In vitro derivation of oligodendrocyte precursors from neural progenitors harboured in the adult human bone marrow : implications for remyelination therapy

Abstract

Oligodendrocytes (OLs) are the myelinating glia in the central nervous system (CNS). In congenital myelin disorders, OL dysfunction or death results not only in loss of myelin important for axonal conduction of nerve impulse, but also in neuronal/axonal loss impacting information flow in neuronal networks. Progressive and irreversible impairments to motor and cognitive functions that follow are amongst the most disabling of neurological disorders.

Perinatal engraftment of glial progenitor cells (GPCs) promises correction of myelin defects in the congenitally dysmyelinated brain, thereby preserving brain function and quality of life of patients. However, autologous sources of glial progenitors are inherently inadequate whereas derivation from such sources as embryonic stem cells and induced-pluripotent stem cells faces considerable ethical and safety issues.

To circumvent such hurdles, attempts were made to translate the derivation of glial progenitor cells from rat bone marrow stromal cells (BMSCs) (Tsui, PhD thesis, 2013) to a human protocol in this project. Neuroprogenitor cells harboured among human BMSCs were therefore expanded in neurosphere suspension culture. Following transfer of selected neurospheres to adherent culture, cells exiting the spheres acquired glial progenitor cell (GPC) phenotype. This was accomplished in 14 days with use of bone marrow samples collected with consent from 3 human donors. Flow cytometric analysis of the hBMSC-GPCs indicated that >90% of the population was positive for the oligodendrocyte progenitor markers OLIG2, PDGFRα, NG2, SOX10 and O4. Following transplantation of the derived GPCs into the corpus callosum of postnatal day 7 (P7) myelin-deficient shiverer mice, CNS–type compact myelin was observable in in mid- and hind-brain regions in 12 weeks. These were in correlation with the extended lifespan and improved motor function of recipient mice.

The hBMSC-GPCs so derived hold promise for development into cell therapies for myelin disorders, overcoming hurdles of cell source restriction and time frame requirement.