title: Functionalized composite scaffolds improve the engraftment of transplanted dopaminergic progenitors in a mouse model of Parkinson's disease.
abstract: With the brain's limited capacity for repair there is a need for new and innovative therapies to promote regeneration. Stem/progenitor cell transplantation has received increasing attention, and whilst clinical trials demonstrating functional integration exist, inherent variability between patients has hindered development of this therapy. Variable outcomes have largely been attributed to poor survival and insufficient reinnervation of target tissues due in part to the suboptimal host environment. Here we examined whether improving the physical properties of the host milieu, by way of bioengineered scaffolds, may enhance engraftment. We developed a composite scaffold, incorporating electrospun poly(l-lactic acid) short nanofibers embedded within a thermo-responsive xyloglucan hydrogel, which could be easily injected into the injured brain. Furthermore, to improve the trophic properties of the host brain, glial derived neurotrophic factor (GDNF), a protein known to promote cell survival and axonal growth, was blended into and/or covalently attached onto the composite scaffolds to provide controlled delivery. In vitro we confirmed the ability of the scaffolds to support ventral midbrain (VM) dopamine progenitors, and provide sustained delivery of GDNF - capable of eliciting effects on cell survival and dopaminergic axon growth. In Parkinsonian mice, we show that these composite scaffolds, whilst having no deleterious impact on the host immune response, enhanced the survival of VM grafts and reinnervation of the striatum, an effect that was augmented through the scaffold delivery of GDNF. Taken together, these functionalized composite scaffolds provide a means to significantly improve the milieu of the injured brain, enabling enhanced survival and integration of grafted neurons.
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Ting-Yi
authors.initials: TY
authors.lastname: Wang
authors.affiliation: Research School of Engineering, The Australian National University, Canberra, 2601, Australia.
authors.forename: Kiara F
authors.initials: KF
authors.lastname: Bruggeman
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Kauhausen
authors.affiliation: Research School of Engineering, The Australian National University, Canberra, 2601, Australia.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Rodriguez
authors.affiliation: Research School of Engineering, The Australian National University, Canberra, 2601, Australia. Electronic address: david.nisbet@anu.edu.au.
authors.forename: David R
authors.initials: DR
authors.lastname: Nisbet
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3010, Australia. Electronic address: cparish@unimelb.edu.au.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Parish
mesh_terms: D000818:Animals; D002470:Cell Survival; D017690:Cell Transplantation; D004195:Disease Models, Animal; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage; D051379:Mice; D008855:Microscopy, Electron, Scanning; D058953:Neural Stem Cells / Q000166:cytology*; D010300:Parkinson Disease / Q000473:pathology / Q000628:therapy*; D056951:Photoelectron Spectroscopy; D054457:Tissue Scaffolds
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor
keywords: Dopamine; Electrospinning; GDNF; Glial derived neurotropic factor; Hydrogel; Neural transplantation; PLLA; Parkinson's disease; Xyloglucan