Transplanted human glial-restricted progenitors can rescue the survival of dysmyelinated mice independent of the production of mature, compact myelin.
The therapeutic effect of glial progenitor transplantation in diseases of dysmyelination is currently attributed to the formation of new myelin. Using magnetic resonance imaging (MRI), we show that the therapeutic outcome in dysmyelinated shiverer mice is dependent on the extent of cell migration but not the presence of mature and compact myelin. Human or mouse glial restricted progenitors (GRPs) were transplanted into rag2-/-shiverer mouse neonates and followed for over one year. Mouse GRPs produced mature myelin as detected with multi-parametric MRI, but showed limited migration without extended animal lifespan. In sharp contrast, human GRPs migrated extensively and significantly increased animal survival, but production of mature myelin did not occur until 46weeks post-grafting. We conclude that human GRPs can extend the survival of transplanted shiverer mice prior to production of mature myelin, while mouse GRPs fail to extend animal survival despite the early presence of mature myelin. This paradox suggests that transplanted GRPs provide therapeutic benefits through biological processes other than the formation of mature myelin capable to foster rapid nerve conduction, challenging the current dogma of the primary role of myelination in regaining function of the central nervous system.
Russell H. Morgan Dept. of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, United States.
Agatha
A
Lyczek
Russell H. Morgan Dept. of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, United States.
Antje
A
Arnold
Russell H. Morgan Dept. of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States.
Jiangyang
J
Zhang
Q Therapeutics, Inc., Salt Lake City, UT 84108, United States.
James T
JT
Campanelli
Russell H. Morgan Dept. of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, United States; Dept. of Neurosurgery, Mossakowski Med. Res. Center, Polish Acad. of Sci., Warsaw, Poland; Dept. of NeuroRepair, Mossakowski Med. Res. Center, Polish Acad. of Sci., Warsaw, Poland.
Miroslaw
M
Janowski
Russell H. Morgan Dept. of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, United States.
Jeff W M
JW
Bulte
Russell H. Morgan Dept. of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD 21205, United States; Dept. of Neurology and Neurosurgery, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland. Electronic address: pwalczak@mri.jhu.edu.
Piotr
P
Walczak
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging; D002454:Cell Differentiation; D002465:Cell Movement; D002470:Cell Survival / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003711:Demyelinating Diseases / Q000000981:diagnostic imaging / Q000473:pathology / Q000601:surgery*; D004195:Disease Models, Animal; D005732:Gangliosides / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology / Q000637:transplantation* / Q000648:ultrastructure; D000076104:Oligodendrocyte Transcription Factor 2; D013116:Spinal Cord / Q000000981:diagnostic imaging; D033581:Stem Cell Transplantation; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D005732:Gangliosides; D005904:Glial Fibrillary Acidic Protein; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D014404:Tubulin; C499047:Mbp protein, mouse; C512773:Olig2 protein, mouse; C047516:Plp1 protein, mouse; C499308:Rag2 protein, mouse; C462941:beta3 tubulin, mouse; C062875:ganglioside A2B5
Glial progenitors; MRI; Myelin; Shiverer; Transplantation