Intrathecal Injection of the Secretome from ALS Motor Neurons Regulated for miR-124 Expression Prevents Disease Outcomes in SOD1-G93A Mice.
Marta BarbosaMarta SantosNídia de SousaSara Duarte-SilvaAna Rita VazAntónio J SalgadoDora BritesPublished in: Biomedicines (2022)
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with short life expectancy and no effective therapy. We previously identified upregulated miR-124 in NSC-34-motor neurons (MNs) expressing human SOD1-G93A (mSOD1) and established its implication in mSOD1 MN degeneration and glial cell activation. When anti-miR-124-treated mSOD1 MN (preconditioned) secretome was incubated in spinal cord organotypic cultures from symptomatic mSOD1 mice, the dysregulated homeostatic balance was circumvented. To decipher the therapeutic potential of such preconditioned secretome, we intrathecally injected it in mSOD1 mice at the early stage of the disease (12-week-old). Preconditioned secretome prevented motor impairment and was effective in counteracting muscle atrophy, glial reactivity/dysfunction, and the neurodegeneration of the symptomatic mSOD1 mice. Deficits in corticospinal function and gait abnormalities were precluded, and the loss of gastrocnemius muscle fiber area was avoided. At the molecular level, the preconditioned secretome enhanced NeuN mRNA/protein expression levels and the PSD-95/TREM2/IL-10/arginase 1/MBP/PLP genes, thus avoiding the neuronal/glial cell dysregulation that characterizes ALS mice. It also prevented upregulated GFAP/Cx43/S100B/vimentin and inflammatory-associated miRNAs, specifically miR-146a/miR-155/miR-21, which are displayed by symptomatic animals. Collectively, our study highlights the intrathecal administration of the secretome from anti-miR-124-treated mSOD1 MNs as a therapeutic strategy for halting/delaying disease progression in an ALS mouse model.
Keyphrases
- amyotrophic lateral sclerosis
- cell proliferation
- long non coding rna
- long noncoding rna
- spinal cord
- early stage
- poor prognosis
- mouse model
- high fat diet induced
- single cell
- squamous cell carcinoma
- skeletal muscle
- type diabetes
- endothelial cells
- mesenchymal stem cells
- oxidative stress
- clinical trial
- adipose tissue
- gene expression
- nitric oxide
- wild type
- newly diagnosed
- bone marrow
- metabolic syndrome
- lymph node
- study protocol
- high frequency
- metal organic framework