Skeletal muscle regeneration following injury depends on the ability of satellite cells (SCs) to proliferate, self-renew, and eventually differentiate. Besides SCs, it is becoming clear that a precisely regulated cross talk between muscle, interstitial and immune cells, is required for muscle repair and maintenance of muscle homeostasis. However, the complexity of these interactions is still not completely understood. Monocytes and macrophages are considered the major component of the immune response in muscle repair. These cells are thought to be prevalently recruited from Bone Marrow; however, recent studies have identified the spleen as the dominant reservoir of these cells during chronic inflammation. Indeed, we recently described the hitherto unexplored contribution of splenic Ly6Chi monocytes to dystrophic muscle pathology. We found that Ly6Chi monocytes accumulate in great numbers in the spleen over the course of the disease. Importantly, in the absence of splenic Ly6Chi monocytes there was a significant reduction in dystrophic muscle inflammation and necrosis, along with improved regeneration during early disease. However, during late disease, lack of splenic Ly6Chi monocytes adversely affected muscle fibre repair, due to a delay in the phenotypic shift of pro-inflammatory to anti-inflammatory macrophages. Splenic monocytes are thus critical players in both muscle fibre injury and repair, a role which appears not to be replaced by Bone Marrow-derived monocytes. Using a model of acute muscle injury in mouse, where the phases of muscle repair are timely defined, in this project we aim to characterize the phenotype and behavior of Ly6Chi splenic monocytes and their role in muscle regeneration. The accomplishment of this project will determine whether splenic monocytes acquire a specific phenotype and behaviour within the spleen, different from those derived from Bone Marrow, and whether the spleen represents an important monocyte training ground.
While it is clear that a precisely regulated cross talk between muscle, interstitial and immune cells, is required for muscle repair and maintenance of muscle homeostasis, the complexity of these interactions is still not completely understood. Indeed, a complete understanding of these mechanisms and of the cell populations involved should allow the design of interventions to attenuate inefficient muscle repair, as it happens in aging and in MDs pathology, without disrupting regenerative processes.
The power of this study is that it is based on the unexplored role of splenic monocytes in muscle repair, which we recently described for the first time. Recent studies have identified the spleen as the dominant reservoir of these cells during chronic inflammation. Characterization of this cell population will surely add new insight on our understanding of the cellular and molecular network underlying muscle repair processes, in physiological and pathological conditions, and will pave the way for the design of therapeutical strategies.