Extracellular Vesicles from Mesenchymal Stem Cells Reverse Neuroinflammation and Restore Motor Coordination in Hyperammonemic Rats.

Autores de CIPF

• 

  Paula Izquierdo Altarejos

  Autor

• Maria Mar Martínez García

  Autor

• Iván Atienza Pérez

  Autor

• Alberto Hernandez Cano

  Autor

• 

  M Victoria Moreno Manzano

  Autor

• 

  Marta Llansola Gil

  Autor

• 

  Vicente Felipo Orts

  Autor

Grupos de Investigación

• Laboratorio de Neurobiología

  

  Jefe/a de Grupo

  Vicente Felipo Orts

• Laboratorio de Regeneración Tisular y Neuronal

  

  Jefe/a de Grupo

  M Victoria Moreno Manzano

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 TNFa, 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). TGFß 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.

Keywords

• Extracellular vesicles, GABAergic neurotransmission, Hepatic encephalopathy, Mesenchymal stem cells, Motor coordination, Neuroinflammation