Mesenchymal stem cells restore cortical rewiring after neonatal ischemia in mice.
OBJECTIVE
A study was undertaken to investigate the effect of neonatal hypoxic-ischemic (HI) brain damage and mesenchymal stem cell (MSC) treatment on the structure and contralesional connectivity of motor function-related cerebral areas.


METHODS
Brain remodeling after HI±MSC treatment in neonatal mice was analyzed using diffusion tensor magnetic resonance imaging, immunohistochemistry, anterograde tracing with biotinylated dextran amine (BDA), and retrograde tracing with fluorescent pseudorabies virus (PRV).


RESULTS
MSC treatment after HI reduced contralesional rewiring taking place after HI. Following MSC treatment, fractional anisotropy values, which were increased in both ipsi- and contralesional cortices and decreased in the corpus callosum (CC) after HI, were normalized to the level observed in sham-operated mice. These results were corroborated by myelin basic protein intensity and staining pattern in these areas. Anterograde tracing of ipsilesional motor neurons showed that after MSC treatment, fewer BDA-positive fibers crossed the CC and extended into the contralesional motor cortex compared to HI mice. This remodeling was functional, because retrograde labeling showed increased connectivity between impaired (left) forepaw and the contralesional (left) motor cortex after HI, whereas MSC treatment reduced this connection and increased the connection between the impaired (left) forepaw and the ipsilesional (right) motor cortex. Finally, the extent of contralesional rewiring measured with BDA and PRV tracing was related to sensorimotor dysfunction.


CONCLUSIONS
This is the first study to describe MSC treatment after neonatal HI markedly reducing contralesional axonal remodeling induced by HI brain injury.
Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Lundlaan 6, Utrecht, the Netherlands.
Cindy T J
CT
van Velthoven
Yohan
Y
van de Looij
Annemieke
A
Kavelaars
Jitske
J
Zijlstra
Frank
F
van Bel
Petra S
PS
Huppi
Stéphane
S
Sizonenko
Cobi J
CJ
Heijnen
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D016880:Anisotropy; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D001369:Axons / Q000502:physiology; D001710:Biotin / Q000031:analogs & derivatives; D002545:Brain Ischemia / Q000473:pathology / Q000601:surgery*; D002540:Cerebral Cortex / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003911:Dextrans; D056324:Diffusion Tensor Imaging; D004195:Disease Models, Animal; D007839:Functional Laterality; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000378:metabolism; D009434:Neural Pathways / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology; D020127:Recovery of Function / Q000502:physiology*; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases; D000097573:Red Fluorescent Protein; D000070584:Tripartite Motif Proteins
D000951:Antigens, Neoplasm; D001710:Biotin; D004268:DNA-Binding Proteins; D003911:Dextrans; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D004676:Myelin Basic Protein; D009687:Nuclear Proteins; D044767:Ubiquitin-Protein Ligases; D000097573:Red Fluorescent Protein; C440529:UBC antigen; C076397:biotinylated dextran amine; C489296:Trim27 protein, mouse; D000070584:Tripartite Motif Proteins