Genetically modified Schwann cells producing glial cell line-derived neurotrophic factor inhibit neuronal apoptosis in rat spinal cord injury

Abstract

Schwann cells (SCs) are the major cells constituting the peripheral nerve structure and function, and also secret a variety of neurotrophic factors. Schwann cell (SC) transplantation has recently emerged as a promising therapeutic strategy for spinal cord injury (SCI). In the present study, the ability of genetically modified SCs producing high levels of glial cell line‑derived neurotrophic factor (GDNF) to promote spinal cord repair was assessed. The GDNF gene was transduced into SCs. The engineered SCs were characterized by their ability to express and secrete biologically active GDNF, which was shown to inhibit apoptosis of primary rat neurons induced by radiation, and upregulate the expression of B‑cell lymphoma 2 (Bcl‑2) and downregulate the expression of Bcl‑2 associated X protein (Bax) in vitro. Following SC implantation into the spinal cord of adult rats with SCI induced by weight‑drop impact, the survival of rats with transplanted SCs, histology of the spinal cord and expression levels of Bcl‑2 and Bax were examined. Transplantation of unmodified and genetically modified SCs producing GDNF attenuated SCI by inhibiting apoptosis via the Bcl‑2/Bax pathways. The genetically modified SCs demonstrated markedly improved recovery of SCI as compared with unmodified SCs. The present study combined the outgrowth‑promoting property of SCs with the neuroprotective effects of overexpressed GDNF and identified this as a potential novel therapeutic strategy for SCI.

GDNF Schwann cells in hydrogel scaffolds promote regional axon regeneration, remyelination and functional improvement after spinal cord transection in rats

“…The combination of GDNF‐SCs improved axonal regeneration beyond SCs alone, which supports other studies (Deng et al, ; Kanno et al, ). GDNF‐SCs have a direct neuroprotective effect on spinal motor neuron survival by inhibiting apoptosis following injury (Liu et al, ). GDNF promotes spinal motor neuron axonal extension (Bohn, ), targeting and synaptic remodeling (Keller‐Peck et al, ).…”

Adenoviral vector carrying glial cell-derived neurotrophic factor for direct gene therapy in comparison with human umbilical cord blood cell-mediated therapy of spinal cord injury in rat

“…19,20 Native human UCB-MCs can differentiate into endothelial and microglial cells and UCB-MCs transfected with plasmid vectors that concurrently expressed VEGF and NCAM-L1 showed considerable potential to differentiate into endothelial cells; moreover, UCB-MCs overexpressing VEGF and FGF2 transformed into astrocyte-like S100 + cells and Oct4-Sox2 transfected UCB-MCs expressed the neuronal marker PGP9.5. 26 Studies conducted using various approaches to deliver the GDNF gene have increasingly focused on examining the functional deficits and the preservation of the gray matter of the spinal cord, but these studies have primarily examined the survival of neurons 10,13,27,28 and have mostly ignored the changes in glial cells. Therefore, in this study, we paid particular attention to the effects of direct and cell-mediated delivery of the GDNF gene on the phenotypic and quantitative characteristics of glial cells in the injured spinal cord.…”

Thermosensitive heparin‐poloxamer hydrogels enhance the effects of GDNF on neuronal circuit remodeling and neuroprotection after spinal cord injury

“…GDNF inhibited cell apoptosis on day 28, which was consistent with previous reports. 57,61 Interestingly, the inhibition of cell apoptosis by GDNF was accompanied by the decreased expression of autophagy-induced proteins (Beclin-1, LC3), suggesting that GDNF could protect neural cells against cell death by inhibiting autophagy-induced apoptosis (Fig. 5B,C).…”

“…These findings suggest that HP hydrogels may have an important role in recovering the injured spinal cord, probably due to its LMWH. A recent study showed that LMWH can protect against lipopolysaccharide‐induced cognitive impairments by attenuating microglial activation, cytokine release, oxidative stress and loss of synaptic plasticity . Taken together, the efficient cellular uptake, controlled release behavior and LMWH bioactivity of HP hydrogels may contribute to enhance the effects of GDNF on neuronal circuit remodeling and neuroprotection in SCI.…”