Olfactory glia enhance neonatal axon regeneration

Abstract

Olfactory ensheathing cells (OECs) migrate with olfactory axons that extend from the nasal epithelium into the olfactory bulb. Unlike other glia, OECs are thought to migrate ahead of growing axons instead of following defined axonal paths. However it remains unknown how the presence of axons and OECs influences the growth and migration of each other during regeneration. We have developed a regeneration model in neonatal mice to examine whether (i) the presence of OECs ahead of olfactory axons affects axonal growth and (ii) the presence of olfactory axons alters the distribution of OECs. We performed unilateral bulbectomy to ablate olfactory axons followed by methimazole administration to further delay neuronal growth. In this model OECs filled the cavity left by the bulbectomy before new axons extended into the cavity. We found that delaying axon growth increased the rate at which OECs filled the cavity. The axons subsequently grew over a significantly larger region and formed more distinct fascicles and glomeruli in comparison with growth in animals that had undergone only bulbectomy. In vitro, we confirmed (i) that olfactory axon growth was more rapid when OECs were more widely distributed than the axons and (ii) that OECs migrated faster in the absence of axons. These results demonstrate that the distribution of OECs can be increased by repressing by growth of olfactory axons and that olfactory axon growth is significantly enhanced if a permissive OEC environment is present prior to axon growth.

The Migration of Olfactory Ensheathing Cells during Development and Regeneration

“…The OECs are thought to promote axon growth by providing a cellular substrate containing molecules that facilitate axonal adhesion and extension and by expressing growth-promoting agents such as brain-derived neurotrophic factor, glia-derived nexin and nerve growth factor [16,17,18,19,20,21]. Indeed, OECs always extend processes ahead of the pioneer olfactory axons they ensheathe, and thus it would appear that the growth of olfactory axons is reliant on the OECs [22,23,24]. This is in contrast to Schwann cells which migrate along already defined axonal pathways during development of the peripheral nervous system [25].…”

“…Only 4 factors have been identified to functionally modulate OEC migration, 3 of which are known modulators of axonal extension (glial derived neurotrophic factor, GDNF, Nogo-66 and Slit-2) [46,47,48], and 1 extracellular matrix protein, fibulin 3 [49]. Because OECs are regarded as such important regulators of axon growth and guidance, and particularly since we have recently shown that an increased OEC migration rate leads to enhanced axon growth [22], a clear characterisation of how migration of OECs is regulated is also interesting from a clinical perspective.…”

“…Using in vitro cocultures of OECs and neonatal primary olfactory neurons [40], we have recently shown that OECs always migrate ahead of extending primary olfactory neurons [22,41]. We have also demonstrated that a GNDF-mediated increase in lamellipodial wave activity and subsequent OEC migration rate leads to faster axonal extension.…”

The role of olfactory ensheating cells in regenerative medicine: review of the literature

“…When the olfactory neuroepithelium is damaged, stem cells from the mucosa differentiate and repair it, accompanying the glial cells up to the level of the olfactory bulb. Being ensheathed by the OECs, the olfactory axons can grow and access the central nervous system; this property is not seen in axons that regenerate after injuries of the dorsal roots; they fail to enter too far into the nervous tissue of the spinal cord 10 . It was shown that adhesion molecules L1/neuron-glia cell adhesion molecule (L1/Ng-CAM) and neural cell adhesion molecule (N-CAM), both present in the plasma membranes of ensheathing cells and immature olfactory receptor neurons, help the olfactory axons to use the glial cell surfaces as a growth substratum 6 .…”

One-Dimensional Migration of Olfactory Ensheathing Cells on Synthetic Materials: Experimental and Numerical Characterization

“…Some of the experimental therapies pursue the reconnection of axons and neurites, for which the guided growth of axons within or along filamentous structures might be useful (1)(2)(3). Olfactory ensheathing cells (OECs) or Schwann cells (SCs) are thought to help this process, by ensheathing and guiding the growing axons (4)(5)(6)(7)(8)(9).…”