title: Bone marrow-derived cells do not engraft into skeletal muscle microvasculature but promote angiogenesis after acute injury.
abstract: The skeletal muscle is supported by a vast network of microvessels with the capacity to regenerate in response to injury. However, the dynamics of microvascular repair and the origin of reconstituted endothelial cells in the skeletal muscle are poorly understood. A growing body of literature exists to indicate bone marrow (BM)-derived cells engraft into regenerating vascular endothelium and muscle macrovasculature. Therefore, we investigated the extent of BM contribution to skeletal muscle microvasculature after acute injury. Because reporters and markers commonly used to trace donor BM cells are not endothelial specific but are also expressed by leukocytes, we generated novel BM chimeras utilizing Tie2-green fluorescent protein BM cells transplanted into CD31 and Caveolin-1 knockout recipients. In turn, we surveyed BM vascular contribution, not just by the presence of green fluorescent protein, but also CD31 and Caveolin-1, respectively. After stable BM reconstitution, chimera limb muscles were cardiotoxin (CTX) injured and examined 21 days post-injury for the presence of green fluorescent protein, CD31, and Caveolin-1. Acute muscle injury by CTX is characterized by initial microvasculature death followed by rapid endothelial regeneration within 14 days post-damage. Histological analysis of injured and uninjured contralateral limb muscles revealed a complete absence of BM engraftment in the muscle vasculature of wild-type and CD31/Caveolin-1 knockout chimeras. In contrast, F4/80(+) cells isolated from CTX-injured muscle, expressed endothelial-related markers and promoted angiogenesis in vitro. Therefore, despite the absence of BM engraftment to regenerated skeletal muscle microvasculature, macrophages recruited after injury promote angiogenesis and, in turn, vascular regeneration.
authors.affiliation: Departments of Pathology and Lab Medicine, University of Washington School of Medicine, Seattle, Wash., USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ieronimakis
authors.forename: Aislinn
authors.initials: A
authors.lastname: Hays
authors.forename: Morayma
authors.initials: M
authors.lastname: Reyes
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D051242:Caveolin 1 / Q000172:deficiency; D002455:Cell Division; D019070:Cell Lineage; D002478:Cells, Cultured; D004179:Cobra Cardiotoxin Proteins / Q000633:toxicity; D004730:Endothelium, Vascular / Q000502:physiology; D017930:Genes, Reporter; D018380:Hematopoietic Stem Cell Transplantation; D006614:Hindlimb / Q000098:blood supply; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032342:Muscle Cells / Q000166:cytology; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009928:Organ Specificity; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D011828:Radiation Chimera; D012038:Regeneration; D013047:Specific Pathogen-Free Organisms; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis
chemical_list: D051242:Caveolin 1; D004179:Cobra Cardiotoxin Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D040301:Vascular Endothelial Growth Factor Receptor-2