Lu H, Huang D, Saederup N et al.Macrophages recruited via CCR2 produce insulin-like growth factor-1 to repair acute skeletal muscle injury. FASEB J 25:358-369

Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave./S90, Cleveland, OH 44195, USA.
The FASEB Journal (Impact Factor: 5.04). 10/2010; 25(1):358-69. DOI: 10.1096/fj.10-171579
Source: PubMed


CC chemokine receptor 2 (CCR2) is essential to acute skeletal muscle injury repair. We studied the subpopulation of inflammatory cells recruited via CCR2 signaling and their cellular functions with respect to muscle regeneration. Mobilization of monocytes/macrophages (MOs/MPs), but not lymphocytes or neutrophils, was impaired from bone marrow to blood and from blood to injured muscle in Ccr2(-/-) mice. While the Ly-6C(+) but not the Ly-6C(-) subset of MOs/MPs was significantly reduced in blood, both subsets were drastically reduced in injured muscle of Ccr2(-/-) mice. Expression of insulin-like growth factor-1 (IGF-I) was markedly up-regulated in injured muscle of wild-type but not Ccr2(-/-) mice. IGF-I was strongly expressed by macrophages within injured muscle, more prominently by the Ly-6C(-) subset. A single injection of IGF-I, but not PBS, into injured muscle to replace IGF-I remarkably improved muscle regeneration in Ccr2(-/-) mice. CCR2 was not detected in myogenic cells or capillary endothelial cells in injured muscle to suggest its direct involvement in muscle regeneration or angiogenesis. We conclude that CCR2 is essential to acute skeletal muscle injury repair primarily by recruiting Ly-6C(+) MOs/MPs. Within injured muscle, these cells conduct phagocytosis, contribute to accumulation of intramuscular Ly-6C(-) macrophages, and produce a high level of IGF-I to promote muscle regeneration.

19 Reads
  • Source
    • "MCP-1 and its receptor CCR2 are involved in recruitment of various cells, including leukocytes, BMSCs and hematopoietic stem cells [30]–[33], and in the regeneration of damaged tissues [34], [35]. As established in earlier developmental studies, CCR2 is necessary for organ-specific homing of bone marrow-derived pluripotent mesenchymal stem cells into damaged tissues [36], [37]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective The purpose of this study was to investigate chemokine profiles and their functional roles in the early phase of fracture healing in mouse models. Methods The expression profiles of chemokines were examined during fracture healing in wild-type (WT) mice using a polymerase chain reaction array and histological staining. The functional effect of monocyte chemotactic protein-1 (MCP-1) on primary mouse bone marrow stromal cells (mBMSCs) was evaluated using an in vitro migration assay. MCP-1−/− and C-C chemokine receptor 2 (CCR2)−/− mice were fractured and evaluated by histological staining and micro-computed tomography (micro-CT). RS102895, an antagonist of CCR2, was continuously administered in WT mice before or after rib fracture and evaluated by histological staining and micro-CT. Bone graft exchange models were created in WT and MCP-1−/− mice and were evaluated by histological staining and micro-CT. Results MCP-1 and MCP-3 expression in the early phase of fracture healing were up-regulated, and high levels of MCP-1 and MCP-3 protein expression observed in the periosteum and endosteum in the same period. MCP-1, but not MCP-3, increased migration of mBMSCs in a dose-dependent manner. Fracture healing in MCP-1−/− and CCR2−/− mice was delayed compared with WT mice on day 21. Administration of RS102895 in the early, but not in the late phase, caused delayed fracture healing. Transplantation of WT-derived graft into host MCP-1−/− mice significantly increased new bone formation in the bone graft exchange models. Furthermore, marked induction of MCP-1 expression in the periosteum and endosteum was observed around the WT-derived graft in the host MCP-1−/− mouse. Conversely, transplantation of MCP-1−/− mouse-derived grafts into host WT mice markedly decreased new bone formation. Conclusions MCP-1/CCR2 signaling in the periosteum and endosteum is essential for the recruitment of mesenchymal progenitor cells in the early phase of fracture healing.
    PLoS ONE 08/2014; 9(8):e104954. DOI:10.1371/journal.pone.0104954 · 3.23 Impact Factor
  • Source
    • "Some researchers reported that AKI induced kidney inflammation and fibrosis involving M1 and M2 macrophages, respectively [95, 96]. M1 macrophages predominate in the early stage of AKI and produce multiple cytokines and chemokines to recruit the immune cells and activate the innate host defense. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute kidney injury (AKI) remains to be an independent risk factor for mortality and morbidity. Inflammation is believed to play a major role in the pathophysiology of AKI. Exogenous mesenchymal stem cells (MSCs) are now under extensive investigation as a potential therapy for AKI. Various preclinical studies indicated the beneficial effects of MSCs in alleviating renal injury and accelerating tissue repair. However the mechanisms responsible for these effects are incompletely understood. In the recent years, anti-inflammatory/immunoregulatory properties of MSCs have become one of the important issues in the treatment of AKI. This review will summarize the current literature on the regulation of inflammatory mediators via exogenous MSCs contributing to the recovery from AKI.
    Mediators of Inflammation 04/2014; 2014(6):261697. DOI:10.1155/2014/261697 · 3.24 Impact Factor
  • Source
    • "Recently, it has been demonstrated that intramuscular F4/80 macrophage in injured muscle is the major cellular source of IGF-1 [34]. Many studies have proven increased IGF-1 mRNA levels during muscle regeneration. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Skeletal muscle, a tissue endowed with remarkable endogenous regeneration potential, is still under focused experimental investigation mainly due to treatment potential for muscle trauma and muscular dystrophies. Resident satellite cells with stem cell features were enthusiastically described quite a long time ago, but activation of these cells is not yet controlled by any medical interventions. However, after thorough reports of their existence, survival, activation, and differentiation there are still many questions to be answered regarding the intimate mechanism of tissue regeneration. This review delivers an up-to-date inventory of the main known key players in skeletal muscle repair, revealed by various models of tissue injuries in mechanical trauma, toxic lesions, and muscular dystrophy. A better understanding of the spatial and temporal relationships between various cell populations, with different physical or paracrine interactions and phenotype changes induced by local or systemic signalling, might lead to a more efficient approach for future therapies.
    03/2014; 2014(5):957014. DOI:10.1155/2014/957014
Show more