CXCR4 enhances engraftment of muscle progenitor cells.
Cell-based therapy is a possible avenue for the treatment of Duchenne muscular dystrophy (DMD), an X-linked skeletal muscle-wasting disease. We have demonstrated that cultured myogenic progenitors derived from the adult skeletal muscle side population can engraft into dystrophic fibers of non-irradiated, non-chemically injured mouse models of DMD (mdx(5cv)) after intravenous and intraarterial transplantation, with engraftment rates approaching 10%. In an effort to elucidate the cell-surface markers that promote progenitor cell extravasation and engraftment after systemic transplantation, we found that expression of the chemokine receptor CXCR4, whose ligand SDF-1 is overexpressed in dystrophic muscle, enhances the extravasation of these cultured progenitor cells into skeletal muscle after intraarterial transplantation. At 1 day post-transplantation, mice that received CXCR4-positive enhanced green fluorescent protein (eGFP)-positive cultured cells derived from the skeletal muscle side population displayed significantly higher amounts of eGFP-positive mononuclear cells in quadriceps and tibialis anterior than mice that received CXCR4-negative eGFP-positive cells derived from the same cultured population. At 30 days posttransplantation, significantly higher engraftment rates of donor cells were observed in mice that received CXCR4-positive cells compared with mice transplanted with CXCR4-negative fractions. Our data suggest that CXCR4 expression by muscle progenitor cells increases their extravasation into skeletal muscle shortly after transplantation. Furthermore, this enhanced extravasation likely promotes higher donor cell engraftment rates over time.
Perez
Antonio L
AL
Howard Hughes Medical Institute, Program in Genomics, Children's Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
Bachrach
Estanislao
E
Illigens
Ben M W
BM
Jun
Susan J
SJ
Bagden
Eric
E
Steffen
Leta
L
Flint
Alan
A
McGowan
Francis X
FX
Del Nido
Pedro
P
Montecino-Rodriguez
Enca
E
Tidball
James G
JG
Kunkel
Louis M
LM
D000818:Animals; D002469:Cell Separation; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D032342:Muscle Cells / Q000378:metabolism / Q000637:transplantation*; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism*; D014161:Transduction, Genetic
C514936:CXCR4 protein, mouse; D019718:Receptors, CXCR4; D011956:Receptors, Cell Surface; D049452:Green Fluorescent Proteins