Reduced expression of mitochondrial fumarate hydratase in progressive multiple sclerosis contributes to impaired in vitro mesenchymal stromal cell-mediated neuroprotection.
Mult Scler
; 28(8): 1179-1188, 2022 07.
Article
em En
| MEDLINE
| ID: mdl-34841955
ABSTRACT
BACKGROUND:
Cell-based therapies for multiple sclerosis (MS), including those employing autologous bone marrow-derived mesenchymal stromal cells (MSC) are being examined in clinical trials. However, recent studies have identified abnormalities in the MS bone marrow microenvironment.OBJECTIVE:
We aimed to compare the secretome of MSC isolated from control subjects (C-MSC) and people with MS (MS-MSC) and explore the functional relevance of findings.METHODS:
We employed high throughput proteomic analysis, enzyme-linked immunosorbent assays and immunoblotting, as well as in vitro assays of enzyme activity and neuroprotection.RESULTS:
We demonstrated that, in progressive MS, the MSC secretome has lower levels of mitochondrial fumarate hydratase (mFH). Exogenous mFH restores the in vitro neuroprotective potential of MS-MSC. Furthermore, MS-MSC expresses reduced levels of fumarate hydratase (FH) with downstream reduction in expression of master regulators of oxidative stress.CONCLUSIONS:
Our findings are further evidence of dysregulation of the bone marrow microenvironment in progressive MS with respect to anti-oxidative capacity and immunoregulatory potential. Given the clinical utility of the fumaric acid ester dimethyl fumarate in relapsing-remitting MS, our findings have potential implication for understanding MS pathophysiology and personalised therapeutic intervention.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Esclerose Múltipla Crônica Progressiva
/
Células-Tronco Mesenquimais
/
Neuroproteção
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Fumarato Hidratase
/
Mitocôndrias
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Mult Scler
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Reino Unido