Transplanted human glial-restricted progenitors can rescue the survival of dysmyelinated mice independent of the production of mature, compact myelin

Abstract

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 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 46 weeks 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 early presence of mature myelin. This paradox suggests that transplanted GRPs provide therapeutic benefits through biological processes other than mature myelin capable to facilitate rapid conduction, challenging the current dogma of the role of myelin in the function of the central nervous system.

Migratory potential of transplanted glial progenitors as critical factor for successful translation of glia replacement therapy: The gap between mice and men

“…Conversely, human GPs at the same time point had already migrated extensively away from the transplantation site, and were present within the entire brain, including white matter and grey matter areas. No production of compact myelin could be detected by histology, which was confirmed by the MRI findings (Lyczek et al, 2017). This study thus revealed that an extensive migration and distribution of GPs within the entire brain is a pre-requisite to achieve the therapeutic effect ( Figure 1).…”

“…While no post-mortem studies from these patients were reported, the MRI data added an interesting clue. A widespread improvement of MRI parameters in the white matter, as found in the preclinical study by Lyczek et al (Lyczek et al 2017), was not observed (Gupta et al 2012). Only a few small hypointensities indicative of potential myelination were observed, which could correspond to the sites of cell injections.…”

“…The head-to-head comparison of mouse and human GPs neonatally transplanted into dysmyelinated mice revealed striking species-specific differences in their therapeutic potential (Lyczek et al 2017). Human GPs extended the life span of dysmyelinated mice, as previously reported, but there was no therapeutic effect after transplantation of their mouse counterparts.…”

“…The head-to-head comparison of mouse and human GPs neonatally transplanted into dysmyelinated mice revealed striking speciesspecific differences in their therapeutic potential (Lyczek et al, 2017).…”

Proliferation and differentiation of human fetal brain neural stem cells in vitro

“…The role of glial progenitors and transplantation is critically important due to their proven role in rescuing myelination phenotype in mice. [14][15][16] NSCs play pivotal roles in everything from infection to psychiatric disorders. Multiple studies from our lab have utilized these hNSC culture and differentiation techniques to improve efficacy of stem cell transplantation in the context of traumatic brain and spinal cord injury.…”