Collagen-Binding Hepatocyte Growth Factor (HGF) alone or with a Gelatin- furfurylamine Hydrogel Enhances Functional Recovery in Mice after Spinal Cord Injury

Abstract

The treatment of spinal cord injury (SCI) is currently a significant challenge. Hepatocyte growth factor (HGF) is a multipotent neurotrophic and neuroregenerative factor that can be beneficial for the treatment of SCI. However, immobilized HGF targeted to extracellular matrix may be more effective than diffusible, unmodified HGF. In this study, we evaluated the neurorestorative effects of an engineered HGF with a collagen biding domain (CBD-HGF). CBD-HGF remained in the spinal cord for 7 days after a single administration, while unmodified HGF was barely seen at 1 day. When a gelatin-furfurylamine (FA) hydrogel was applied on damaged spinal cord as a scaffold, CBD-HGF was retained in gelatin-FA hydrogel for 7 days, whereas HGF had faded by 1 day. A single administration of CBD-HGF enhanced recovery from spinal cord compression injury compared with HGF, as determined by motor recovery, and electrophysiological and immunohistochemical analyses. CBD-HGF alone failed to improve recovery from a complete transection injury, however CBD-HGF combined with gelatin-FA hydrogel promoted endogenous repair and recovery more effectively than HGF with hydrogel. These results suggest that engineered CBD-HGF has superior therapeutic effects than naïve HGF. CBD-HGF combined with hydrogel scaffold may be promising for the treatment of serious SCI.

Growth Factor Engineering Strategies for Regenerative Medicine Applications

“…In another study, CBD-fused FGF-2 showed the ability to induce significantly higher mesenchymal cell proliferation and callus formation in a mice fracture model compared to wild-type FGF-2 (Sekiguchi et al, 2018). Similarly, a CBD-fused hepatocyte growth factor (HGF) delivered via hydrogel improved recovery after spinal cord injury in mice compared to wild-type HGF (Yamane et al, 2018).…”

Multipotent Neurotrophic Effects of Hepatocyte Growth Factor in Spinal Cord Injury

“…HGF also inhibits the infiltration of neutrophils through the down-regulation of adhesion molecules [23]. Our previous report demonstrated that the infiltration of macrophages and neutrophils was reduced under the influence of HGF in the acute phase of SCI [7]. The anti-inflammatory activities of HGF contribute to reduce secondary damage and improve functional recovery after SCI.…”

“…Optimization of the routes of drug administration is essential to increase drug efficacy and address clinical medicines. Previous in vivo animal studies tackling the subject of SCI treatment evaluated different HGF therapy approaches, such as the use of recombinant HGF [9], viral vectors [6], grafting of mesenchymal stem cells that over-express HGF [8], or utilization of engineered HGF with a collagen biding domain (CBD-HGF) [7]. Irrespective of the therapeutic approach, local administration of HGF is required as the endogenous HGF supply is limited in the acute phase of SCI.…”

“…HGF is in the spotlight as one of the neurotrophic growth factors that exerts pleiotropic effects on the central nervous system. Recent studies have revealed that HGF exerts multiple neurotrophic activities in SCI [6,7,8,9]. Our previous study showed promising results for a new SCI combination therapy, using a scaffold and a novel HGF fused to the collagen-binding domain (CBD) derived from fibronectin (CBD-HGF) [7].…”

“…Recent studies have revealed that HGF exerts multiple neurotrophic activities in SCI [6,7,8,9]. Our previous study showed promising results for a new SCI combination therapy, using a scaffold and a novel HGF fused to the collagen-binding domain (CBD) derived from fibronectin (CBD-HGF) [7]. To gain further insights into the effects and benefits of HGF on neural tissue regeneration, we review the molecular mechanisms underlying the therapeutic effects of HGF in the spinal cord.…”