Anti-inflammatory hydrogel enrichment for cell-based brain repair in Parkinson's disease
Cabré Giménez, Sílvia
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Cell transplantation as a therapeutic approach for Parkinson’s disease has been extensively studied over the past decades. The transplantation of primary dopaminergic neurons in the degenerated striatum has shown that these cells can survive the transplantation process, attach into the host tissue, provide dopamine and re-innervate the depleted striatum resulting in functional motor recovery. However, its broad use in the clinical field has been hampered by the poor survival of the transplanted cells. Biomaterials - such as injectable hydrogels - have the potential to address this issue by providing a supportive matrix enriched with neuroprotective growth factors that can preserve the transplanted cells from the traumatic transplantation process and the growth-factor deprived host environment. Nevertheless, cell grafting generates a host glial response – even when cells are encapsulated in a scaffold – that plays a key role in the survival of dopaminergic neuronal grafts. For this reason, the aim of this project was to assess the effects of an anti-inflammatory cytokine loaded collagen hydrogel on the host innate immune response and the long-term survival of primary dopaminergic cell grafts in the parkinsonian brain. Firstly, several collagen hydrogel compositions were optimised for cell and cytokine encapsulation and intra-striatal delivery through a battery of tests. Through a series of preliminary in vivo studies, the best IL-10 loaded collagen hydrogel composition was chosen. Later, we assessed if the encapsulation of primary ventral mesencephalon cells in an IL-10 loaded collagen hydrogel could reduce the host immune response and ultimately improve the dopaminergic cell survival. Based on these results, we evaluated the effects of encapsulating primary ventral mesencephalon cells alongside IL-10 and GDNF in a collagen hydrogel on the dopaminergic cell survival and host immune response. Collagen hydrogels proved to be biocompatible both in vitro and in vivo, and they successfully retained and released IL-10 over time in neuronal cultures and in the brain. More importantly, IL-10 was retained to a greater extent in the striatum when encapsulated in a collagen hydrogel 24h post-implantation. Furthermore, in an in vivo pilot study, the encapsulation of primary dopaminergic cells in an IL-10 collagen hydrogel reduced the striatal microgliosis at 4 weeks post-transplantation. However, the encapsulation of primary ventral mesencephalic cells in an IL-10 rich collagen hydrogel did not reduce the host immune response or improve the dopaminergic cell survival of the resulting grafts at longer timepoints. Furthermore, we observed no amelioration of the host immune response nor an increase on cell survival when a multi-modal IL-10 and GDNF rich collagen hydrogel was used. In conclusion, although functionalised collagen hydrogel scaffolds can be beneficial for the survival of the grafted cells, further studies are required to assess their potential in ameliorating the host immune response and ultimately enhancing the survival of the dopaminergic neurons.
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