Neural stem cells LewisX+ CXCR4+ modify disease progression in an amyotrophic lateral sclerosis model.
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by the degeneration of the motor neurons. We tested whether treatment of superoxide dismutase (SOD1)-G93A transgenic mouse, a model of ALS, with a neural stem cell subpopulation double positive for Lewis X and the chemokine receptor CXCR4 (LeX+CXCR4+) can modify the disease's progression. In vitro, after exposure to morphogenetic stimuli, LeX+CXCR4+ cells generate cholinergic motor neuron-like cells upon differentiation. LeX+CXCR4+ cells deriving from mice expressing Green Fluorescent Protein in all tissues or only in motor neurons, after a period of priming in vitro, were grafted into spinal cord of SOD1-G93A mice. Transplanted transgenic mice exhibited a delayed disease onset and progression, and survived significantly longer than non-treated animals by 23 days. Examination of the spinal cord revealed integration of donor-derived cells that differentiated mostly in neurons and in a lower proportion in motor neuron-like cells. Quantification of motor neurons of the spinal cord suggests a significant neuroprotection by LeX+CXCR4+ cells. Both VEGF- and IGF1-dependent pathways were significantly modulated in transplanted animals compared to controls, suggesting a role of these neurotrophins in MN protection. Our results support the therapeutic potential of neural stem cell fractions through both neurogenesis and growth factors release in motor neuron disorders.
Corti
Stefania
S
Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena, Milan, Italy.
Locatelli
Federica
F
Papadimitriou
Dimitra
D
Del Bo
Roberto
R
Nizzardo
Monica
M
Nardini
Martina
M
Donadoni
Chiara
C
Salani
Sabrina
S
Fortunato
Francesco
F
Strazzer
Sandra
S
Bresolin
Nereo
N
Comi
Giacomo P
GP
D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology / Q000601:surgery*; D000818:Animals; D001369:Axons / Q000473:pathology; D015415:Biomarkers / Q000032:analysis; D002452:Cell Count; D002454:Cell Differentiation; D002999:Clone Cells; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D016256:Lewis X Antigen / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009046:Motor Neurons / Q000473:pathology; D039902:Multipotent Stem Cells / Q000378:metabolism / Q000637:transplantation*; D009416:Nerve Regeneration; D019718:Receptors, CXCR4 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D016256:Lewis X Antigen; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I; D013482:Superoxide Dismutase