Tissue Programmed Hydrogels Functionalized with GDNF Improve Human Neural Grafts in Parkinson's Disease

Abstract

The survival and synaptic integration of transplanted dopaminergic (DA) progenitors are essential for ameliorating motor symptoms in Parkinson's disease (PD). Human pluripotent stem cell (hPSC)‐derived DA progenitors are, however, exposed to numerous stressors prior to, and during, implantation that result in poor survival. Additionally, hPSC‐derived grafts show inferior plasticity compared to fetal tissue grafts. These observations suggest that a more conducive host environment may improve graft outcomes. Here, tissue‐specific support to DA progenitor grafts is provided with a fully characterized self‐assembling peptide hydrogel. This biomimetic hydrogel matrix is programmed to support DA progenitors by i) including a laminin epitope within the matrix; and ii) shear encapsulating glial cell line‐derived neurotrophic factor (GDNF) to ensure its sustained delivery. The biocompatible hydrogel biased a 51% increase in A9 neuron specification—a subpopulation of DA neurons critical for motor function. The sustained delivery of GDNF induced a 2.7‐fold increase in DA neurons and enhanced graft plasticity, resulting in significant improvements in motor deficits at 6 months. These findings highlight the therapeutic benefit of stepwise customization of tissue‐specific hydrogels to improve the physical and trophic support of human PSC‐derived neural transplants, resulting in improved standardization, predictability and functional efficacy of grafts for PD.

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

“…While biomaterials have been trialled and developed in other neural injuries-often to fill tissue voids and bridge gaps within fibre bundles, they have been less commonly employed to support grafts where the host tissue architecture remains intact. We were the first to demonstrate a benefit for utilising a (xyloglucan) hydrogel to support VM fetal tissue grafts [24], also demonstrated by others using a collagen-based hydrogels [49]. In both instances the biomaterials provided only modest effects, likely underpinned by the hydrogel composition and mode of synthesis, with the greatest benefit on graft outcome observed in their capacity to sustain the delivery of GDNF.…”

“…While the host inflammatory response to both implanted VM progenitors and hydrogels has previously been examined by us [24,36,37,39], SDF1 has been shown to act as both pro-and anti-inflammatory molecule, during injury and regeneration [40]. We therefore examined the local host inflammatory response to all grafted conditions.…”

“…All supernatant samples were stored at −80 • C until the time of analysis. The SDF1 levels were quantified by enzyme linked immunosorbent assay (ELISA), using previously described methods [23,24]. Release profiles were performed in triplicate wells for each time point and repeated on 3 independent experiments.…”

“…In an effort to sustain SDF1 expression during periods of graft implantation and integration, and to circumvent complications associated with sustained protein infusion or viral transduction, here we incorporated the functional protein into a bioengineered hydrogel-an approach previously adopted by us to control protein delivery over defined temporal periods ranging from days, to weeks and even months [23][24][25][26][27].…”

Perspective Insights to Bio-Nanomaterials for the Treatment of Neurological Disorders

“…This approach resulted in 51% increase in A9 neuron cells (a subpopulation of dopaminergic neurons) that overall improved motor deficits in study models. The hydrogel matrix further enabled standardization and predictability that is essential to further customize the study designs ( Hunt et al, 2021 ).…”