Assessment of the impact of GDF-5-loaded collagen hydrogels on ventral mesencephalic grafts in a rat model of Parkinson's disease

Introduction

A promising reparative therapy for Parkinson’s disease is the transplantation of dopaminergic neurons harvested from foetal tissue. However, this is limited by poor survival leading to poor striatal reinnervation and motor recovery. We have recently shown that GDNF-enriched hydrogels have the potential to improve these graft outcomes^1,2, suggesting that this approach merits extension to other neurotrophic factors.  One potential neurotrophic factor to use in this context is growth differentiation factor 5 (GDF-5) which is a potent dopaminergic neuroprotective agent. Therefore, this study sought to determine the survival and efficacy of primary dopaminergic grafts in a GDF-5-loaded collagen hydrogel in a rat model of Parkinson's disease.

Methods:

Forty Sprague Dawley rats received a unilateral medial forebrain bundle 6-hydroxydopamine lesion two weeks before transplantation surgery. They then received an intrastriatal transplant of E14 ventral mesencephalic (VM) cells (300k/6µl) with or without encapsulation in a collagen hydrogel with or without enrichment with GDF-5 (20µg/6µl). Methamphetamine induced rotations were assessed as a measure of functional restoration, while immunohistochemistry for dopaminergic neurons (tyrosine hydroxylase), microglia (OX-42) and astrocytes (GFAP) was used to identify graft survival, reinnervation, and host immune response post mortem.

Approach for statistical analysis:

A randomised and blinded experimental approach was used throughout. All data were analysed using ANOVA (one-way or two-way with repeated measures where appropriate), with post hoc Bonferroni test as appropriate.

4. Results and conclusions:

Surprisingly, we found that incorporation of GDF-5, but not the collagen hydrogel, into the transplantation process actually reduced the survival, reinnervation and functional capacity of the VM transplants suggesting that the GDF-5 was toxic to the cells. In conclusion, this study suggests that GDF-5, at the dose used in the present study, is detrimental to VM grafts. Therefore, it was not possible to demine if the collagen hydrogel provided any beneficial effects.