TY - JOUR
T1 - The CCL2/CCR2 axis is critical to recruiting macrophages into acellular nerve allograft bridging a nerve gap to promote angiogenesis and regeneration
AU - Pan, Deng
AU - Acevedo-Cintrón, Jesús A.
AU - Sayanagi, Junichi
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, R01 NS115960, and K08 NS096232 to Washington University.
Funding Information:
We thank Daniel Hunter for helpful discussion and Lauren Schellhardt for help with animal care. This work was supported in part by the National Institutes of Neurological Disorders and Stroke of the National Institutes of Health (NIH, USA) under award numbers R01 NS086773 , R01 NS115960 , and K08 NS096232 to Washington University. An award from the McDonnell Center for Cellular and Molecular Neuroscience (MDW), and by a Pilot Project Award from the Hope Center for Neurological Disorders at Washington University (MDW). The content is solely the responsibility of the authors and does not represent the views of the NIH or Washington University.
Funding Information:
We thank Daniel Hunter for helpful discussion and Lauren Schellhardt for help with animal care. This work was supported in part by the National Institutes of Neurological Disorders and Stroke of the National Institutes of Health (NIH, USA) under award numbers R01 NS086773, R01 NS115960, and K08 NS096232 to Washington University. An award from the McDonnell Center for Cellular and Molecular Neuroscience (MDW), and by a Pilot Project Award from the Hope Center for Neurological Disorders at Washington University (MDW). The content is solely the responsibility of the authors and does not represent the views of the NIH or Washington University. 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, R01 NS115960, and K08 NS096232 to Washington University. M.D.W. has consulted for The Foundry, LLC and Foundry Therapeutics, LLC and been a recipient of a sponsored research agreement with Checkpoint Surgical, Inc. All other authors have no competing interests to declare.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/9
Y1 - 2020/9
N2 - Acellular nerve allografts (ANAs) are increasingly used to repair nerve gaps following injuries. However, these nerve scaffolds have yet to surpass the regenerative capabilities of cellular nerve autografts; improved understanding of their regenerative mechanisms could improve design. Due to their acellular nature, both angiogenesis and diverse cell recruitment is necessary to repopulate these scaffolds to promote functional regeneration. We determined the contribution of angiogenesis to initial cellular repopulation of ANAs used to repair nerve gaps, as well as the signaling that drives a significant portion of this angiogenesis. Wild-type (WT) mice with nerve gaps repaired using ANAs that were treated with an inhibitor of VEGF receptor signaling severely impaired angiogenesis within ANAs, as well as hampered cell repopulation and axon extension into ANAs. Similarly, systemic depletion of hematogenous-derived macrophages, but not neutrophils, in these mice models severely impeded angiogenesis and subsequent nerve regeneration across ANAs suggesting hematogenous-derived macrophages were major contributors to angiogenesis within ANAs. This finding was reinforced using CCR2 knockout (KO) models. As macrophages represented the majority of CCR2 expressing cells, a CCR2 deficiency impaired angiogenesis and subsequent nerve regeneration across ANAs. Furthermore, an essential role for CCL2 during nerve regeneration across ANAs was identified, as nerves repaired using ANAs had reduced angiogenesis and subsequent nerve regeneration in CCL2 KO vs WT mice. Our data demonstrate the CCL2/CCR2 axis is important for macrophage recruitment, which promotes angiogenesis, cell repopulation, and subsequent nerve regeneration and recovery across ANAs used to repair nerve gaps.
AB - Acellular nerve allografts (ANAs) are increasingly used to repair nerve gaps following injuries. However, these nerve scaffolds have yet to surpass the regenerative capabilities of cellular nerve autografts; improved understanding of their regenerative mechanisms could improve design. Due to their acellular nature, both angiogenesis and diverse cell recruitment is necessary to repopulate these scaffolds to promote functional regeneration. We determined the contribution of angiogenesis to initial cellular repopulation of ANAs used to repair nerve gaps, as well as the signaling that drives a significant portion of this angiogenesis. Wild-type (WT) mice with nerve gaps repaired using ANAs that were treated with an inhibitor of VEGF receptor signaling severely impaired angiogenesis within ANAs, as well as hampered cell repopulation and axon extension into ANAs. Similarly, systemic depletion of hematogenous-derived macrophages, but not neutrophils, in these mice models severely impeded angiogenesis and subsequent nerve regeneration across ANAs suggesting hematogenous-derived macrophages were major contributors to angiogenesis within ANAs. This finding was reinforced using CCR2 knockout (KO) models. As macrophages represented the majority of CCR2 expressing cells, a CCR2 deficiency impaired angiogenesis and subsequent nerve regeneration across ANAs. Furthermore, an essential role for CCL2 during nerve regeneration across ANAs was identified, as nerves repaired using ANAs had reduced angiogenesis and subsequent nerve regeneration in CCL2 KO vs WT mice. Our data demonstrate the CCL2/CCR2 axis is important for macrophage recruitment, which promotes angiogenesis, cell repopulation, and subsequent nerve regeneration and recovery across ANAs used to repair nerve gaps.
KW - Acellular nerve allograft
KW - Angiogenesis
KW - Macrophage
KW - Peripheral nerve
KW - Regeneration
UR - http://www.scopus.com/inward/record.url?scp=85085578640&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2020.113363
DO - 10.1016/j.expneurol.2020.113363
M3 - Article
C2 - 32450192
AN - SCOPUS:85085578640
SN - 0014-4886
VL - 331
JO - Experimental Neurology
JF - Experimental Neurology
M1 - 113363
ER -