Neural Stem Cell Grafts Promote Astroglia-Driven Neurorestoration in the Aged Parkinsonian Brain via Wnt/β-Catenin Signaling.
Francesca L'EpiscopoCataldo TiroloLuca Peruzzotti-JamettiMaria F SerapideNunzio TestaSalvatore CanigliaBeatrice BalzarottiStefano PluchinoBianca MarchettiPublished in: Stem cells (Dayton, Ohio) (2018)
During aging-one the most potent risk factors for Parkinson's disease (PD)-both astrocytes and microglia undergo functional changes that ultimately hamper homoeostasis, defense, and repair of substantia nigra pars compacta (SNpc) midbrain dopaminergic (mDA) neurons. We tested the possibility of rejuvenating the host microenvironment and boosting SNpc DA neuronal plasticity via the unilateral transplantation of syngeneic neural stem/progenitor cells (NSCs) in the SNpc of aged mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced experimental PD. Transplanted NSCs within the aged SNpc engrafted and migrated in large proportions to the tegmental aqueduct mDA niche, with 30% acquiring an astroglial phenotype. Both graft-derived exogenous (ex-Astro) and endogenous astrocytes (en-Astro) expressed Wnt1. Both ex-Astro and en-Astro were key triggers of Wnt/β-catenin signaling in SNpc-mDA neurons and microglia, which was associated with mDA neurorescue and immunomodulation. At the aqueduct-ventral tegmental area level, NSC grafts recapitulated a genetic Wnt1-dependent mDA developmental program, inciting the acquisition of a mature Nurr1+ TH+ neuronal phenotype. Wnt/β-catenin signaling antagonism abolished mDA neurorestoration and immune modulatory effects of NSC grafts. Our work implicates an unprecedented therapeutic potential for somatic NSC grafts in the restoration of mDA neuronal function in the aged Parkinsonian brain. Stem Cells 2018;36:1179-1197.
Keyphrases
- stem cells
- breast cancer cells
- cell cycle arrest
- cell proliferation
- spinal cord
- cerebral ischemia
- cell therapy
- inflammatory response
- type diabetes
- white matter
- genome wide
- neuropathic pain
- gene expression
- copy number
- spinal cord injury
- signaling pathway
- blood brain barrier
- mesenchymal stem cells
- diabetic rats
- brain injury
- dna methylation
- drug induced
- skeletal muscle
- deep brain stimulation