Macrophages Promote Muscle Regeneration via Secretion of ADAMTS1

The immune cells known as macrophages play an important role in regenerative processes, as demonstrated by the fact that if they removed from the picture, the pace and quality of tissue healing deteriorates considerably. A number of studies suggest that macrophages have two characteristic behavior patterns, the first an inflammatory behavior associated with destruction of invading pathogens, and the second focused on coordination of regeneration. Both behaviors are in evidence at the site of a wound, and healing can be improved by adjusting their proportions away from inflammation and towards regeneration. Further, studies are beginning to show that differences in macrophage behavior appear to be part of the reason why species such as salamanders and zebrafish have such proficient regenerative capacities. This is evidently a promising area of research, and here scientists report on the identification of one of the specific signals involved in the macrophage influence on regeneration:

The progressive activation and differentiation of satellite cells is critical for proper skeletal muscle growth and muscle regeneration after injury. This cascade is initiated when satellite cells are activated to break quiescence, progress through differentiation, and fuse to nascent or injured muscle fibers. Therefore, elucidating the signals and pathways that regulate this cascade is central to understanding muscle physiology and could provide a foundation for developing novel therapies for the treatment of muscle disorders and regenerative medicine.

Activation of satellite cells occurs in response to a variety of chemical, physical and physiological cues to mediate muscle tissue homeostasis and regeneration. The specialized niche of satellite cells, which are located between the basal lamina and the myofiber, is a critical element in the regulation of satellite cell quiescence and activation. For example, activated Notch signaling, which is directly regulated by proximal extracellular signals, is a well-studied example of a potent pathway that plays an important role in maintaining satellite cell quiescence. In addition, ADAM10, an enzyme known to promote Notch signaling, was found to have a role in the maintenance of the quiescent state. Yet, in spite of the apparent canonical role of Notch signaling in the regulation of satellite cell activation, the extracellular triggers that inhibit Notch signaling and promote satellite cells to break quiescence and differentiate are largely unknown.

Here we describe our discovery that macrophages, which are enriched at the site of muscle injuries, secrete a protein called ADAMTS1 (A Disintegrin-Like And Metalloproteinase With Thrombospondin Type 1 Motif). ADAMTS1 contains two disintegrin loops and three C-terminal thrombospondin type-1 motifs. We established that ADAMTS1 functions as an extracellular signal to satellite cells that promotes activation. We also found that constitutive overexpression of Adamts1 in macrophages accelerates satellite cell activation and muscle regeneration in young mice. Our data indicate that the mechanism of this ADAMTS1 activity is by targeting NOTCH1 protein on the satellite cells. These findings significantly enrich our understanding of the extracellular signals that regulate satellite cell activation and identify a pathway that could potentially be targeted with therapeutics to enhance muscle regeneration.


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