Abstract
Poor graft survival limits the use of primary dopaminergic neurons for neural repair in Parkinson’s disease. Injectable hydrogels have the potential to significantly improve the outcome of such reparative approaches by providing a physical matrix for cell encapsulation which can be further enriched with pro-survival factors. Therefore, this study sought to determine the survival and efficacy of primary dopaminergic grafts after intra-striatal delivery in a glial-derived neurotrophic factor (GDNF)-loaded collagen hydrogel in a rat model of Parkinson’s disease. After intra-striatal transplantation into the lesioned striatum, the GDNF-enriched collagen hydrogel significantly improved the survival of dopaminergic neurons in the graft (5-fold), increased their capacity for striatal re-innervation (3-fold), and enhanced their functional efficacy. Additional studies suggested that this was due to the hydrogel’s ability to retain GDNF in the microenvironment of the graft, and to protect the transplanted cells from the host immune response. In conclusion, the encapsulation of dopaminergic neurons in a GDNF-loaded hydrogel dramatically increased their survival and function, providing further evidence of the potential of biomaterials for neural transplantation and brain repair in neurodegenerative diseases such as Parkinson’s disease.
Highlights
The relatively selective loss of dopaminergic neurons from the substantia nigra pars compacta makes Parkinson’s disease an ideal candidate for cell replacement therapies[1,2]
In order to determine if the collagen hydrogels of rising cross-linker concentrations (1, 2 or 4 mg/ml 4s-StarPEG) had any detrimental effects on the viability of mesenchymal stem cells (MSC), they were incubated with pre-formed collagen hydrogels
The presence of hydrogels did not have any negative impact on overall ventral mesencephalon (VM) cell viability (Fig. 2C; Group, F(2,6) = 0.5757, P > 0.05), and when the survival of dopaminergic neurons within these cultures was assessed, the hydrogels had no negative effect on the number of surviving tyrosine hydroxylase (TH)+ cells (Fig. 2D; Group, F(3,16) = 0.5143, P > 0.05) and importantly, the presence of the hydrogels did not hinder the neural outgrowth from these TH+ dopaminergic neurons (Fig. 2E; Group, F(3,12) = 0.0865, P > 0.05)
Summary
The relatively selective loss of dopaminergic neurons from the substantia nigra pars compacta makes Parkinson’s disease an ideal candidate for cell replacement therapies[1,2]. While the efficacy of dopamine neuron-rich foetal VM grafts is still being investigated clinically through the TRANSEURO consortium[10], the field of cell replacement therapy in Parkinson’s disease is moving towards more readily available dopaminergic cell sources, such as those derived from embryonic stem cells and induced pluripotent stem cells[11] While these cells show extrordinary regenerative potential, their use is still in the experimental stages and has not yet reached a clinical setting. The majority of cell death in VM grafts occurs through apoptosis at various points of the transplantation process[12] by factors such as detachment from the extracellular matrix during tissue dissection[13], growth factor deprivation upon transplantation[14], and recruitment of host neuro-immune cells to the exogenous graft[15] Each of these stages provides a target point of intervention at which graft survival could be improved. We hypothesised that the type 1 collagen hydrogel would provide a local GDNF reservoir and reduce the host immune response to the transplanted cells, thereby improving the overall survival, re-innervation and functionality of primary dopaminergic neurons after intra-striatal transplantation
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