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

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.