Neural Stem Cell Grafts Promote Astroglia-Driven Neurorestoration in the Aged Parkinsonian Brain via Wnt/β-Catenin Signaling. (16th April 2018) - L'Episcopo, Francesca
Abstract : 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. Abstract : Schematics of the " Wnt on " neurorestoration instructed by grafted neural stem/progenitor cells (NSCs) in the aged Parkinson's disease brain. With age, the inflammed midbrain microenvironment coupled to dysfunctional astrocyte-microglia interactions and environmental toxin exposure (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine [MPTP]) inhibit active Wnt-signaling in astrocytes ("Wnt-off" condition), resulting in exacerbation of inflammation and inhibition of Wnt-dependent neuroprotective and pro-regenerative capacities of astrocytes with harmful consequences for midbrain dopaminergic neuron survival and repair from MPTP injury. NSCs, NSC-derived astrocytes, and endogenous astrocytes switch the inflammatory/Wnt-genetic cascade via astrocyte-neuron and astrocyte-microglia crosstalk both at the substantia nigra pars compacta and aqueduct periventricular regions dopaminergic niche levels. Reciprocally, astrocyte-derived Wnt1 further influence both exogenous and endogenous NSCs, reduce microglia pro-inflammatory status, thus favoring beneficial effects for an overall tyrosine hydroxylase neurorescue ("Wnt on") program.