CCR2 mediates hematopoietic stem and progenitor cell trafficking to sites of inflammation in mice
CCR2 mediates hematopoietic stem and progenitor cell trafficking to sites of inflammation in mice
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DOI：
10.1172/jci40310
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发表时间：
2010-04-01
影响因子：
15.9
通讯作者：
Charo, Israel F.
中科院分区：
文献类型：
--
作者：
Si, Yue;Tsou, Chia-Lin;Charo, Israel F.
造血干细胞来源于脑卒中，是一种自我更新的多能细胞，可发育成循环血细胞。它们与炎症实质组织的修复有关，但调节它们向炎症部位运输的信号尚不清楚。由于单核细胞通过激活表面CCR2的化学引诱剂被募集到炎症部位，我们研究了造血干细胞是否也通过CCR2被募集到炎症部位。初步分析表明，在小鼠中，CCR2在造血干细胞和造血祖细胞（HPCs）亚群上表达，并且新分离的原始造血细胞(Lin（-)c-Kit（+）细胞）在体外对CCR2配体有应答。体内分析表明，在注射巯基乙酸酯引起无菌性炎症和给药对乙酰氨基酚引起肝损伤后，内源性hsc /HPCs分别被积极募集到腹膜和肝脏，而Ccr2（-/-）小鼠则没有。从腹膜中恢复的造血干细胞/造血干细胞成功地移植到放射的原发性和继发性受体骨髓中，证实了它们的自我更新和多能性。重要的是，外源性WT而不是Ccr2（-/-）、hsc /HPCs加速了对乙酰氨基酚诱导的肝损伤的消退，并触发了巨噬细胞M2或修复表型特征基因的表达。这些发现揭示了我们认为CCR2在hsc /HPCs归巢到炎症部位中的新作用，并提示趋化因子在促进组织修复和再生中的新功能。
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.