Differentially Activated Macrophages Orchestrate Myogenic Precursor Cell Fate During Human Skeletal Muscle Regeneration

Abstract

Macrophages (MPs) exert either beneficial or deleterious effects on tissue repair, depending on their activation/ polarization state. They are crucial for adult skeletal muscle repair, notably by acting on myogenic precursor cells. However, these interactions have not been fully characterized. Here, we explored both in vitro and in vivo, in human, the interactions of differentially activated MPs with myogenic precursor cells (MPCs) during adult myogenesis and skeletal muscle regeneration. We showed in vitro that through the differential secretion of cytokines and growth factors, proinflammatory MPs inhibited MPC fusion while anti-inflammatory MPs strongly promoted MPC differentiation by increasing their commitment into differentiated myocytes and the formation of mature myotubes. Furthermore, the in vivo time course of expression of myogenic and MP markers was studied in regenerating human healthy muscle after damage. We observed that regenerating areas containing proliferating MPCs were preferentially associated with MPs expressing proinflammatory markers. In the same muscle, regenerating areas containing differentiating myogenin-positive MPCs were preferentially coupled to MPs harboring anti-inflammatory markers. These data demonstrate for the first time in human that MPs sequentially orchestrate adult myogenesis during regeneration of damaged skeletal muscle. These results support the emerging concept that inflammation, through MP activation, controls stem cell fate and coordinates tissue repair. STEM CELLS 2013;31:384-396 Disclosure of potential conflicts of interest is found at the end of this article.

Photobiomodulation and different macrophages phenotypes during muscle tissue repair

“…M1 cell surface marker CD68 is a receptor for oxidized low‐density lipoproteins that activate phagocytosis and increase the production of proinflammatory cytokines when specifically connected. Normal muscle tissue does not express CD68 + macrophages 3, 4…”

“…M2 macrophages produce anti‐inflammatory cytokines and growth factors as TGF‐ β and IL‐10 as well as enzymes that are important to angiogenesis, fibroblast proliferation and the differentiation of myogenic precursor cells 1, 4, 5. M2 macrophage surface marker CD206 is a mannose receptor that internalizes sugar moieties on molecules in inflamed tissue, such as myeloperoxidase 3.…”

“…CD163 is a specific receptor for hemoglobin and haptaglobin complexes 3. Specific binding to the both receptors triggers the expression of anti‐inflammatory cytokines, such as IL‐10 and TGF‐ β, leading to the deactivation of M1 macrophages1, 3, 4 and enabling the predominance of M2 macrophages at the injury site during the transition from the proliferative stage to the differentiation and growth stage of myogenesis 1, 3, 4…”

“…It is well accepted that although there are different degrees of differentiation between the populations of macrophages that inhabit the muscle tissue after an injury, the coordinated activation of proinflammatory or anti‐inflammatory macrophage predominance in each step of the muscle repair process is essential to the resolution of the inflammatory process and regeneration of the muscle tissue 1, 4, 5…”

Skeletal muscle regeneration involves macrophage-myoblast bonding

“…4 Similar kinetics of macrophage subtypes and adult myogenesis sequences were demonstrated during normal regeneration in human samples. 5 Though, most studies looking at the involvement of macrophages in the regeneration process have focused on soluble molecules like prostaglandins, cytokines and chemokines, 6 only few reports assumed the importance of intercellular contacts. Sonnet et.…”