Migration and Differentiation of Neural Stem Cells Diverted From the Subventricular Zone by an Injectable Self-Assembling β-Peptide Hydrogel.

Sepideh Motamed,Kun Zhou,Tobias D Merson,Ketav Kulkarni,Peter J Crack,Marie-Isabel Aguilar,John S Forsythe,David I Finkelstein,Mark P Del Borgo

doi:10.3389/fbioe.2019.00315

Abstract

Neural stem cells, which are confined in localised niches are unable to repair large brain lesions because of an inability to migrate long distances and engraft. To overcome these problems, previous research has demonstrated the use of biomaterial implants to redirect increased numbers of endogenous neural stem cell populations. However, the fate of the diverted neural stem cells and their progeny remains unknown. Here we show that neural stem cells originating from the subventricular zone can migrate to the cortex with the aid of a long-lasting injectable hydrogel within a mouse brain. Specifically, large numbers of neuroblasts were diverted to the cortex through a self-assembling β-peptide hydrogel that acted as a tract from the subventricular zone to the cortex of transgenic mice (NestinCreERT2:R26eYFP) in which neuroblasts and their progeny are permanently fluorescently labelled. Moreover, neuroblasts differentiated into neurons and astrocytes 35 days post implantation, and the neuroblast-derived neurons were Syn1 positive suggesting integration into existing neural circuitry. In addition, astrocytes co-localised with neuroblasts along the hydrogel tract, suggesting that they assisted migration and simulated pathways similar to the native rostral migratory stream. Lower levels of astrocytes were found at the boundary of hydrogels with encapsulated brain-derived neurotrophic factor, comparing with hydrogel implants alone.

Highlights

Brain lesions are a consequence of physical injury, stroke and neurodegeneration (Lindvall et al, 2004; Hyder et al, 2007; Eltzschig and Eckle, 2011; Hernández-Ortega et al, 2011) resulting in severe neurological disabilities (Orive et al, 2009)
We have previously investigated the feasibility of using scaffolds to promote neuroblast migration, which include the use of injectable gelatin-based hydrogels consisting of glial cell linederived neurotrophic factor, electrospun poly-ε-caprolactone nanofibers releasing a brain-derived neurotrophic factor (BDNF) mimetic, and graphene coated electrospun poly-ε-caprolactone fibres from the subventricular zone (SVZ) (Fon et al, 2014a,b; Zhou et al, 2016)
Considering the critical role of astrocytes in the rostral migratory stream (RMS), we investigated the astrocyte-neuroblast co-location along the implanted β-peptide hydrogel tract

Summary

Introduction

Brain lesions are a consequence of physical injury, stroke and neurodegeneration (Lindvall et al, 2004; Hyder et al, 2007; Eltzschig and Eckle, 2011; Hernández-Ortega et al, 2011) resulting in severe neurological disabilities (Orive et al, 2009). While cell transplantation is an important strategy to replace lost neural tissue, issues with immune rejection, poor engraftment, ethical issues. Neural progenitor cells are continuously being produced in the adult brain, but their genesis is confined to the subgranular zone and the subventricular zone (SVZ) (Ma et al, 2009). Neural progenitor cells migrate into the injured region where they attempt differentiation and repair (Rennert et al, 2012). The implications for the patient are serious, manifesting in drastic and permanent disabilities

Methods

Results

Conclusion