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Extracellular Vesicles from Mesenchymal Stem Cells Reverse Neuroinflammation and Restore Motor Coordination in
Paula Izquierdo-Altarejos1, Mar Martínez-García1, Iván Atienza-Pérez1
1Laboratory of Neurobiology, Príncipe Felipe Research Centre, Valencia, 46012, Spain.
Abstract:
Cirrhotic patients may show minimal hepatic encephalopathy (MHE), with mild cognitive impairment and motor deficits. Hyperammonemia and inflammation are the main contributors to the cognitive and motor alterations of MHE. Hyperammonemic rats reproduce these alterations. There are no specific treatments for the neurological alterations of MHE. Extracellular vesicles from mesenchymal stem cells (MSC-EVs) are promising to treat inflammatory and immune diseases. We aimed to assess whether treatment of hyperammonemic rats with MSC-EVs reduced neuroinflammation in cerebellum and restored motor coordination and to study the mechanisms involved. The effects of MSC-EVs were studied in vivo by intravenous injection to hyperammonemic rats and ex vivo in cerebellar slices. Motor coordination was analyzed using the beam walking test. Effects on neuroinflammation were assessed by immunohistochemistry, immunofluorescence and Western blot. Injection of MSC-EVs reduced microglia and astrocytes activation in cerebellum and restored motor coordination in hyperammonemic rats. Ex vivo experiments show that MSC-EVs normalize pro-inflammatory factors, including TNFα, NF-kB activation and the activation of two key pathways leading to motor incoordination (TNFR1-NF-kB-glutaminase-GAT3 and TNFR1-CCL2-BDNF-TrkB-KCC2). TGFβ in the EVs was necessary for these beneficial effects. MSC-EVs treatment reverse neuroinflammation in the cerebellum of hyperammonemic rats and the underlying mechanisms leading to motor incoordination. Therapy with MSC-EVs may be useful to improve motor function in patients with MHE.
Insights
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show promise for treating minimal hepatic encephalopathy (MHE). MSC-EVs reduced neuroinflammation and improved motor coordination in hyperammonemic rats, suggesting potential therapeutic benefits for MHE patients.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Minimal hepatic encephalopathy (MHE) involves cognitive and motor deficits linked to hyperammonemia and neuroinflammation.
- Current treatments for MHE's neurological effects are lacking.
- Extracellular vesicles from mesenchymal stem cells (MSC-EVs) are explored for treating inflammatory and immune conditions.
Purpose of the Study:
- To evaluate if MSC-EV treatment reduces cerebellar neuroinflammation and restores motor coordination in hyperammonemic rats.
- To elucidate the underlying mechanisms of MSC-EVs' therapeutic effects.
Main Methods:
- In vivo studies involved intravenous injection of MSC-EVs into hyperammonemic rats.
- Ex vivo experiments utilized cerebellar slices to analyze molecular pathways.
- Motor coordination was assessed using the beam walking test; neuroinflammation was evaluated via immunohistochemistry, immunofluorescence, and Western blot.
Main Results:
- MSC-EV treatment significantly reduced microglia and astrocyte activation in the cerebellum of hyperammonemic rats.
- Motor coordination was restored in rats treated with MSC-EVs.
- Ex vivo analysis revealed that MSC-EVs normalized pro-inflammatory factors and key pathways implicated in motor incoordination, with TGFβ being essential for these effects.
Conclusions:
- MSC-EV therapy effectively reverses neuroinflammation in the cerebellum of hyperammonemic rats.
- The study identified specific molecular mechanisms through which MSC-EVs improve motor function.
- MSC-EVs represent a potential therapeutic strategy for enhancing motor function in MHE patients.
