Journal
STEM CELLS
Volume 36, Issue 8, Pages 1179-1197Publisher
WILEY
DOI: 10.1002/stem.2827
Keywords
Astrocyte-neuron crosstalk; Parkinson's disease; Wnt/beta-catenin signaling; Neural stem cells transplantation; Neuroinflammation; Brain plasticity
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Funding
- Italian Ministry of Health [RCL13-RC014, RCL115, RCL16-17, GR-08-7]
- Italian Ministry of Research and University (MIUR)
- OASI (IRCCS) Institution Troina (EN) Italy
- BIOMETEC Department (University of Catania, Medical School, Catania, Italy)
- Italian Multiple Sclerosis Association (AISM) [2010//R/31, 2014/PMS/4]
- United States Department of Defense (DoD) Congressionally Directed Medical Research Programs (DMRP) [MS140019]
- European Research Council (ERC) [260511-SEM-SEM]
- Evelyn Trust [RG 69865]
- Wellcome Trust [RG79423]
- MRC
- Wellcome Trust Research Training Fellowship [RG79423]
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During agingone 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/beta-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/beta-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.
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