Following peripheral nerve injury comprising a segmental defect, the extent of axon regeneration decreases precipitously with increasing gap length. Schwann cells play a key role in driving axon re-growth by forming aligned tubular guidance structures called bands of Büngner, which readily occurs in distal nerve segments as well as within autografts – currently the most reliable clinically-available bridging strategy. However, host Schwann cells generally fail to infiltrate large-gap acellular scaffolds, resulting in markedly inferior outcomes and motivating the development of next-generation bridging strategies capable of fully exploiting the inherent pro-regenerative capability of Schwann cells. We sought to create preformed, implantable Schwann cell-laden microtissue that emulates the anisotropic structure and function of naturally-occurring bands of Büngner. Accordingly, we developed a biofabrication scheme leveraging biomaterial-induced self-assembly of dissociated rat primary Schwann cells into dense, fiber-like three-dimensional bundles of Schwann cells and extracellular matrix within hydrogel micro-columns. This engineered microtissue was found to be biomimetic of morphological and phenotypic features of endogenous bands of Büngner, and also demonstrated 8 and 2× faster rates of axonal extension in vitro from primary rat spinal motor neurons and dorsal root ganglion sensory neurons, respectively, compared to 3D matrix-only controls or planar Schwann cells. To our knowledge, this is the first report of accelerated motor axon outgrowth using aligned Schwann cell constructs. For translational considerations, this microtissue was also fabricated using human gingiva-derived Schwann cells as an easily accessible autologous cell source. These results demonstrate the first tissue engineered bands of Büngner (TE-BoBs) comprised of dense three-dimensional bundles of longitudinally aligned Schwann cells that are readily scalable as implantable grafts to accelerate axon regeneration across long segmental nerve defects.
Recent research has identified the lateral habenula (LHb) as a brain region playing an important role in the production of stressful and anxiogenic states. Additionally, norepinephrine (NE) has long been known to be involved in arousal, stress and anxiety, and NE projections to the LHb have been identified emanating from the locus coeruleus (LC). The current research was devised to test the hypothesis that NE release within the LHb contributes to the occurrence of anxiogenic behaviors. Male rats were implanted with bilateral guide cannula aimed at the LHb and subsequently treated with intracranial (IC) infusions of the selective α adrenergic autoreceptor agonist, dexmedetomidine (DEX) (0, 0.5, 1.0 μg/side), prior to assessment of ambulatory and anxiogenic behavior in tests of spontaneous locomotion, open field behavior, and acoustic startle-response. Results demonstrated that DEX administration significantly reduced the overall locomotor behavior of subjects at both doses indicating that infusion of even small doses of this α agonist into the LHb can have profound effects on the subjects' general levels of alertness and activity. DEX was also found to attenuate anxiety as evidenced by a reduction in the magnitude of a startle-response to an acoustic 110 dB stimulus. Taken together, these results identify a role for NE release within the LHb in both arousal and anxiety.
The rostral migratory stream (RMS) facilitates neuroblast migration from the subventricular zone to the olfactory bulb throughout adulthood. Brain lesions attract neuroblast migration out of the RMS, but resultant regeneration is insufficient. Increasing neuroblast migration into lesions has improved recovery in rodent studies. We previously developed techniques for fabricating an astrocyte-based Tissue-Engineered RMS (TE-RMS) intended to redirect endogenous neuroblasts into distal brain lesions for sustained neuronal replacement. Here, we demonstrate that astrocyte-like-cells can be derived from adult human gingiva mesenchymal stem cells and used for TE-RMS fabrication. We report that key proteins enriched in the RMS are enriched in TE-RMSs. Furthermore, the human TE-RMS facilitates directed migration of immature neurons in vitro. Finally, human TE-RMSs implanted in athymic rat brains redirect migration of neuroblasts out of the endogenous RMS. By emulating the brain’s most efficient means for directing neuroblast migration, the TE-RMS offers a promising new approach to neuroregenerative medicine.
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