Neonatal chimerization with human glial progenitor cells can both remyelinate and rescue the otherwise lethally hypomyelinated shiverer mouse.
Congenitally hypomyelinated shiverer mice fail to generate compact myelin and die by 18-21 weeks of age. Using multifocal anterior and posterior fossa delivery of sorted fetal human glial progenitor cells into neonatal shiverer x rag2(-/-) mice, we achieved whole neuraxis myelination of the engrafted hosts, which in a significant fraction of cases rescued this otherwise lethal phenotype. The transplanted mice exhibited greatly prolonged survival with progressive resolution of their neurological deficits. Substantial myelination in multiple regions was accompanied by the acquisition of normal nodes of Ranvier and transcallosal conduction velocities, ultrastructurally normal and complete myelination of most axons, and a restoration of a substantially normal neurological phenotype. Notably, the resultant mice were cerebral chimeras, with murine gray matter but a predominantly human white matter glial composition. These data demonstrate that the neonatal transplantation of human glial progenitor cells can effectively treat disorders of congenital and perinatal hypomyelination.
Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Martha S
MS
Windrem
Steven J
SJ
Schanz
Min
M
Guo
Guo-Feng
GF
Tian
Vaughn
V
Washco
Nancy
N
Stanwood
Matthew
M
Rasband
Neeta S
NS
Roy
Maiken
M
Nedergaard
Leif A
LA
Havton
Su
S
Wang
Steven A
SA
Goldman
D053687:Adult Stem Cells / Q000378:metabolism / Q000637:transplantation*; D061085:Agenesis of Corpus Callosum; D000818:Animals; D000831:Animals, Newborn / Q000002:abnormalities / Q000196:embryology; D064987:Cell- and Tissue-Based Therapy; D003337:Corpus Callosum / Q000196:embryology / Q000378:metabolism / Q000637:transplantation*; D003711:Demyelinating Diseases / Q000151:congenital / Q000628:therapy; D006801:Humans; D016867:Immunocompromised Host; D051379:Mice; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism* / Q000637:transplantation*; D009431:Neural Conduction; D009457:Neuroglia / Q000378:metabolism / Q000637:transplantation*; D011901:Ranvier's Nodes / Q000378:metabolism / Q000637:transplantation; D033581:Stem Cell Transplantation; D014018:Tissue Distribution; D018183:Transplantation Chimera / Q000196:embryology