Complete repair of dystrophic skeletal muscle by mesoangioblasts with enhanced migration ability.
Efficient delivery of cells to target tissues is a major problem in cell therapy. We report that enhancing delivery of mesoangioblasts leads to a complete reconstitution of downstream skeletal muscles in a mouse model of severe muscular dystrophy (alpha-sarcoglycan ko). Mesoangioblasts, vessel-associated stem cells, were exposed to several cytokines, among which stromal- derived factor (SDF) 1 or tumor necrosis factor (TNF) alpha were the most potent in enhancing transmigration in vitro and migration into dystrophic muscle in vivo. Transient expression of alpha4 integrins or L-selectin also increased several fold migration both in vitro and in vivo. Therefore, combined pretreatment with SDF-1 or TNF-alpha and expression of alpha4 integrin leads to massive colonization (>50%) followed by reconstitution of >80% of alpha-sarcoglycan-expressing fibers, with a fivefold increase in efficiency in comparison with control cells. This study defines the requirements for efficient engraftment of mesoangioblasts and offers a new potent tool to optimize future cell therapy protocols for muscular dystrophies.
Galvez
Beatriz G
BG
Stem Cell Research Institute, San Raffaele Hospital, 20132 Milan, and Department of Experimental Medicine, Human Anatomy Institute, University of Pavia, Italy.
Sampaolesi
Maurilio
M
Brunelli
Silvia
S
Covarello
Diego
D
Gavina
Manuela
M
Rossi
Barbara
B
Constantin
Gabriela
G
Costantin
Gabriela
G
Torrente
Yvan
Y
Cossu
Giulio
G
D016475:3T3 Cells; D000375:Aging; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D039441:Integrin alpha4 / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D016513:Mice, SCID; D018485:Muscle Fibers, Skeletal / Q000166:cytology; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D049031:Sarcoglycans / Q000172:deficiency / Q000235:genetics; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014945:Wound Healing
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D012333:RNA, Messenger; D049031:Sarcoglycans; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin; D039441:Integrin alpha4