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Bone marrow-derived cell regulation of skeletal muscle regeneration

Dongxu Sun^*, Carlo O. Martinez^*, Oscar Ochoa^*, Lourdes Ruiz-Willhite^*, Jose R. Bonilla^*, Victoria E. Centonze, Lindsay L. Waite, Joel E. Michalek, Linda M. McManus^,¶,|| and Paula K. Shireman^*,||,**,,1

^* Department of Surgery,

Department of Cell and Structural Biology,

Department of Epidemiology and Biostatistics,

Department of Pathology,

^¶ Department of Periodontics,

^|| Department of Medicine, and

^** Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas, USA; and

Audie Murphy Veterans Hospital, South Texas Veterans Health Care System, San Antonio, Texas, USA

¹Correspondence: Department of Surgery, 7703 Floyd Curl Dr., MC 7741, San Antonio, TX 78229-3900, USA. E-mail: shireman{at}uthscsa.edu

Limb regeneration requires the coordination of multiple stem cell populations to recapitulate the process of tissue formation. Therefore, bone marrow (BM) -derived cell regulation of skeletal muscle regeneration was examined in mice lacking the CC chemokine receptor 2 (CCR2). Myofiber size, numbers of myogenic progenitor cells (MPCs), and recruitment of BM-derived cells and macrophages were assessed after cardiotoxin-induced injury of chimeric mice produced by transplanting BM from wild-type (WT) or CCR2^–/– mice into irradiated WT or CCR2^–/– host mice. Regardless of the host genotype, muscle regeneration and recruitment of BM-derived cells and macrophages were similar in mice replenished with WT BM, whereas BM-derived cells and macrophage accumulation were decreased and muscle regeneration was impaired in all animals receiving CCR2^–/– BM. Furthermore, numbers of MPCs (CD34⁺/Sca-1^–/CD45^– cells) were significantly increased in mice receiving CCR2^–/– BM despite the decreased size of regenerated myofibers. Thus, the expression of CCR2 on BM-derived cells regulated macrophage recruitment into injured muscle, numbers of MPC, and the extent of regenerated myofiber size, all of which were independent of CCR2 expression on host-derived cells. Future studies in regenerative medicine must include consideration of the role of BM-derived cells, possibly macrophages, in CCR2-dependent events that regulate effective skeletal muscle regeneration.—Sun, D., Martinez, C. O., Ochoa, O., Ruiz-Willhite, L., Bonilla, J. R., Centonze, V. E., Waite, L. L., Michalek, J. E., McManus, L. M., Shireman, P. K. Bone marrow-derived cell regulation of skeletal muscle regeneration.

Key Words: CC chemokine receptor 2 • CCR2 • chimera • inflammation • monocyte/macrophage • myogenic progenitor cell