The potential of injectable collagen hydrogels to enhance dopaminergic cell replacement therapies for Parkinson's disease

Abstract

Extensive pre-clinical and clinical assessment has shown that, when transplanted into the Parkinsonian brain, primary dopaminergic neurons can survive, integrate with the host system, produce dopamine and provide functional recovery. However, their widespread use as a routine clinical procedure is hindered by their extremely poor survival after transplantation and the subsequent requirement to use multiple fetal donors for each Parkinson’s disease patient. Injectable biomaterial scaffolds, particularly collagen hydrogels, have the potential to improve the engraftment of encapsulated cells through the provision of a supportive and growth factor-rich environment that can shield cells from the external environment. Thus, the overarching aim of this project was to assess the effect of a glial-derived neurotrophic factor (GDNF)-loaded collagen hydrogel on the long-term survival and efficacy of dopaminergic neurons after transplantation into the Parkinsonian brain. Through a series of preliminary in vitro and in vivo studies, we first optimised a collagen hydrogel for the intra-cranial delivery of dopaminergic neurons. Following this, we assessed whether the encapsulation of primary dopaminergic neurons (derived from the developing ventral mesencephalon (VM)) in a GDNF-loaded collagen hydrogel could enhance their survival, re-innervative capacity and function after transplantation. Based on these results, we investigated the potential of the GDNF-loaded collagen hydrogel to enhance the survival and efficacy of human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons. In brief, we found that crosslinked collagen hydrogels were well tolerated in the brain and supported the survival and neural outgrowth of encapsulated cells. Moreover, we demonstrated that the encapsulation of primary dopaminergic neurons within a collagen hydrogel attenuated the host immune response to the transplanted cells, and that the encapsulation of GDNF in our collagen hydrogel resulted in a significantly greater retention of striatal GDNF immediately post-transplantation. Together, these preliminary findings demonstrated that crosslinked collagen hydrogels possessed attractive characteristics that warranted further investigation into their ability to enhance long-term dopaminergic cell transplantation strategies. Building on this, we found that the encapsulation of embryonic day (E) 14 VM cells in a GDNF-loaded collagen hydrogel could dramatically improve the survival (5-fold), re-innervation (3-fold) and functionality of primary dopaminergic neurons after transplantation into the Parkinsonian brain. Furthermore, the encapsulation of VM cells derived from younger embryonic donors (including their meningeal layer), namely E12, also resulted in a dramatic improvement in the survival (4-fold), re-innervation (5-fold) and functionality of dopaminergic neurons after transplantation. However, unfortunately the assessment of iPSC-derived dopaminergic cell survival and efficacy was impeded by widespread graft rejection that was seen across all groups. In conclusion, GDNF-loaded collagen hydrogels can improve the efficacy of primary dopaminergic neuron cell replacement therapies in Parkinson’s disease by providing cells with a supportive environment throughout delivery, increased trophic factor support upon transplantation and the attenuation of the host immune response. While these collagen hydrogel scaffolds show great potential to enhance such neurorestorative approaches in Parkinson’s disease, further studies are required to assess their potential to enhance stem cell based cell replacement therapies.