TY - JOUR
T1 - The accumulation of T cells within acellular nerve allografts is length-dependent and critical for nerve regeneration
AU - Pan, Deng
AU - Hunter, Daniel A.
AU - Schellhardt, Lauren
AU - Jo, Sally
AU - Santosa, Katherine B.
AU - Larson, Ellen L.
AU - Fuchs, Anja
AU - Snyder-Warwick, Alison K.
AU - Mackinnon, Susan E.
AU - Wood, Matthew D.
N1 - Funding Information:
This work was supported in part by the National Institutes of Neurological Disorders and Stroke of the National Institutes of Health (NIH) under award numbers R01 NS086773 and P30 NS057105 to Washington University and by a Pilot Project Award from the Hope Center for Neurological Disorders at Washington University. The content is solely the responsibility of the authors and does not represent the views of the NIH or Washington University.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/8
Y1 - 2019/8
N2 - 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), axon regeneration across longer 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.
AB - 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), axon regeneration across longer 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.
KW - Acellular nerve allograft
KW - Peripheral nerve
KW - Regeneration
KW - Schwann cells
KW - T cells
UR - http://www.scopus.com/inward/record.url?scp=85065711660&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2019.05.009
DO - 10.1016/j.expneurol.2019.05.009
M3 - Article
C2 - 31085199
AN - SCOPUS:85065711660
VL - 318
SP - 216
EP - 231
JO - Experimental Neurology
JF - Experimental Neurology
SN - 0014-4886
ER -