Extracellular Matrix Biomimetic Hydrogels, Encapsulated with Stromal Cell-Derived Factor 1, Improve the Composition of Foetal Tissue Grafts in a Rodent Model of Parkinson’s Disease

Abstract

Clinical studies have provided evidence for dopamine (DA) cell replacement therapy in Parkinson’s Disease. However, grafts derived from foetal tissue or pluripotent stem cells (PSCs) remain heterogeneous, with a high proportion of non-dopaminergic cells, and display subthreshold reinnervation of target tissues, thereby highlighting the need to identify new strategies to improve graft outcomes. In recent work, Stromal Cell-Derived Factor-1 (SDF1), secreted from meninges, has been shown to exert many roles during ventral midbrain DA development and DA-directed differentiation of PSCs. Related, co-implantation of meningeal cells has been shown to improve neural graft outcomes, however, no direct evidence for the role of SDF1 in neural grafting has been shown. Due to the rapid degradation of SDF1 protein, here, we utilised a hydrogel to entrap the protein and sustain its delivery at the transplant site to assess the impact on DA progenitor differentiation, survival and plasticity. Hydrogels were fabricated from self-assembling peptides (SAP), presenting an epitope for laminin, the brain’s main extracellular matrix protein, thereby providing cell adhesive support for the grafts and additional laminin–integrin signalling to influence cell fate. We show that SDF1 functionalised SAP hydrogels resulted in larger grafts, containing more DA neurons, increased A9 DA specification (the subpopulation of DA neurons responsible for motor function) and enhanced innervation. These findings demonstrate the capacity for functionalised, tissue-specific hydrogels to improve the composition of grafts targeted for neural repair.

Survival and maturation of human induced pluripotent stem cell-derived dopaminergic progenitors in the parkinsonian rat brain is enhanced by transplantation in a neurotrophin-enriched hydrogel

“…We, and others, have demonstrated the positive beneficial effects of biomaterial-mediated neurotrophic support on transplanted primary foetal cells in parkinsonian models [9,10,[33][34][35][36], but importantly there is a deficit of data on effects on stemcell derived DAPs. Various approaches have been used including poly(lactic-co-glycolic acid) microcarriers releasing GDNF which improved the therapeutic efficacy of foetal dopaminergic transplants in parkinsonian rats [34].…”

“…Other groups, including ourselves, have used hydrogels, with Wang et al [35] demonstrating the ability of a GDNF-functionalised composite poly(l-lactic acid)/xyloglucan hydrogel to enhance survival of, and striatal reinnervation from, transplanted foetal grafts in parkinsonian mice. Hydrogels made from self-assembling peptides functionalised with GDNF [36] or stomal cell factor-1 [33] have also been shown to improve the outcome of brain repair induced by primary foetal dopaminergic grafts. In our own work, we demonstrated that the reparative capacity of transplanted foetal grafts in the rat parkinsonian brain was significantly enhanced when the cells were transplanted in the same neurotrophin-loaded collagen hydrogel used in the present study [9,10].…”

Self-Assembled Peptide Habitats to Model Tumor Metastasis

“…Previously, flow-induced hydrodynamic shear stress has also increased EMT in 2D and 3D lung-cancer models, thus, future investigations may wish to incorporate a more effective model of measuring the 3D migration of the cells, such as a modified transwell system, its development into a bioprinted system [ 60 ] or a microfluidic platform to further access cell mobility and drug effectiveness within an artificial TME [ 61 ] The precise nature of the migrating cells and the EMT such as features of the system can be further explored via the modular approach we have detailed here. For example, other proteins [ 62 , 63 ] and biopolymers [ 64 ] can be coassembled to the system, or a population of healthy cells can be cultured in 3D before the addition of a spheroid. The lung tumour model detailed within this study could be used to further explore effective treatment of lung cancer via more tumour-like conditions, drug delivery and a model of cell mobility.…”

Past, present, and future of cell replacement therapy for parkinson’s disease: a novel emphasis on host immune responses

“…4 ). 168 – 170 Additionally, considering that needle trauma may occur in CRT for other CNS and non-CNS diseases, it is of significant interest to test whether T REG cell co-transplantation can similarly reduce needle trauma-induced inflammation and enhance the survival of desired therapeutic cell products in general. 171 …”