Targeting human oligodendrocyte progenitors for myelin repair

Abstract

Oligodendrocyte development has been studied for several decades, and has served as a model system for both neurodevelopmental and stem/progenitor cell biology. Until recently, the vast majority of studies have been conducted in lower species, especially those focused on rodent development and remyelination. In humans, the process of myelination requires the generation of vastly more myelinating glia, occurring over a period of years rather than weeks. Furthermore, as evidenced by the presence of chronic demyelination in a variety of human neurologic diseases, it appears likely that the mechanisms that regulate development and become dysfunctional in disease may be, in key ways, divergent across species. Improvements in isolation techniques, applied to primary human neural and oligodendrocyte progenitors from both fetal and adult brain, as well as advancements in the derivation of defined progenitors from human pluripotent stem cells, have begun to reveal the extent of both species-conserved signaling pathways and potential key differences at cellular and molecular levels. In this article, we will review the commonalities and differences in myelin development between rodents and man, describing the approaches used to study human oligodendrocyte differentiation and myelination, as well as heterogeneity within targetable progenitor pools, and discuss the advances made in determining which conserved pathways may be both modeled in rodents and translate into viable therapeutic strategies to promote myelin repair.

Keywords: Human cell implantation; Oligodendrocyte progenitor; Remyelination.

Fig. 1

Solifenacin treatment enhances myelination and functional recovery by transplanted human oligodendrocyte progenitor cells (hOPCs). CD140a-sorted fetal-derived hOPCs were transplanted into neonatal hypomyelinated shiverer mice, which do not express myelin basic protein (MBP). A) The differentiation of transplanted hOPCs was accelerated by systemic administration of solifenacin, a muscarinic receptor antagonist, as observed as increased immunostaining for MBP in the corpus callosum after eight weeks (human nuclei are stained with hNA in red; scale bar = 100 µm). B) Solifenacin also enhanced myelination of cerebral peduncle axons (marked by neurofilament [NF]) by hOPCs when transplanted into the ventral midbrain (scale bar = 10 µm). C) The increased myelination of ventral midbrain structures resulting in increased conduction velocity and functional recovery of the auditory brainstem response (ABR), observed as reduced interpeak latencies, with significantly shorter latencies between peaks II and IV (modified from Abiraman et al., 2015).

Fig. 2

Myelination is enhanced in regions with high densities of transplanted human oligodendrocyte progenitor cells. Human oligodendrocyte progenitor cells were transplanted into the corpus callosum of 2–3 postnatal day shiverer/rag2 mice (as described in Abiraman et al. (2015). A–C) The densities of engrafted human cells (human nuclear antigen [hNA], red) observed within the corpus callosum (demarcated by dotted lines) varied at 12 weeks post-transplantation. Oligodendrocyte differentiation identified by staining for myelin basic protein (MBP, green) was strongest in areas with a high density of hNA⁺ cells (scale bar = 100 µm). D) A strong, positive correlation was found between the density of human cells and the area of MBP staining within the corpus callosum.