Schwann cell-neuron interactions and axonal strain application in peripheral nervous system regeneration
Love, James Matthew
Shah, Sameer B
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Peripheral nervous system (PNS) injuries affect many people worldwide and if not repaired can leave individuals with the burden of living with chronic pain or motor dysfunction. My thesis focused on understanding the relationship nerves and neurons have with their environment during development and normal function in order to identify means by which the regenerative process might be manipulated and enhanced. The implementation of a two-armed study allowed me to investigate the interactions between Schwann cells (SCs), a vital neuronal support cell, and neurons, as well as, the role strain has in local protein synthesis. First, I detailed the changes in membrane stability within the two cell types. I was able to identify decreased velocity and correlative movement of neuronal membranes compared to SCs suggestive of a higher level of membrane stability. Both cell types saw a decreased trend in both velocity and correlative movement following development of contact with the other pointing to increased cellular membrane stability upon establishment of cellular contact. The next study looked into the development of ribosomal clusters within SC processes, which have been suggested to be a ribosomal source for axons following injury. I found that SCs develop ribosomal distributions early and use anterograde transport to maintain these populations. Upon the initiation of myelination, transport is depressed suggestive of a reduce role of ribosomes within the myelin fraction. The final portion of my work focused on neuronal adaptation to strain. I initially found that nerves are able to accommodate strains by straightening axons in a linear fashion. I further found moderate strain application to nerves upregulates the activation of both mTOR and S6, two molecules integral in enhancing protein synthesis. Additionally, increases in the cytoskeletal proteins β-actin and SMI31 were observed in response to strain. Suppression of the mTOR pathway with rapamycin led to an elimination of the effect on SMI31 but not β-actin. Rapamycin also enabled a strain-dependent reduction in tubulin levels. The results of my thesis contextualize the results of a number of studies that have observed advantageous regenerative outcomes from the use of SCs and strain for PNS recovery.