Correction of hostile brain environment by co-grafting astrocytes improves cell therapeutic outcomes

Abstract

Transplantation of neural progenitor cells (NPCs) is a potential future therapy to treat neurodegenerative disorders, but has faced many challenges with limited success reported so far. A major reason is inhospitable host brain environments, which interfere with enriched neuron engraftment and function. Astrocytes are regarded as a cell type that can modify hostile brain environments based on their neurotrophic roles in the developing and adult brain. In this study, we examined if astrocytic function could be utilized to overcome the current concerns of cell-based therapies in an animal model of Parkinson’s disease (PD), which is characterized by dopamine (DA) neuron degeneration in the midbrain. We show here that co-grafting astrocytes, especially those derived from the midbrain, remarkably enhanced NPC-based cell therapeutic outcomes along with robust DA neuron engraftment in a PD animal model for at least 6 months post-transplantation. We further show that engineering of donor astrocytes with Nurr1 and Foxa2, the transcription factors recently reported to polarize harmful immunogenic glia into the neurotrophic form, further promoted the neurotrophic actions of grafted astrocytes in the cell therapeutic approach. These findings collectively suggest that co-grafting astrocytes could be a future strategy for successful cell therapeutic outcomes in neurodegenerative disorders