In situ macrophage phenotypic transition is affected by altered cellular composition prior to acute sterile muscle injury

Abstract

Skeletal muscle regeneration is a complex interplay between various cell types including invading macrophages. Their recruitment to damaged tissues upon acute sterile injuries is necessary for clearance of necrotic debris and for coordination of tissue regeneration. This highly dynamic process is characterized by an in situ transition of infiltrating monocytes from an inflammatory (Ly6C ) to a repair (Ly6C ) macrophage phenotype. The importance of the macrophage phenotypic shift and the cross-talk of the local muscle tissue with the infiltrating macrophages during tissue regeneration upon injury are not fully understood and their study lacks adequate methodology. Here, using an acute sterile skeletal muscle injury model combined with irradiation, bone marrow transplantation and in vivo imaging, we show that preserved muscle integrity and cell composition prior to the injury is necessary for the repair macrophage phenotypic transition and subsequently for proper and complete tissue regeneration. Importantly, by using a model of in vivo ablation of PAX7 positive cells, we show that this radiosensitive skeletal muscle progenitor pool contributes to macrophage phenotypic transition following acute sterile muscle injury. In addition, local muscle tissue radioprotection by lead shielding during irradiation preserves normal macrophage transition dynamics and subsequently muscle tissue regeneration. Taken together, our data suggest the existence of a more extensive and reciprocal cross-talk between muscle tissue compartments, including satellite cells, and infiltrating myeloid cells upon tissue damage. These interactions shape the macrophage in situ phenotypic shift, which is indispensable for normal muscle tissue repair dynamics.

In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury

“…We selected GDF3 for a proof‐of‐concept experiment to evaluate whether the observed impaired phenotypic transition in macrophage phenotype from inflammatory to repair type (Patsalos et al, 2017) can contribute to age‐related delay in muscle regeneration. In line with previous findings (Varga et al, 2016), GDF3 protein expression in whole‐muscle lysates of CTX‐injured young mice showed a pronounced induction, which peaked at Day 4 (Figure 2a), at the time when inflammation subsides, and regenerative processes start to dominate within the injured muscle.…”

The Role of Metabolic Remodeling in Macrophage Polarization and Its Effect on Skeletal Muscle Regeneration

“…MF affect myogenesis and muscle fibrosis, after acute damage and in chronic diseases, by producing cytokines, chemokines, soluble factors, and cross-talking with muscle resident cells, for example, fibroadipogenic progenitor cells (FAPs), fibroblasts, SCs, and endothelial cells (218,275). A reciprocal cross-talk between muscle cells and infiltrating immune cells also occurs, with muscle cells responsible for modulating the MF phenotypic shift during repair (261). The proper interplay among different cell types ensures phagocytosis of necrotic myofibers, activation of SCs, execution of the myogenic program (6), angiogenesis (247), and SC self-renewal to restore stem cell pool (225), thus forming new functional myofibers and allowing muscle homeostasis.…”

Dehydrated Human Amnion Chorion Membrane as Treatment for Pediatric Burns

“…After an injury, damaged tissue and tissueresident macrophages secrete a number of chemokines that facilitate the rapid influx of innate immune cells, including neutrophils and inflammatory monocytes. 11,[18][19][20][21][22][23] Natural killer cells and T cells also enter the tissue and act in concert to drive the differentiation of inflammatory monocytes into inflammatory macrophages. 14,19,21,24 Collectively, these cells constitute the acute inflammatory phase of repair necessary for induction of the immune response, activation of stem cell populations, and clearance of necrotic debris.…”