title: Effects of adult neural precursor-derived myelination on axonal function in the perinatal congenitally dysmyelinated brain: optimizing time of intervention, developing accurate prediction models, and enhancing performance.
abstract: Stem cell repair shows substantial translational potential for neurological injury, but the mechanisms of action remain unclear. This study aimed to investigate whether transplanted stem cells could induce comprehensive functional remyelination. Subventricular zone (SVZ)-derived adult neural precursor cells (aNPCs) were injected bilaterally into major cerebral white matter tracts of myelin-deficient shiverer mice on postnatal day (P) 0, P7, and P21. Tripotential NPCs, when transplanted in vivo, integrated anatomically and functionally into local white matter and preferentially became Olig2+, Myelin Associated Glycoprotein-positive, Myelin Basic Protein-positive oligodendrocytes, rather than Glial Fibrillary Acidic Protein-positive astrocytes or Neurofiliment 200-positive neurons. Processes interacted with axons and transmission electron microscopy showed multilamellar axonal ensheathment. Nodal architecture was restored and by quantifying these anatomical parameters a computer model was generated that accurately predicted action potential velocity, determined by ex vivo slice recordings. Although there was no obvious phenotypic improvement in transplanted shi/shis, myelinated axons exhibited faster conduction, lower activation threshold, less refractoriness, and improved response to high-frequency stimulation than dysmyelinated counterparts. Furthermore, they showed improved resilience to ischemic insult, a promising finding in the context of perinatal brain injury. This study describes, for the first time mechanistically, the functional characteristics and anatomical integration of nonimmortalized donor SVZ-derived murine aNPCs in the dysmyelinated brain at key developmental time points.
authors.affiliation: Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, Toronto, Ontario M5T 2S8, Canada.
authors.forename: Crystal A
authors.initials: CA
authors.lastname: Ruff
authors.forename: Hui
authors.initials: H
authors.lastname: Ye
authors.forename: Jean M
authors.initials: JM
authors.lastname: Legasto
authors.forename: Natasha A
authors.initials: NA
authors.lastname: Stribbell
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fehlings
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism / Q000637:transplantation*; D000818:Animals; D001369:Axons / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002552:Cerebral Ventricles / Q000166:cytology* / Q000378:metabolism; D003711:Demyelinating Diseases / Q000151:congenital / Q000503:physiopathology* / Q000601:surgery; D004195:Disease Models, Animal; D051379:Mice; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000502:physiology*; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism / Q000637:transplantation*; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D033581:Stem Cell Transplantation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004676:Myelin Basic Protein; D018992:Myelin-Associated Glycoprotein; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; C512773:Olig2 protein, mouse