Encapsulation of young donor age dopaminergic grafts in a GDNF‐loaded collagen hydrogel further increases their survival, reinnervation, and functional efficacy after intrastriatal transplantation in hemi‐Parkinsonian rats

Abstract

Biomaterials have been shown to significantly improve the outcome of cellular reparative approaches for Parkinson's disease in experimental studies because of their ability to provide transplanted cells with a supportive microenvironment and shielding from the host immune system. However, given that the margin for improvement in such reparative therapies is considerable, further studies are required to fully investigate and harness the potential of biomaterials in this context. Given that several recent studies have demonstrated improved brain repair in Parkinsonian models when using dopaminergic grafts derived from younger foetal donors, we hypothesized that encapsulating these cells in a supportive biomaterial would further improve their reparative efficacy. Thus, this study aimed to determine the impact of a GDNF-loaded collagen hydrogel on the survival, reinnervation, and functional efficacy of dopaminergic neurons derived from young donors. To do so, hemi-Parkinsonian (6-hydroxydopamine-lesioned) rats received intrastriatal transplants of embryonic day 12 cells extracted from the rat ventral mesencephalon either alone, in a collagen hydrogel, with GDNF, or in a GDNF-loaded collagen hydrogel. Methamphetamine-induced rotational behaviour was assessed at three weekly intervals for a total of 12 weeks, after which rats were sacrificed for postmortem assessment of graft survival. We found that, following intrastriatal transplantation to the lesioned striatum, the GDNF-loaded collagen hydrogel significantly increased the survival (4-fold), reinnervation (5.4-fold), and functional efficacy of the embryonic day 12 dopaminergic neurons. In conclusion, this study further demonstrates the significant potential of biomaterial hydrogel scaffolds for cellular brain repair approaches in neurodegenerative diseases such as Parkinson's disease.

Harnessing stem cells and biomaterials to promote neural repair

“…A further challenge for the field has been graft integration, with numerous studies observing that human PSC‐derived dopamine transplants show notably poorer striatal innervation than their human VM fetal counterparts, with a recent direct comparative study reporting a fourfold reduction within the target dorsolateral striatum (Grealish et al ., ). While a variety of trophic cues, namely, glial cell line‐derived neurotrophic factor (GDNF), have been demonstrated to improve the survival and plasticity of fetal tissue grafts, their potential for PSC‐derived grafts are only just beginning to be realized (Moriarty et al , ). Moving forwards, in addition to the identification of trophic cues capable of supporting survival and plasticity of human PSC‐derived grafts, will be the need for safe and efficient delivery approaches that are both spatially and temporally relevant to the duration of graft integration.…”

“…Numerous groups have fabricated a variety of hydrogel-based biomaterials targeted at modelling the native 3D neural environment, repeatedly demonstrating that neural progenitors/neurons cultured on these scaffolds adopt more in vivo-like morphologies, differentiate and survive longer than those cultured on conventionally coated culture-ware. Many of these biocompatible scaffolds have also been shown to enhance survival and integration of transplanted neural progenitors (Rodriguez et al, 2012;Moriarty et al, 2018a).…”

Primary tissue for cellular brain repair in Parkinson's disease: Promise, problems and the potential of biomaterials

“…Hence, the delivery of cells in a biomaterial matrix to which they can adhere may provide them with the necessary support needed both during and after transplantation. Indeed, studies have shown that the attachment of neural cells to biomaterials scaffolds (particularly compressive biosynthetic materials) prior to transplantation can provide cells with an adherent surface throughout the transplantation process, therefore reducing the detrimental effects of anoikis on cell survival (Béduer et al., ; Jgamadze et al., ; Moriarty, Cabre, Alamilla, Pandit, & Dowd, ; Moriarty & Dowd, ; Moriarty, Pandit, & Dowd, ; Newland et al., ).…”

“…Finally, Moriarty et al. (, ) demonstrated that encapsulating VM grafts in a GDNF‐loaded collagen hydrogel resulted in a dramatic increase in the survival of dopaminergic neurons and that this correlated with enhanced striatal reinnervation and restoration of motor function in hemiparkinsonian rats.…”

“…() and Moriarty et al. (, ) have recently demonstrated the efficacy of PEG cross‐linked collagen hydrogels for brain repair in Parkinson's disease. Thus, given the clinically biocompatible, immunoprotective and supportive properties of collagen hydrogels, they hold immense potential to improve the survival and efficacy of dopaminergic cell replacement therapies in Parkinson's disease.…”