Rodríguez Gutiérrez, Cristina (2024) Unraveling the role of Cripto in macrophage plasticity and EndMT in skeletal muscle regeneration. [Tesi di dottorato]

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Skeletal muscle regeneration requires the coordination of different cell types, such as satellite cells and inflammatory cells. Inflammation has been always considered a detrimental process; however, emerging evidences suggest that it plays a crucial role in skeletal muscle regeneration, which is predominantly driven by macrophages (1,2). Muscle infiltrating macrophages mainly exhibit pro- and anti-inflammatory states which promote inflammation and coordinate tissue repair by modulating angiogenesis and extracellular matrix (ECM) deposition. However, the factors that influence macrophage identity and the interactions between macrophages and other muscle populations are poorly understood. Here, we provide unprecedented evidences of the role of Cripto in the regulation of macrophage and endothelial populations during skeletal muscle regeneration. Upon acute muscle injury, Cripto is re-expressed in activated satellite cells and in a subset of anti-inflammatory macrophages (3,4). Previous findings have demonstrated that Cripto modulates macrophage plasticity during skeletal muscle regeneration. Indeed, the deletion of Cripto in the myeloid lineage leads to the defective accumulation of CD206+ anti-inflammatory macrophages, affecting vascular remodeling by inducing an increased Endothelial-to-Mesenchymal Transition (EndMT) (4). However, the role of Cripto in the inflammatory compartment and the mechanisms by which it regulates the vascular progenitors fate remains an enigma. To address this issue, we used the myeloid lineage-specific Cripto loss-of-function mouse model (Tg:LysMCre::Criptofl/fl), referred as Cripto KO, upon acute skeletal muscle injury. We found that Cripto directly regulates the accumulation of CD206+ anti-inflammatory macrophages without exerting a direct effect on EndMT in vivo. Furthermore, we provided evidences that Cripto is required for the pro- and anti-inflammatory polarization of macrophages in vitro that could be partially rescued by the addition of the soluble form of the protein. In addition, we found that the defective macrophage polarization in vitro in the absence of Cripto also implies a dysregulation in macrophage metabolism.

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