Adult rat myelin enhances axonal outgrowth from neural stem cells

Abstract

Axon regeneration after spinal cord injury (SCI) is attenuated by growth inhibitory molecules associated with myelin. We report that rat myelin stimulated the growth of axons emerging from rat neural progenitor cells (NPCs) transplanted into sites of SCI in adult rat recipients. When plated on a myelin substrate, neurite outgrowth from rat NPCs and from human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) was enhanced threefold. In vivo, rat NPCs and human iPSC-derived NSCs extended greater numbers of axons through adult central nervous system white matter than through gray matter and preferentially associated with rat host myelin. Mechanistic investigations excluded Nogo receptor signaling as a mediator of stem cell-derived axon growth in response to myelin. Transcriptomic screens of rodent NPCs identified the cell adhesion molecule neuronal growth regulator 1 (Negr1) as one mediator of permissive axon-myelin interactions. The stimulatory effect of myelin-associated proteins on rodent NPCs was developmentally regulated and involved direct activation of the extracellular signal-regulated kinase (ERK). The stimulatory effects of myelin on NPC/NSC axon outgrowth should be investigated further and could potentially be exploited for neural repair after SCI.

Single-cell transcriptomic analysis of Alzheimer’s disease

“…One such example is myelination, axonal outgrowth and regeneration. Top DEGs included LINGO1, which was upregulated in Ex and Oli and is a negative regulator of neuronal survival, axonal integrity, oligodendrocyte differentiation and myelination 26,27 , ERBB2IP, required for remyelination of axons 28 , CNTNAP2, a cell-adhesion molecule that mediates axon-myelin interactions 29 , NEGR1, a cell-adhesion molecule mediating myelin-stimulated axonal outgrowth 30 , BEX1, a gene involved in regeneration of axons after injury 31 , and NTNG1, a factor promoting neurite outgrowth of axons and dendrites (Fig. 1h) 32 .…”

Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

“…Furthermore, myelin preparations from MAG knockout mice do not inhibit neurite elongation or cause growth cone collapse compared to myelin preparations from wild type mice (Bartsch et al, 1995). Additionally, myelin preparations from adult rats actually stimulated axon growth of rodent neural progenitor cells and human induced pluripotent stem cellderived neural stem cells, which was dependent on interactions with neuronal growth regulator 1 (Negr1) (Poplawski et al, 2018). Therefore, highlighting these differences in MAIs and downstream mediators are important when designing translational neural regeneration applications.…”

Neural Stem Cell Transplantation for Neurodegenerative Diseases

“…Axonal regeneration and outgrowth in the CNS seem to be suppressed by several molecules associated with myelin, such as Nogo [103], myelin-associated glycoprotein [104], and oligodendrocyte myelin glycoprotein [105]. Recently, Poplawski et al [106] pointed out that rat myelin promotes axonal outgrowth from rat NSCs transplanted into sites of damage in adult rats. In particular, they determined that the cell adhesion molecule neuronal growth regulator 1 (Negr1), which is expressed on NSCs, is a key regulator of stem cell-derived axon growth in response to myelin, excluding involvement of Nogo receptor signaling [106].…”