Eosinophils stimulate FAPs expansion by forming a transitional niche favorable to clear necrotic debris and prevent FAPs differentiation into adipocytes 19. Other immune cells, such as regulatory T cells (known as Treg) 231 and eosinophils, also infiltrate the regenerating muscle after injury. During the second stage, multiple cell types proliferate, including MuSC. During the first phase, neutrophils 224, 225, 226, 227, 228 and proinflammatory macrophages (also known as M1) are required to clean the muscle cell debris and participate in the recruitment and activation of other cell types 229, 230. The starting phase of muscle regeneration, also known as a proinflammatory response, is characterized by the infiltration of immune cells that will clear the damaged fibers from the injured site. Upon injury, this tissue recruits several cell types (represented in the figure) to repair myofibers. Skeletal muscle tissue comprises multiple cell types and compartments, including multinucleated myofibers, blood vessels, and neuromuscular junctions. The niche enables MuSC to maintain their quiescent state and provides them the ability to proliferate, migrate, self-renew, progress through the myogenic lineage, and differentiate to repair the damaged tissue (Fig. The stem cell niche plays a critical role in transmitting mechanical signals to MuSC to sense the structure, stiffness, and strength of the muscle 12. Extrinsic signals sent by the niche are essential to maintain cell stemness, as described 40 years ago by Schofield for hematopoietic stem cells 11. Several intrinsic and extrinsic factors regulate MuSC function in the stem cell niche. The use of this recombination-based lineage tracing mouse model showed that elimination of MuSC abrogates tissue repair upon acute injury 8, 9, 10, thus suggesting that MuSC are the major source of muscle regeneration. The conditional mouse model Pax7 CreER R26R DTA allows the specific depletion of MuSC through the Cre-mediated activation (in PAX7-expressing cells) of diphtheria toxin fragment A (DTA), an inhibitor of protein translation that kills specifically DTA-positive cells. The niche is a local anatomic milieu instructing MuSC to participate in tissue formation, maintenance, and repair 7. He defined satellite cells as “merely dormant myoblasts… ready to recapitulate the embryonic development of skeletal muscle fiber when the main multinucleate cell is damaged” 6. In 1961, Alexander Mauro identified satellite cells in a specialized niche between the myofiber sarcolemma and the basal lamina. However, when the tissue reaches homeostasis, their numbers decline as they enter and remain in a quiescent state of adult stages 5. Muscle stem cells (MuSC), also known as satellite cells, participate in postnatal myofiber growth 4. Myofibers harbor multiple proteins and enzymes, allowing the production of contractile forces for movements such as locomotion and posture 3. Skeletal muscle is a highly organized tissue composed of blood vessels, nerves, connective tissue, and long multinucleated muscle cells named myofibers 2. This tissue allows body posture, breathing, and voluntary movements, organism metabolism, and maintenance of body temperature 1. The most abundant tissue in the human body is skeletal muscle, representing about 40% of total body weight. Further understanding about extrinsic signals from the microenvironment controlling MuSC function and innovative technologies are still required to develop new therapies to improve muscle repair. Recent discoveries have improved our knowledge about the ECM composition of skeletal muscle, which has helped to mimic the architecture of the stem cell niche and improved the regenerative capacity of MuSC. We discuss relevant ECM proteins and how their mutations or dysregulation impact young and aged muscle tissue or contribute to diseases. This review provides an overview of the composition and importance of the MuSC microenvironment. However, during aging and muscle-associated diseases, muscle progressively loses its regenerative ability, in part due to a dysregulation of ECM components. Major components of the niche are extracellular matrix (ECM) proteins, able to instruct MuSC behavior. These cells reside adjacent to the myofiber and are surrounded by a specific and complex microenvironment, the stem cell niche. Among these populations, muscle stem cells (MuSC), also known as satellite cells, in response to stress or injury, are able to proliferate, fuse, and form new myofibers to repair the damaged tissue. Over the past decades, significant advances, including lineage tracing and single-cell RNA sequencing, have contributed to identifying multiple muscle resident cell populations participating in muscle maintenance and repair. Skeletal muscle requires a highly orchestrated coordination between multiple cell types and their microenvironment to exert its function and to maintain its homeostasis and regenerative capacity.
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