Neuronal Transplants into the Distal Nerve Segment Maintain Pro-Regenerative Schwann Cells in a Model of Chronic Axotomy
Zarina S. Ali, MD1; Joseph P. Morand, BS1; Kritika S. Katiyar, BS1; Harry C. Ledebur, PhD2; Douglas H. Smith, MD1; D. Kacy Cullen, PhD1
1Neurosurgery, University of Pennsylvania, Philadelphia, PA; 2Axonia Medical, Inc, Kalamazoo, MI
Peripheral nerve injury (PNI) often results in a choreographed sequence of Wallerian degeneration and alterations in Schwann cell (SC) structure and function. Initially, SCs assume a pro-regenerative phenotype to form the bands of Bungner, which are aligned columns to facilitate axon regrowth. However, this pro-regenerative environment degrades over several months, ultimately blunting the extent of axonal regeneration and hence functional recovery. This is particularly relevant in cases of long segmental defects and/or proximal injuries where this pro-regenerative capacity is present over a shorter timeframe than necessary to support axonal regeneration to distal targets.
In a novel approach, we utilize tissue engineering strategies to implant living neurons to prolong the pro-regenerative capacity of SCs in otherwise axotomized nerves. In the current study, we assessed the ability of allogeneic neuronal constructs to “babysit” distal nerve SCs following sciatic nerve axotomy in the rat. In this paradigm, tissue engineered constructs were attached to the transected distal nerve and the proximal nerve was capped to prevent host axonal ingrowth.
Histological analyses were performed up to 16 weeks post-transection to determine distal nerve cytoarchitecture, graft survival, and graft axon integration with distal nerve. Over 2-4 weeks post-transection, distal nerve SCs formed stereotypical aligned regenerative columns. In control animals (not receiving neuronal implants), the density of these columns decreased over 6-8 weeks, with a marked reduction in SC presence and alignment after 9 weeks and widespread SC degeneration and a complete absence of alignment by 16 weeks. In animals receiving neuronal implants, we found surviving graft neurons – despite an absence of immunosuppression therapy – and substantial graft axon penetration deep into the distal nerve to interact directly with host SCs. Remarkably, this led to an abundance of SCs which maintained their pro-regenerative alignment and phenotype out to at least 16 weeks.
These findings demonstrate the promise of living axonal constructs to maintain the regenerative capacity of resident SCs. For clinical deployment, we envision secondary “satellite” neuronal transplants at metered locations distal to a primary repair, with the sole purpose to maintain pro-regenerative SCs ahead of regenerating axons. We are currently assessing the ability of such satellite transplants to “babysit” distal SCs in support of host axonal regeneration following repair of major (?4cm) nerve lesions in rodent and porcine models. This tissue engineering strategy may enable host axons to reinnervate long-distance targets and potentially facilitate functional recovery following currently untreatable PNI.
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