Extracellular vesicles from mesenchymal stem cells reduce neuroinflammation in hippocampus and restore cognitive function in hyperammonemic rats.
Por:
Izquierdo-Altarejos P, Cabrera-Pastor A, Martínez-García M, Sánchez-Huertas C, Hernández A, Moreno-Manzano V and Felipo V
Publicada:
2 ene 2023
Resumen:
Chronic hyperammonemia, a main contributor to hepatic encephalopathy (HE), leads to neuroinflammation which alters neurotransmission leading to cognitive impairment. There are no specific treatments for the neurological alterations in HE. Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) reduce neuroinflammation in some pathological conditions. The aims were to assess if treatment of hyperammonemic rats with EVs from MSCs restores cognitive function and analyze the underlying mechanisms. EVs injected in vivo reach the hippocampus and restore performance of hyperammonemic rats in object location, object recognition, short-term memory in the Y-maze and reference memory in the radial maze. Hyperammonemic rats show reduced TGFß levels and membrane expression of TGFß receptors in hippocampus. This leads to microglia activation and reduced Smad7-IkB pathway, which induces NF-?B nuclear translocation in neurons, increasing IL-1ß which alters AMPA and NMDA receptors membrane expression, leading to cognitive impairment. These effects are reversed by TGFß in the EVs from MSCs, which activates TGFß receptors, reducing microglia activation and NF-?B nuclear translocation in neurons by normalizing the Smad7-IkB pathway. This normalizes IL-1ß, AMPA and NMDA receptors membrane expression and, therefore, cognitive function. EVs from MSCs may be useful to improve cognitive function in patients with hyperammonemia and minimal HE.
Filiaciones:
:
Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Eduardo Primo-Yufera 3, 46012, Valencia, Spain
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Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Eduardo Primo-Yufera 3, 46012, Valencia, Spain
Fundación Investigación Hospital Clínico, Instituto de Investigación Sanitaria, INCLIVA, Valencia, Spain
Martínez-García M:
Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Eduardo Primo-Yufera 3, 46012, Valencia, Spain
Sánchez-Huertas C:
Neuronal and Tissue Regeneration Laboratory, Centro Investigación Príncipe Felipe, Valencia, Spain
Laboratory of Bilateral Neural Circuits, Instituto de Neurociencias (CSIC-UMH), Alicante, Spain
:
Optical and Confocal Microscopy Service, Centro Investigación Príncipe Felipe, Valencia, Spain
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Neuronal and Tissue Regeneration Laboratory, Centro Investigación Príncipe Felipe, Valencia, Spain
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Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Eduardo Primo-Yufera 3, 46012, Valencia, Spain.
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