The accumulation of T cells within acellular nerve allografts is length-dependent and critical for nerve regeneration

• Published in: Experimental neurology 2019-08, Vol.318, p.216-231
• Main Authors: Pan, Deng, Hunter, Daniel A., Schellhardt, Lauren, Jo, Sally, Santosa, Katherine B., Larson, Ellen L., Fuchs, Anja G., Snyder-Warwick, Alison K., Mackinnon, Susan E., Wood, Matthew D.
• Format: Article
• Language: English
• Subjects: Acellular nerve allograft; Allografts; Animals; Guided Tissue Regeneration - methods; Nerve Regeneration - physiology; Peripheral nerve; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Regeneration; Schwann cells; Sciatic Nerve - injuries; Sciatic Nerve - transplantation; T cells; T-Lymphocytes - immunology; Tissue Scaffolds
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2019.05.009

Repair of traumatic nerve injuries can require graft material to bridge the defect. The use of alternatives to bridge the defect, such as acellular nerve allografts (ANAs), is becoming more common and desired. Although ANAs support axon regeneration across short defects (3 cm) is limited. It is unclear why alternatives, including ANAs, are functionally limited by length. After repairing Lewis rat nerve defects using short (2 cm) or long (4 cm) ANAs, we showed that long ANAs have severely reduced axon regeneration across the grafts and contain Schwann cells with a unique phenotype. But additionally, we found that long ANAs have disrupted angiogenesis and altered leukocyte infiltration compared to short ANAs as early as 2 weeks after repair. In particular, long ANAs contained fewer T cells compared to short ANAs. These outcomes were accompanied with reduced expression of select cytokines, including IFN-γ and IL-4, within long versus short ANAs. T cells within ANAs did not express elevated levels of IL-4, but expressed elevated levels of IFN-γ. We also directly assessed the contribution of T cells to regeneration across nerve grafts using athymic rats. Interestingly, T cell deficiency had minimal impact on axon regeneration across nerve defects repaired using isografts. Conversely, T cell deficiency reduced axon regeneration across nerve defects repaired using ANAs. Our data demonstrate that T cells contribute to nerve regeneration across ANAs and suggest that reduced T cells accumulation within long ANAs could contribute to limiting axon regeneration across these long ANAs. •Nerve gaps repaired using short, but not long, ANAs facilitated axon regeneration.•Schwann cells within long ANAs expressed reduced myelination and repair genes.•T cells accumulate within short ANAs while few accumulate within long ANAs.•Long ANA environments contained reduced expression of cytokines, IFN-γ and IL-4.•T cells contribute to regeneration across ANAs, as a deficit reduced regeneration.