TY - JOUR
T1 - Increasing nerve autograft length increases senescence and reduces regeneration
AU - Hoben, Gwendolyn M.
AU - Ee, Xueping
AU - Schellhardt, Lauren
AU - Yan, Ying
AU - Hunter, Daniel A.
AU - Moore, Amy M.
AU - Snyder-Warwick, Alison K.
AU - Stewart, Sheila
AU - Mackinnon, Susan E.
AU - Wood, Matthew D.
N1 - Funding Information:
This work was supported by THE PLASTIC SURGERY FOUNDATION.
Publisher Copyright:
Copyright © 2018 by the American Society of Plastic Surgeons.
PY - 2018
Y1 - 2018
N2 - Background: Nerve grafting with an autograft is considered the gold standard. However, the functional outcomes of long (>3 cm) nerve autografting are often poor. The authors hypothesized that a factor contributing to these outcomes is the graft microenvironment, where long compared to short autografts support axon regeneration to different extents. Methods: A rat sciatic nerve defect model was used to compare regeneration in short (2 cm) and long (6 cm) isografts. Axon regeneration and cell populations within grafts were assessed using histology, retrograde labeling of neurons regenerating axons, immunohistochemistry, quantitative reverse transcriptase polymerase chain reaction, and electron microscopy at 4 and/or 8 weeks. Results: At 8 weeks, for distances of both 1 and 2 cm from the proximal coaptation (equivalent regenerative distance), long isografts had reduced numbers of regenerated fibers compared with short isografts. Similarly, the number of motoneurons regenerating axons was reduced in the presence of long isografts compared with short isografts. Considering the regenerative microenvironments between short and long isografts, cell densities and general populations within both short and long isografts were similar. However, long isografts had significantly greater expression of senescence markers, which included senescence-associated β-galactosidase, p21, and p16, and distinct chromatin changes within Schwann cells. Conclusions: This study shows that axon regeneration is reduced in long compared with short isografts, where long isografts contained an environment with an increased accumulation of senescent markers. Although autografts are considered the gold standard for grafting, these results demonstrate that we must continue to strive for improvements in the autograft regenerative environment.
AB - Background: Nerve grafting with an autograft is considered the gold standard. However, the functional outcomes of long (>3 cm) nerve autografting are often poor. The authors hypothesized that a factor contributing to these outcomes is the graft microenvironment, where long compared to short autografts support axon regeneration to different extents. Methods: A rat sciatic nerve defect model was used to compare regeneration in short (2 cm) and long (6 cm) isografts. Axon regeneration and cell populations within grafts were assessed using histology, retrograde labeling of neurons regenerating axons, immunohistochemistry, quantitative reverse transcriptase polymerase chain reaction, and electron microscopy at 4 and/or 8 weeks. Results: At 8 weeks, for distances of both 1 and 2 cm from the proximal coaptation (equivalent regenerative distance), long isografts had reduced numbers of regenerated fibers compared with short isografts. Similarly, the number of motoneurons regenerating axons was reduced in the presence of long isografts compared with short isografts. Considering the regenerative microenvironments between short and long isografts, cell densities and general populations within both short and long isografts were similar. However, long isografts had significantly greater expression of senescence markers, which included senescence-associated β-galactosidase, p21, and p16, and distinct chromatin changes within Schwann cells. Conclusions: This study shows that axon regeneration is reduced in long compared with short isografts, where long isografts contained an environment with an increased accumulation of senescent markers. Although autografts are considered the gold standard for grafting, these results demonstrate that we must continue to strive for improvements in the autograft regenerative environment.
UR - http://www.scopus.com/inward/record.url?scp=85056835765&partnerID=8YFLogxK
U2 - 10.1097/PRS.0000000000004759
DO - 10.1097/PRS.0000000000004759
M3 - Article
C2 - 29994844
AN - SCOPUS:85056835765
SN - 0032-1052
VL - 142
SP - 952
EP - 961
JO - Plastic and Reconstructive Surgery
JF - Plastic and Reconstructive Surgery
IS - 4
ER -