1 million of nonhepatocytes are shown. Values are mean ± SD. *P < 0.01 vs. WT. (D–G) Donor Lin– BM cells differentiate primarily into IMs. (D) Two macrophage populations in the liver of mice 48 hours after APAP challenge. Nonhepatocytes were isolated and stained with anti-CD45.2, anti-CD11b, and anti-F4/80. CD45.2+ cells were gated and evaluated for the expression of F4/80 and CD11b to separate IMs from KCs. (E) IMs and KCs from mice who received WT CD45.2+Lin– cells. (F) IMs and KCs from mice who received Ccr2–/– CD45.2+Lin– cells. (G) Quantification of FACS plots. Values are mean ± SD per 1 million nonhepatocytes. *P < 0.05 versus IM cells derived from WT Lin– BM cells. (H–J) Hepatic IMs and KCs from mice 48 hours after APAP challenge were purified by FACS. RNA was extracted, and mRNA levels were determined by qRT-PCR, including (H) chemokine receptors CCR2 and CX3CR1 and genes associated with classical (M1) macrophage activation (I) or M2 macrophage activation (J). Values are mean ± SD.