Macrophages commit postnatal endothelium-derived progenitors to angiogenesis and restrict endothelial to mesenchymal transition during muscle regeneration.
The damage of the skeletal muscle prompts a complex and coordinated response that involves the interactions of many different cell populations and promotes inflammation, vascular remodeling and finally muscle regeneration. Muscle disorders exist in which the irreversible loss of tissue integrity and function is linked to defective neo-angiogenesis with persistence of tissue necrosis and inflammation. Here we show that macrophages (MPs) are necessary for efficient vascular remodeling in the injured muscle. In particular, MPs sustain the differentiation of endothelial-derived progenitors to contribute to neo-capillary formation, by secreting pro-angiogenic growth factors. When phagocyte infiltration is compromised endothelial-derived progenitors undergo a significant endothelial to mesenchymal transition (EndoMT), possibly triggered by the activation of transforming growth factor-β/bone morphogenetic protein signaling, collagen accumulates and the muscle is replaced by fibrotic tissue. Our findings provide new insights in EndoMT in the adult skeletal muscle, and suggest that endothelial cells in the skeletal muscle may represent a new target for therapeutic intervention in fibrotic diseases.
Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milano, Italy.
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Zordan
Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milano, Italy.
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Rigamonti
Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milano, Italy.
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Freudenberg
1] Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milano, Italy [2] Department of Health Sciences, University of Milano-Bicocca, San Raffaele Scientific Institute, Milano, Italy.
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Conti
1] Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milano, Italy [2] Department of Health Sciences, University of Milano-Bicocca, San Raffaele Scientific Institute, Milano, Italy.
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Azzoni
1] Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milano, Italy [2] San Raffaele University, Milano, Italy.
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Rovere-Querini
1] Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milano, Italy [2] Department of Health Sciences, University of Milano-Bicocca, San Raffaele Scientific Institute, Milano, Italy.
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Brunelli
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D003094:Collagen / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000098:blood supply / Q000293:injuries / Q000378:metabolism / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology*; D012038:Regeneration; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen