Motor and sensory Schwann cell phenotype commitment is diminished by extracorporeal shockwave treatment in vitro

Abstract

The gold standard for peripheral nerve regeneration uses a sensory autograft to bridge a motor/sensory defect site. For motor nerves to regenerate, Schwann cells (SC) myelinate the newly grown axon. Sensory SCs have a reduced ability to produce myelin, partially explaining low success rates of autografts. This issue is masked in pre‐clinical research by the excessive use of the rat sciatic nerve defect model, utilizing a mixed nerve with motor and sensory SCs. Aim of this study was to utilize extracorporeal shockwave treatment as a novel tool to influence SC phenotype. SCs were isolated from motor, sensory and mixed rat nerves and in vitro differences between them were assessed concerning initial cell number, proliferation rate, neurite outgrowth as well as ability to express myelin. We verified the inferior capacity of sensory SCs to promote neurite outgrowth and express myelin‐associated proteins. Motor Schwann cells demonstrated low proliferation rates, but strongly reacted to pro‐myelination stimuli. It is noteworthy for pre‐clinical research that sciatic SCs are a strongly mixed culture, not representing one or the other. Extracorporeal shockwave treatment (ESWT), induced in motor SCs an increased proliferation profile, while sensory SCs gained the ability to promote neurite outgrowth and express myelin‐associated markers. We demonstrate a strong phenotype commitment of sciatic, motor, and sensory SCs in vitro, proposing the experimental use of SCs from pure cultures to better mimic clinical situations. Furthermore we provide arguments for using ESWT on autografts to improve the regenerative capacity of sensory SCs.

ESWT Diminishes Axonal Regeneration following Repair of the Rat Median Nerve with Muscle-In-Vein Conduits but Not after Autologous Nerve Grafting

“…As it was shown that the ex vivo ESWT-treated Schwann cells showed increased proliferative activity and—upon respective inductive cues—expression of myelin-associated phenotypic markers [ 25 ], they might exert negative effects on lymphatic endothelial vasculature cells in vivo. Given the few published reports [ 17 , 24 , 25 , 97 ] addressing the effects of ESWT on Schwann cells, we advise for further studies to elucidate the underlying reasons for this phenomenon.…”

“…Among these effects, improved vascularization via activation of nitric oxide synthase (NOS), increased expression of growth factors like activating transcription factor 3 (ATF-3) and growth-associated phosphoprotein 43 (GAP-43), local anti-inflammatory effects and influencing of target cells, too, are thought to be the main drivers for improved tissue and nerve regeneration following ESWT [ 21 , 22 , 23 ]. Schwann cells proliferation and phenotype is also directly influenced by ESWT, enhancing peripheral nerve regeneration through activation of these glial cells [ 18 , 24 , 25 , 26 ]. Application of ESWT to improve nerve regeneration was first described by Hausner et al in a rat model of sciatic nerve autograft repair [ 27 ].…”

Schwann Cells Contribute to Alveolar Bone Regeneration by Promoting Cell Proliferation

“…( 62 ) Though these two types of SCs differ, the SCs of sciatic nerve, which is the mixed nerve, behave almost the same as sensory SCs. ( 63 ) Also, it has been proved that the motor phenotype could be modified to the sensory phenotype by reinnervation of sensory nerve. ( 61 ) Thus, sciatic nerve–derived SCs were used in our transplant model.…”

Physical Considerations for In Vitro ESWT Research Design

“…It has distinguished itself for its safe, non-invasive approach in regenerative medicine [ 1 ] when it adheres to established protocols. A well-established wide range of indications like non-union fractures, some tendinopathies, and chronic non-healing wounds is continuously expanded by new experimental investigations into novel indications in urology, peripheral nerve regeneration, spinal cord injury, and trans-cranial applications [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ].…”