Neurotrophin‐3 released from implant of tissue‐engineered fibroin scaffolds inhibits inflammation, enhances nerve fiber regeneration, and improves motor function in canine spinal cord injury

Abstract

Spinal cord injury (SCI) normally results in cell death, scarring, cavitation, inhibitory molecules release, etc., which are regarded as a huge obstacle to reconnect the injured neuronal circuits because of the lack of effective stimulus. In this study, a functional gelatin sponge scaffold was used to inhibit local inflammation, enhance nerve fiber regeneration, and improve neural conduction in the canine. This scaffold had good porosity and modified with neurotrophin‐3 (NT‐3)/fibroin complex, which showed sustained release in vitro. After the scaffold was transplanted into canine spinal cord hemisection model, hindlimb movement, and neural conduction were improved evidently. Migrating host cells, newly formed neurons with associated synaptic structures together with functional blood vessels with intact endothelium in the regenerating tissue were identified. Taken together, the results demonstrated that using bioactive scaffold could establish effective microenvironment stimuli for endogenous regeneration, providing a potential and practical strategy for treatment of spinal cord injury. © 2018 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2158‐2170, 2018.

Transplantation of neural precursors generated from spinal progenitor cells reduces inflammation in spinal cord injury via NF-κB pathway inhibition

“…This implies that their observed therapeutic effect is not due to cell replacement but is likely of paracrine nature as suggested by increased gene expression of neural growth factor and Nt3 in host tissue and in case of NGF in SPC-01 cells as well [23]. It has been shown that NT-3 reduces inflammation while enhancing regeneration in the injured spinal cords leading to functional improvements [35]. Our findings provided additional evidence to elucidate the mechanisms of neural progenitor cell therapy.…”

An NT-3-releasing bioscaffold supports the formation of TrkC-modified neural stem cell-derived neural network tissue with efficacy in repairing spinal cord injury

“…To construct bioscaffolds with sustained NT-3 release and with a low swelling property that would allow subsequent cell seeding, we adopted a method previously used to produce NF-GS scaffolds [ 6 , 17 ]. Immunoelectron microscope (IEM) was employed to visualize the actual loading and distribution of NT-3 molecules inside the scaffolds with the aid of nanogold-conjugated secondary antibodies.…”

“…Over recent years, accumulating evidence in both canines [ 17 ] and nonhuman primates [ 4 ] has indicated that a single neural trophic factor, NT-3, can be a potent inducer of a pro-regenerative microenvironment that favors endogenous repair after severe SCI. However, several technical hurdles must be overcome before NT-3-producing neuronal grafts with augmented efficacy in treating SCI can be generated.…”

HIF‐1α promotes bone marrow stromal cell migration to the injury site and enhances functional recovery after spinal cord injury in rats

“…NT-3 is also a very important member of the neurotrophin family, playing a crucial role in exerting neuroprotective and neuroregenerative effects that can also guide stem cell migration, as well as mediate stem cell survival and neuronal differentiation. 26 NT-3, when delivered through various vectors, has been shown to improve stem cell survival, axonal regeneration and hind-limb functional recovery in animal models of SCI. 27,28 In the present study, we found that Adv-HIF-1α treatment significantly enhanced the expression of NT-3, which may promote the migration and survival of the BMSCs and improve the functional recovery.…”

“…NT‐3 is also a very important member of the neurotrophin family, playing a crucial role in exerting neuroprotective and neuroregenerative effects that can also guide stem cell migration, as well as mediate stem cell survival and neuronal differentiation . NT‐3, when delivered through various vectors, has been shown to improve stem cell survival, axonal regeneration and hind‐limb functional recovery in animal models of SCI .…”