Extracellular vesicles from mesenchymal stem cells improve neuroinflammation and neurotransmission in hippocampus and cognitive impairment in rats with mild liver damage and minimal hepatic encephalopathy
Abstract Background Patients with steatotic liver disease may show mild cognitive impairment. Rats with mild liver damage reproduce this cognitive impairment, which is mediated by neuroinflammation that alters glutamate neurotransmission in the hippocampus. Treatment with extracellular vesicles (EV)...
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BMC
2024-12-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-024-04076-6 |
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| author | Gergana Mincheva Victoria Moreno-Manzano Vicente Felipo Marta Llansola |
| author_facet | Gergana Mincheva Victoria Moreno-Manzano Vicente Felipo Marta Llansola |
| author_sort | Gergana Mincheva |
| collection | DOAJ |
| description | Abstract Background Patients with steatotic liver disease may show mild cognitive impairment. Rats with mild liver damage reproduce this cognitive impairment, which is mediated by neuroinflammation that alters glutamate neurotransmission in the hippocampus. Treatment with extracellular vesicles (EV) from mesenchymal stem cells (MSC) reduces neuroinflammation and improves cognitive impairment in different animal models of neurological diseases. TGFβ in these EVs seems to be involved in its beneficial effects. The aim of this work was to assess if MSCs-EVs may improve cognitive impairment in rats with mild liver damage and to analyze the underlying mechanisms, assessing the effects on hippocampal neuroinflammation and neurotransmission. We also aimed to analyze the role of TGFβ in the in vivo effects of MSCs-EVs. Methods Male Wistar rats with CCl4-induced mild liver damage were treated with EVs from unmodified MSC or with EVs derived from TGFβ—silenced MSCs and its effects on cognitive function and on neuroinflammation and altered neurotransmission in the hippocampus were analysed. Results Unmodified MSC-EVs reversed microglia activation and TNFα content, restoring membrane expression of NR2 subunit of NMDA receptor and improved object location memory. In contrast, EVs derived from TGFβ—silenced MSCs did not induce these effects but reversed astrocyte activation, IL-1β content and altered GluA2 AMPA receptor subunit membrane expression leading to improvement of learning and working memory in the radial maze. Conclusions EVs from MSCs with TGFβ silenced induce different effects on behavior, neuroinflammation and neurotransmitter receptors alterations than unmodified MSC-EVs, indicating that the modification of TGFβ in the MSC-EVs has a notable effect on the consequences of the treatment. This work shows that treatment with MSC-EVs improves learning and memory in a model of mild liver damage and MHE in rats, suggesting that MSC-EVs may be a good therapeutic option to reverse cognitive impairment in patients with steatotic liver disease. |
| format | Article |
| id | doaj-art-2f76bca80eca4568aefbd4bf05f20ca9 |
| institution | Kabale University |
| issn | 1757-6512 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj-art-2f76bca80eca4568aefbd4bf05f20ca92024-12-22T12:18:43ZengBMCStem Cell Research & Therapy1757-65122024-12-0115112010.1186/s13287-024-04076-6Extracellular vesicles from mesenchymal stem cells improve neuroinflammation and neurotransmission in hippocampus and cognitive impairment in rats with mild liver damage and minimal hepatic encephalopathyGergana Mincheva0Victoria Moreno-Manzano1Vicente Felipo2Marta Llansola3Laboratory of Neurobiology, Centro de Investigación Príncipe FelipeNeuronal and Tissue Regeneration Laboratory, Centro Investigación Príncipe FelipeLaboratory of Neurobiology, Centro de Investigación Príncipe FelipeLaboratory of Neurobiology, Centro de Investigación Príncipe FelipeAbstract Background Patients with steatotic liver disease may show mild cognitive impairment. Rats with mild liver damage reproduce this cognitive impairment, which is mediated by neuroinflammation that alters glutamate neurotransmission in the hippocampus. Treatment with extracellular vesicles (EV) from mesenchymal stem cells (MSC) reduces neuroinflammation and improves cognitive impairment in different animal models of neurological diseases. TGFβ in these EVs seems to be involved in its beneficial effects. The aim of this work was to assess if MSCs-EVs may improve cognitive impairment in rats with mild liver damage and to analyze the underlying mechanisms, assessing the effects on hippocampal neuroinflammation and neurotransmission. We also aimed to analyze the role of TGFβ in the in vivo effects of MSCs-EVs. Methods Male Wistar rats with CCl4-induced mild liver damage were treated with EVs from unmodified MSC or with EVs derived from TGFβ—silenced MSCs and its effects on cognitive function and on neuroinflammation and altered neurotransmission in the hippocampus were analysed. Results Unmodified MSC-EVs reversed microglia activation and TNFα content, restoring membrane expression of NR2 subunit of NMDA receptor and improved object location memory. In contrast, EVs derived from TGFβ—silenced MSCs did not induce these effects but reversed astrocyte activation, IL-1β content and altered GluA2 AMPA receptor subunit membrane expression leading to improvement of learning and working memory in the radial maze. Conclusions EVs from MSCs with TGFβ silenced induce different effects on behavior, neuroinflammation and neurotransmitter receptors alterations than unmodified MSC-EVs, indicating that the modification of TGFβ in the MSC-EVs has a notable effect on the consequences of the treatment. This work shows that treatment with MSC-EVs improves learning and memory in a model of mild liver damage and MHE in rats, suggesting that MSC-EVs may be a good therapeutic option to reverse cognitive impairment in patients with steatotic liver disease.https://doi.org/10.1186/s13287-024-04076-6Mild liver damageExtracellular vesiclesTGFβCognitive impairmentGlial activationGABA and glutamate receptors |
| spellingShingle | Gergana Mincheva Victoria Moreno-Manzano Vicente Felipo Marta Llansola Extracellular vesicles from mesenchymal stem cells improve neuroinflammation and neurotransmission in hippocampus and cognitive impairment in rats with mild liver damage and minimal hepatic encephalopathy Stem Cell Research & Therapy Mild liver damage Extracellular vesicles TGFβ Cognitive impairment Glial activation GABA and glutamate receptors |
| title | Extracellular vesicles from mesenchymal stem cells improve neuroinflammation and neurotransmission in hippocampus and cognitive impairment in rats with mild liver damage and minimal hepatic encephalopathy |
| title_full | Extracellular vesicles from mesenchymal stem cells improve neuroinflammation and neurotransmission in hippocampus and cognitive impairment in rats with mild liver damage and minimal hepatic encephalopathy |
| title_fullStr | Extracellular vesicles from mesenchymal stem cells improve neuroinflammation and neurotransmission in hippocampus and cognitive impairment in rats with mild liver damage and minimal hepatic encephalopathy |
| title_full_unstemmed | Extracellular vesicles from mesenchymal stem cells improve neuroinflammation and neurotransmission in hippocampus and cognitive impairment in rats with mild liver damage and minimal hepatic encephalopathy |
| title_short | Extracellular vesicles from mesenchymal stem cells improve neuroinflammation and neurotransmission in hippocampus and cognitive impairment in rats with mild liver damage and minimal hepatic encephalopathy |
| title_sort | extracellular vesicles from mesenchymal stem cells improve neuroinflammation and neurotransmission in hippocampus and cognitive impairment in rats with mild liver damage and minimal hepatic encephalopathy |
| topic | Mild liver damage Extracellular vesicles TGFβ Cognitive impairment Glial activation GABA and glutamate receptors |
| url | https://doi.org/10.1186/s13287-024-04076-6 |
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