Shared signaling systems in myeloid cell-mediated muscle regeneration

Abstract

Much of the focus in muscle regeneration has been placed on the identification and delivery of stem cells to promote regenerative capacity. As those efforts have advanced, we have learned that complex features of the microenvironment in which regeneration occurs can determine success or failure. The immune system is an important contributor to that complexity and can determine the extent to which muscle regeneration succeeds. Immune cells of the myeloid lineage play major regulatory roles in tissue regeneration through two general, inductive mechanisms: instructive mechanisms that act directly on muscle cells; and permissive mechanisms that act indirectly to influence regeneration by modulating angiogenesis and fibrosis. In this article, recent discoveries that identify inductive actions of specific populations of myeloid cells on muscle regeneration are presented, with an emphasis on how processes in muscle and myeloid cells are co-regulated. KEY WORDS: Muscle regeneration, Macrophage phenotype, Signaling systems IntroductionAcute trauma, chronic disease or disruption of vascularization cause rapid death of skeletal muscle. Functional recovery of the damaged tissue is determined by interacting cellular responses, including stem cell activation, proliferation and differentiation, vascular repair, and tissue fibrosis during healing. Experimental approaches to improve muscle regeneration have focused on identifying stem cell populations that promote regeneration and refining their delivery, while using genetic or pharmacological manipulations to influence angiogenesis and fibrosis. However, those approaches are sensitive to the presence of myeloid cells in the injured muscle, suggesting that manipulations of myeloid cells can provide novel strategies to potentiate muscle regeneration. As knowledge of myeloid cell involvement in muscle regeneration has grown, we have come to appreciate that multiple subpopulations interact in complex and delicately balanced ways to influence regeneration. Perturbations in myeloid cell number, phenotype or the stage of regeneration at which they are present can yield vastly different outcomes in the regenerative process. As these complexities become better understood, there is hope that knowledge can be exploited to improve muscle regeneration therapy.In this Review, inductive processes through which myeloid cells influence muscle regeneration are presented, including instructive processes that directly influence developmental gene expression in muscle and permissive processes that modify the environment in which regeneration occurs. Here, muscle 'regeneration' refers to processes in damaged muscle tissue that lead to the restoration of normal structure and homeostasis, especially those events that influence the differentiation and growth of muscle cells that replace damaged tissue (Box 1). In addition, we emphasize discoveries that have contributed to understanding the mechanisms that coordinate phenotypic switches in myeloid cell populations with progressive stages of musc...

Therapeutic Potential of Adipose-Derived Stem Cells and Macrophages for Ischemic Skeletal Muscle Repair

“…In the alternative, IL-4 driven M2 polarization, expression of CCR2 is significantly downregulated, which is consistent with previous reports on MPs trafficking [30] as well as the notion that M2 MPs may downregulate their chemokine receptor expression in order to maintain contact with regenerating fibers [32] persisting within regenerating tissue [54]. The CCL2-CCR2 axis has been long recognized as a primary axis for MPs recruitment into injured skeletal muscle [35,[44][45] as well as its role in MP trafficking toward myoblasts [30][31]47]. According to our data, this could also be an important pathway mediating mASC-mMP as well as mMP-myoblast cross-talk in vivo.…”

“…The expression of mannose receptor (CD206) on mMPs followed in vitro polarization trend, with decreased expression after M1 polarization and significant upregulation after IL-4 treatment. These data are consistent with existing literature reporting CD206 expression on M2 MPs in vivo [32][33][34][35].…”

“…Arginase was previously shown to protect MyoD transcription factor from degradation in the highly inflammatory setting [38,42], while TNF-α was shown to be beneficial for proliferation of myoblasts [43]. The CCR2-CCL2 axis has been long recognized as a primary axis for the recruitment of MPs into injured skeletal muscle [35,[44][45] and facilitation of their interactions with myoblasts [30][31][32][46][47][48]. IL-10 is known to be a potent immunomodulatory cytokine [49][50][51].…”

Cell death, clearance and immunity in the skeletal muscle

“…They disappear once the tissue is completely healed. 66 Polymorphonuclear cells, including neutrophils and eosinophils, are the first leukocytes to be recruited in the damaged tissue. Shortly after, macrophages accumulate and subsequently become the dominant leukocyte population.…”

“…Muscle stem cells fail to activate their regenerative potential in the absence of the inflammatory response. 66,70,74 The release of DAMPs/alarmins as a consequence of cell death and of immune cell activation might be important in the reciprocal activation/regulation of immune and of muscle stem/progenitor cells. The availability of novel elegant genetic inducible cell-fate mapping models will be valuable for the better understanding of the overall scenario.…”