Infiltrating myeloid cells and angiogenesis during skeletal muscle regeneration: role of p38γ/δ mapks in macrophage-phenotype acquisition

• Autores: Antonio Martinez Garcia
• Directores de la Tesis: Purificacion Muñoz Canoves (dir. tes.), Antonio Serrano (codir. tes.), Eusebio Perdiguero Santamaría (codir. tes.)
• Lectura: En la Universitat Pompeu Fabra ( España ) en 2019
• Idioma: español
• Tribunal Calificador de la Tesis: Ana Cuenda Méndez (presid.), Mónica Suelves Esteban (secret.), Roser López Alemany (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad Pompeu Fabra
• Materias:
  • Química
    • Bioquímica
      • Genética bioquímica
  • Ciencias de la vida
    • Biología celular
    • Inmunología
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• Resumen

  • Adult skeletal muscle has the ability to self-repair after a damage thanks to satellite cells, the muscle stem cells. Upon acute injury, satellite cells proliferate, differentiate and fuse to reform new myofibers. Efficient skeletal muscle regeneration requires a carefully orchestrated interaction between the inflammatory response and satellite cells as well as the successful restoration of the microvascular network. After acute muscle damage, different types of leukocytes are recruited into the injured tissue. First, neutrophils and pro-inflammatory monocytes which maturate and differentiate into macrophages promote damaged muscle fiber lysis and phagocytosis of cellular debris. Subsequently, macrophages switch into an anti-inflammatory phenotype promoting the shutdown of the previous pro-inflammatory phase. Pro-inflammatory myeloid subsets are implicated in the promotion of myoblasts proliferation, meanwhile anti-inflammatory monocytes/macrophages induce their differentiation and protect them from apoptosis. Similarly, these timely balanced pro- and anti- inflammatory waves coordinate tissue repair and regulate the function and fate of other cell types. We have defined a third wave of anti-inflammatory macrophages, characterized by the upregulation of MHC2 and a dendritic cell-like phenotype, which appear in the resolving phase of muscle regeneration (between 3th and 4th day after injury).

    p38 MAP Kinases (MAPK) signaling has been shown to regulate the expression of pro- and anti-inflammatory mediators. We have explored the hypothesis that p38 MAPK signaling in myeloid cells play any relevant role in muscle regeneration. We have focused in p38γ and δ, the two less studies MAPK isoforms. To this end, we have generated a mouse line which lacks p38γ/δ MAPK only in the myeloid lineage, by using the Cre-lox recombination system under the Lysozyme M promoter. We showed that skeletal muscle regeneration after acute injury is delayed and was accompanied by ectopic deposition of fat within the tissue. Transcriptomic analysis of the myeloid populations in regenerating muscle showed a characteristic signature for each population. Lack of p38γ/δ MAPK, altered the expression of canonical inflammatory signaling pathways and secretory genes, including important mediators of adipogenesis and angiogenesis. Our analysis also evidenced downregulation of genes implicated in the switch from a pro- to anti-inflammatory phenotype. Our results indicate that p38γand δ are key regulators of myeloid secretory profiles and phenotypical acquisition and function.

    Our findings shed light on the importance of the novel population of infiltrating anti-inflammatory myeloid cells and may have potential biomedical implications in pathologies cursing with poor regeneration of skeletal muscle.