Neural Stem Cell Grafts Promote Astroglia-Driven Neurorestoration in the Aged Parkinsonian Brain via Wnt/β-Catenin Signaling

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. Stem Cells 2018;36:1179-1197.

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…Astrocyte dysfunctions with age and neurodegeneration are well recognized processes leading to a marked downregulation of astrocyte's supportive, neuroprotective and pro‐neurogenic properties (Barkho et al, ; Jiao & Chen, ; L'Episcopo, Tirolo, Peruzzotti‐Jametti, et al, ; L'Episcopo, Tirolo, Serapide, et al, ; Marchetti & Abbracchio, ; Marchetti et al, ; Sousa‐Victor et al, ; Yang et al, ). Within the SVZ niche, astrocyte dysfunction as a consequence of age and exposure to the PD neurotoxin was shown to inhibit both proliferation and neuroblast formation, as observed both in vivo and in vitro.…”

“…Evidence is available that quiescent neuroprogenitors reside in the tegmental aqueduct periventricular region (Aq‐PVRs), which is close to the SNpc and harbors clonogenic NSCs endowed with DAergic potential (Hermann et al, , ; Hermann & Storch, ; L'Episcopo et al, ). Additionally, adult Aq‐PVR NSCs can be activated and induced to differentiate into DAergic neurons, both in vitro and after PD injury in vivo (Hermann et al, , ; Hermann & Stork, ; L'Episcopo et al, , ; L'Episcopo, Tirolo, Peruzzotti‐Jametti, et al, ; Xie et al, ).…”

“…The question therefore arises as to whether it is possible to counteract these age‐dependent and region‐specific restrictive mechanisms inhibiting DAergic plasticity, in order to re‐activate the endogenous neurorepair and regeneration programs in the aged PD brain. In the last decade, we have explored the functional role of adult neurogenesis in PD by addressing the molecular and cellular NSC regulatory mechanisms underlying the age‐dependent decline of neurogenic potential in a 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine/1‐methyl‐4‐phenylpyridinium (MPTP/MPP + )‐induced rodent model of basal ganglia injury, investigating the potential to stimulate adult neurogenesis as a means to support neuroprotective and neurorestorative therapies (L'Episcopo, Serapide, et al, ; L'Episcopo et al, , , , ; L'Episcopo, Tirolo, Serapide, et al, ; Marchetti, ; Marchetti et al, ; Marchetti & Pluchino, ). Particularly, we concentrated on the key pathway regulating DAergic neurogenesis, from neurodevelopment through aging and neurodegeneration: the wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin (WβC) signalling cascade (Brodski, Blaess, Partanen, & Prakash, ; Inestrosa & Arenas, ; Maiese, ; Maiese, Faqi, Chong, & Shang, ; Marchetti, ; Nusse & Clevers, ; Nusse & Varmus, ; Palomer et al, ; Salinas, ; Tapia‐Rojas & Inestrosa, ; Toledo et al, ; Wurst & Prakash, ).…”

“…The critical role of astrocyte‐derived Wnt1 and WβC‐signalling was further shown in the Aq‐PVR DAergic niche, where WβC controls the fate specification of adult DAergic precursors (L'Episcopo et al, , ). Conversely, aging‐dependent oxidative stress and inflammatory pathways correlate with a downregulation of WβC ‐ signalling in NSC niches and a dramatic up‐regulation of endogenous Wnt‐antagonists, with implications for SVZ neurogenesis, Aq‐PVR‐NSC activation, and DAergic self‐repair ability (L'Episcopo et al, , , ; L'Episcopo, Tirolo, Serapide, et al, ; Marchetti et al, ). In 2013, these findings inspired the perspective, “ Wnt your brain be inflamed?…”

“…The mechanisms underlying these phenomena constitute a synergy between (a) the upregulation of proinflammatory glial pathways, (b) the decline of anti‐oxidant self‐defence mechanisms, such as the nuclear factor erythroid‐2‐related factor 2 (Nrf2) ‐heme oxygenase 1 (Hmox1) axis, a key mediator of cellular adaptive response, and (c) the decline of astrocyte‐derived Wnts leading to NSC neurogenic impairment, with a consequent failure to recover from a PD insult. As a result, both pharmacological and cellular therapies involving the up‐regulation of WβC‐signalling and immunomodulation were reported to ameliorate the aged microenvironment, thereby promoting endogenous neurogenesis, ultimately boosting a full neurorestoration program in the aged PD brain (L'Episcopo et al, , , ; L'Episcopo et al, ; L'Episcopo, Tirolo, Serapide, et al, ; Marchetti, ; Marchetti et al, ; Marchetti & Pluchino, ). While little is known on WβC ‐ signalling in the PD‐injured hippocampus, it seems plausible that a comparable dysfunction of the WβC ‐ pathway may well be at play in the SGZ of the DG, with potential consequences for hippocampal neurogenesis in PD and its involvement in non‐motor symptoms of PD.…”