Delivery of FGF genes to wound repair cells enhances arteriogenesis and myogenesis in skeletal muscle.
Tissue repair is driven by migratory macrophages and fibroblasts that infiltrate injury sites and secrete growth factors. We now report the enhancement of skeletal muscle repair by targeting transgene delivery to these repair cells using matrix-immobilized gene vectors. Plasmid and adenovirus vectors immobilized in collagen-gelatin admixtures were delivered to excisional muscle wounds, and when encoding either fibroblast growth factor-2 (FGF2) or FGF6 transgenes, produced early angiogenic responses that subsequently remodeled into arteriogenesis. FGF2 gene delivery enhanced the number of CD31(+) endothelial cells present at treatment sites > 6-fold by day 14, and muscular arteriole density up to 11-fold by day 21 (P<0.0001). Muscle repair was also enhanced, as FGF gene-treated wounds filled with regenerating myotubes expressing the marker CD56 (an average 20-fold increase in CD56 expression versus controls, P<0.0001). These responses required transfection of a threshold level of repair cells, achievable only in injured muscles, and were transgene-driven, as neither platelet-derived growth factor-B (PDGFB) gene nor FGF2 protein delivery produced equivalent responses. In conclusion, using biomatrices to direct gene delivery to repair cells allows for relatively complex regenerative processes such as arteriogenesis and myogenesis, and therefore represents a promising approach to treating injured and ischemic muscle.
Doukas
John
J
Selective Genetics, Inc., San Diego, California 92121, USA. jdoukas@selectivegenetics.com
Blease
Kate
K
Craig
Darren
D
Ma
Chenglie
C
Chandler
Lois A
LA
Sosnowski
Barbara A
BA
Pierce
Glenn F
GF
D000818:Animals; D001160:Arterioles / Q000502:physiology; D019002:CD56 Antigen / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D051522:Fibroblast Growth Factor 6; D005346:Fibroblast Growth Factors / Q000235:genetics*; D005434:Flow Cytometry; D018390:Gene Targeting; D005822:Genetic Vectors; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000293:injuries / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014945:Wound Healing / Q000502:physiology*
D019002:CD56 Antigen; C496452:FGF6 protein, human; C486116:Fgf6 protein, rat; D051522:Fibroblast Growth Factor 6; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D003094:Collagen; D008156:Luciferases