title: The potential of neurotrophin-loaded biomaterials to enhance stem cell-derived brain repair for Parkinson's disease
Creators: name: Comini, Giulia
Publisher: name: University of Galway
Year: 2024
Subjects: subject: stem cell-derived brain repair
subject: Parkinson's disease
subject: Medicine
subject: Pharmacology and Therapeutics
subject: neurotrophin-loaded biomaterials

description: Extensive preclinical and clinical research have demonstrated the potential of cell-derived brain repair for Parkinson’s disease showing that cells can survive, integrate and reinnervate the Parkinsonian brain ultimately providing functional recovery to patients. Although the historical source of dopaminergic neurons for cell replacement therapies had been foetal-derived cells, the ethical concerns related to their supply and various logistical issues have encouraged the field of brain repair to switch towards the transplantation of stem cell-derived dopaminergic progenitors. A multitude of preclinical trials have shown that these cells can survive, differentiate in situ and provide amelioration of motor deficits in animal models leading to the initiation of four clinical trials with the aim to test safety, tolerability and efficacy of both embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC)-derived grafts for patients. However, the preclinical literature suggests poor in vivo survival and maturation of these progenitors undermining the realisation of the full potential of stem cell replacement therapies. In this context, injectable biomaterials have the potential to address these challenges. Specifically, neurotrophin (NTF)-loaded biomaterials could provide the transplanted cells with long-term NTF delivery overcoming the issue of trophic withdrawal post-grafting. Moreover, injectable in situ gelling collagen hydrogels could provide supportive benefits by acting as a matrix for cell adherence, by creating a physical barrier against the host’s neuroimmune cells and by providing the transplanted cells with a NTF-rich microenvironment to aid their survival after transplantation and consequent in situ dopaminergic differentiation. Thus, the overall aim of this project was to assess the potential of NTF-enriched biomaterials for enhancing in situ survival and maturation of human iPSC-derived dopaminergic progenitors in Parkinsonian rats, particularly in immunosuppressed (rather than immunodeficient) rats. Specifically, we firstly conducted a systematic review of the preclinical literature to assess the extent of survival and dopaminergic differentiation of human ESC and iPSC-derived dopaminergic progenitors (DAPs) in the brain of Parkinsonian models. We found that cell survival was very variable (between 0% and 500%) but relatively high, with a median of 51%. However, although also very variable (between 0% and 46%), dopaminergic maturation was poor with a median of 3% of the transplanted cells. Therefore, in an effort to improve survival and differentiation outcomes of cells in preclinical models, we firstly tested two systems - biomaterial microcarriers and engineered mesenchymal stem cells - for the delivery of glial cell line-derived neurotrophic factor (GDNF) in a sustained manner. However, these showed either to not being biocompatible or to not be suitable for co-transplantation with iPSC-DAPs. In parallel, a recently conducted study in our group showed the ability of a GDNF and brain-derived neurotrophic factor (BDNF) functionalised collagen hydrogel to dramatically enhance survival and differentiation of iPSC-DAPs in the brains of athymic nude rats (T-cell deficient) but not in the brains of cyclosporine suppressed rats (T-cell suppressed). Therefore, the focus of this research switched to the hydrogel. Particularly, we firstly studied the immunological profiles of athymic nude rats and cyclosporine suppressed rats after transplantation of iPSC-DAPs either alone, with NTFs, in a hydrogel or in a NTF-enriched hydrogel. We found that cyclosporine suppressed rats were not fully immunosuppressed at the time of transplantation as residual T-cell populations were found infiltrating the brains in the peri-transplant area and circulating in the bloodstream. Next, we used an alternative immunosuppression regime to assess the potential of a NTF-enriched collagen hydrogel for enhancing in situ survival and maturation of iPSC-derived dopaminergic progenitors in immunosuppressed Parkinsonian rats. Although the beneficial effect of this hydrogel was not as pronounced as seen in immunodeficient rats, in immunosuppressed hosts it still showed a beneficial effect on the corridor test performance, and in terms of consistency of survival and differentiation of the cells which generated significantly denser grafts compared to when transplanted alone. In conclusion, a NTF-enriched collagen hydrogel has the potential to improve the efficacy of stem cell replacement therapies in Parkinson’s disease by providing dopaminergic progenitors with a supportive microenvironment throughout delivery and during the first week post-transplantation. However, further studies are required to allow the NTF-enriched collagen hydrogel to realise its full potential in immunosuppressed hosts, rather than immunodeficient, and further functionalisation is required in order to achieve sustained neurotrophic factors delivery in the brain.