Extracellular vesicles from mesenchymal stem cells reduce neuroinflammation in hippocampus and restore cognitive function in hyperammonemic rats

Abstract

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 TGFβ levels and membrane expression of TGFβ receptors in hippocampus. This leads to microglia activation and reduced Smad7–IkB pathway, which induces NF-κB nuclear translocation in neurons, increasing IL-1β which alters AMPA and NMDA receptors membrane expression, leading to cognitive impairment. These effects are reversed by TGFβ in the EVs from MSCs, which activates TGFβ receptors, reducing microglia activation and NF-κB nuclear translocation in neurons by normalizing the Smad7–IkB pathway. This normalizes IL-1β, 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.

Mesenchymal stem cell‐derived extracellular vesicles: Recent therapeutics and targeted drug delivery advances

“…As reported in various studies, bMSC‐EVs have recently been shown to improve cardiac function, promote neo‐angiogenesis both in vitro and in vivo, improve cardiac indices, reduce infarct size, and regulate homeostasis in various rodent models of myocardial infarction (MI) (Kore et al., 2021, Sun et al., 2020, Yao et al., 2021, Zheng et al., 2022). Additionally, MSC‐EVs have been reported to regulate neuroinflammation, neurogenesis (Izquierdo‐Altarejos et al., 2023), repair ischemic stroke (Davis et al., 2021), and improve neurological function in various animal models of traumatic brain injury (TBI) (Amini et al., 2023), Parkinson's disease (PD), and Alzheimer's disease (AD) (Reed & Escayg, 2021). MSC‐EVs can deliver long noncoding RNA (lncRNA) KLF3‐AS1, which promotes SIRT1 deubiquitination, reduces cerebral infarction, and improves neurological function in a mouse model (Xie et al., 2023).…”

Mesenchymal Stem Cells and Purinergic Signaling in Autism Spectrum Disorder: Bridging the Gap between Cell-Based Strategies and Neuro-Immune Modulation

“…This theory is further encouraged by P2X7 antagonists that inhibit the P2X7-NLRP3-IL-1β pathway [ 168 ]. The extracellular vesicles of MSCs, as described above, are already known to reduce neuroinflammation—one of the key factors implicated in the etiology of mood disorders [ 169 ].…”

The effect of rifaximin and lactulose treatments to chronic hepatic encephalopathy rats: An [18F]PBR146 in‐vivo neuroinflammation imaging study

“…These findings were partially consistent with previous studies (Kong et al., 2016, 2021; Luo et al., 2018). Basal ganglia had been proved to be related with brain function and structure in HE (Zhang et al., 2013), and hippocampus was related with cognitive functions including learning and memory (Izquierdo‐Altarejos et al., 2023). Both RIF and LAC proved effective for improving motor ability and reducing neuroinflammation in BDL rats.…”