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.

OBJECTIVE: Although human induced pluripotent stem cell (iPSC)-derived cell replacement for Parkinson's disease has considerable reparative potential, its full therapeutic benefit is limited by poor graft survival and dopaminergic maturation. Injectable biomaterial scaffolds, such as collagen hydrogels, have the potential to address these issues via a plethora of supportive benefits including acting as a structural scaffold for cell adherence, shielding from the host immune response and providing a reservoir of neurotrophic factors to aid survival and differentiation. Thus, the aim of this study was to determine if a neurotrophin-enriched collagen hydrogel could improve the survival and maturation of iPSC-derived dopaminergic progenitors (iPSC-DAPs) after transplantation into the rat Parkinsonian brain.

APPROACH: Human iPSC-DAPs were transplanted into the 6-hydroxydpamine-lesioned striatum either alone, with the neurotrophins GDNF & BDNF, in an unloaded collagen hydrogel, or in a neurotrophin-loaded collagen hydrogel. Post-mortem, human nuclear immunostaining was used to identify surviving iPSC-DAPs while tyrosine hydroxylase immunostaining was used to identify iPSC-DAPs that had differentiated into mature dopaminergic neurons.

MAIN RESULTS: We found that iPSC-DAPs transplanted in the neurotrophin-enriched collagen hydrogel survived and matured significantly better than cells implanted without the biomaterial (8-fold improvement in survival and 16-fold improvement in dopaminergic differentiation). This study shows that transplantation of human iPSC-DAPs in a neurotrophin-enriched collagen hydrogel improves graft survival and maturation in the Parkinsonian rat brain.

SIGNIFICANCE: The data strongly supports further investigation of supportive hydrogels for improving the outcome of iPSC-derived brain repair in Parkinson's disease.