@article{630d3d9dceb54df281220961c8e9ba88,
title = "Transgenic SCs expressing GDNF-IRES-DsRed impair nerve regeneration within acellular nerve allografts",
abstract = "Providing temporally regulated glial cell line-derived neurotrophic factor (GDNF) to injured nerve can promote robust axon regeneration. However, it is poorly understood why providing highly elevated levels of GDNF to nerve can lead to axon entrapment in the zone containing elevated GDNF. This limited understanding represents an obstacle to the translation of GDNF therapies to treat nerve injuries clinically. Here, we investigated how transgenic Schwann cells (SCs) overexpressing GDNF-IRES-DsRed impact nerve regeneration. Cultured primary SCs were transduced with lentiviruses (GDNF-overexpressing transgenic SCs), one of which provides the capability to express high levels of GDNF and regulate temporal GDNF expression. These SC groups were transplanted into acellular nerve allografts (ANAs) bridging a 14 mm rat sciatic nerve defect. GDNF-overexpressing transgenic SCs expressing GDNF for as little as 1 week decreased axon regeneration across ANAs and caused extensive extracellular matrix (ECM) remodeling. To determine whether additional gene expression changes beyond GDNF transgene expression occurred in GDNF-overexpressing transgenic SCs, microarray analysis of GDNF-overexpressing transgenic SCs compared to untreated SCs was performed. Microarray analysis revealed a set of common genes regulated in transgenic SC groups expressing high levels of GDNF compared to untreated SCs. A co-culture model of GDNF-overexpressing transgenic SCs with fibroblasts (FBs) revealed differential FB ECM-related gene expression compared to untreated SCs. These data suggest a component of axon entrapment is independent of GDNF's impact on axons. Biotechnol. Bioeng. 2017;114: 2121–2130.",
keywords = "acellular nerve allograft, candy store effect, gene therapy, glial cell line-derived neurotrophic factor, nerve regeneration, peripheral nerve",
author = "Xueping Ee and Ying Yan and Hunter, {Daniel A.} and Lauren Schellhardt and Sakiyama-Elbert, {Shelly E.} and Mackinnon, {Susan E.} and Wood, {Matthew D.}",
note = "Funding Information: Conflict of interest: The authors declare no competing financial interests. No benefit of any kind will be received either directly or indirectly by the author(s). Correspondence to: M.D. Wood Contract grant sponsor: National Institutes of Neurological Disorders and Stroke of the National Institutes of Health Contract grant number: 2 R01 NS051706 Contract grant sponsor: Alafi Neuroimaging Laboratory Contract grant sponsor: Hope Center for Neurological Disorders Contract grant sponsor: National Institutes of Neurological Disorders and Stroke of the National Institutes of Health Contract grant number: P30 NS057105 Contract grant sponsor: NCI Cancer Center Support Grant Contract grant number: P30 CA91842 Contract grant sponsor: ICTS/CTSA Grant Contract grant number: UL1 TR000448 Contract grant sponsor: National Center for Research Resources (NCRR) Contract grant sponsor: National Institutes of Health (NIH) Contract grant sponsor: NIH Roadmap for Medical Research Received 21 December 2016; Revision received 1 May 2017; Accepted 5 May 2017 Accepted manuscript online 8 May 2017; Article first published online 18 May 2017 in Wiley Online Library (http://onlinelibrary.wiley.com/doi/10.1002/bit.26335/abstract). DOI 10.1002/bit.26335 Funding Information: This work was supported in part by National Institutes of Neurological Disorders and Stroke of the National Institutes of Health under award number 2 R01 NS051706. Lentivirus preparation and construction in this study were supported by the Alafi Neuroimaging Laboratory, the Hope Center for Neurological Disorders, and the National Institutes of Neurological Disorders and Stroke of the National Institutes of Health under award number P30 NS057105 to Washington University. We would like to thank Dr. Mingjie Li and his lab (Washington University) for producing the lentiviruses and technical assistance. We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, Mo., for the use of the Siteman Flow Cytometry Core, which provided cell sorting service. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant P30 CA91842, while the Genome Technology Access Center is partially supported by this NCI Cancer Center Support Grant and by ICTS/CTSA Grant UL1 TR000448 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The authors declare no conflict of interest regarding this work. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or Washington University. Publisher Copyright: {\textcopyright} 2017 Wiley Periodicals, Inc.",
year = "2017",
month = sep,
doi = "10.1002/bit.26335",
language = "English",
volume = "114",
pages = "2121--2130",
journal = "Biotechnology and Bioengineering",
issn = "0006-3592",
number = "9",
}