3 years ago

Transgenic SCs expressing GDNF-IRES-DsRed impair nerve regeneration within acellular nerve allografts

Transgenic SCs expressing GDNF-IRES-DsRed impair nerve regeneration within acellular nerve allografts
Shelly E. Sakiyama-Elbert, Lauren Schellhardt, Daniel A. Hunter, Ying Yan, Matthew D. Wood, Xueping Ee, Susan E. Mackinnon
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. © 2017 Wiley Periodicals, Inc. Transgenic Schwann cells (TSCs) overexpressing GDNF-IRES-DsRed were developed to determine the impact of regulating GDNF transgene temporal expression on nerve regeneration across acellular scaffolds. The authors found these TSCs expressing GDNF for as little as 1 week decreased axon regeneration across scaffolds and caused extensive extracellular matrix (ECM) remodeling. Further characterization of these cells revealed these TSCs expressed a set of genes (beyond GDNF) different than unmodified SCs, while co-culture of TSCs with fibroblasts caused ECM-related gene expression in fibroblasts.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/bit.26335

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