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

Publisher: Springer Science + Business Media Country of Publication: United States NLM ID: 101256586 Publication Model: Electronic Cited Medium: Internet ISSN: 1557-1904 (Electronic) Linking ISSN: 15571890 NLM ISO Abbreviation: J Neuroimmune Pharmacol Subsets: MEDLINE

Original Publication: New York, NY : Springer Science + Business Media, c2006-

Extracellular Vesicles*/transplantation ; Extracellular Vesicles*/metabolism ; Hyperammonemia*/therapy ; Hyperammonemia*/metabolism ; Mesenchymal Stem Cells*/metabolism ; Rats, Wistar*; Animals ; Rats ; Male ; Neuroinflammatory Diseases/therapy ; Cerebellum/metabolism ; Hepatic Encephalopathy/therapy ; Hepatic Encephalopathy/metabolism

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.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Arenas YM, Balzano T, Ivaylova G, Llansola M, Felipo V (2022) The S1PR2-CCL2-BDNF-TrkB pathway mediates neuroinflammation and motor incoordination in hyperammonaemia. Neuropathol Appl Neurobiol 48(4):e12799. https://doi.org/10.1111/nan.12799. (PMID: 10.1111/nan.1279935152448)
Bajaj JS, Barrett AC, Bortey E, Paterson C, Forbes WP (2015) Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis. Aliment Pharmacol Ther 41(1):39–45. https://doi.org/10.1111/apt.12993. (PMID: 10.1111/apt.1299325339518)
Balzano T, Arenas YM, Dadsetan S et al (2020) Sustained hyperammonemia induces TNF-a IN Purkinje neurons by activating the TNFR1-NF-κB pathway. J Neuroinflammation 17(1):70. https://doi.org/10.1186/s12974-020-01746-z. (PMID: 10.1186/s12974-020-01746-z320877237035786)
Bass NM, Mullen KD, Sanyal A et al (2010) Rifaximin treatment in hepatic encephalopathy. N Engl J Med 362(12):1071–1081. https://doi.org/10.1056/NEJMoa0907893. (PMID: 10.1056/NEJMoa090789320335583)
Batrakova EV, Kim MS (2015) Using exosomes, naturally-equipped nanocarriers, for drug delivery. J Control Release 219:396–405. https://doi.org/10.1016/j.jconrel.2015.07.030. (PMID: 10.1016/j.jconrel.2015.07.030262417504656109)
Bogdan C, Paik J, Vodovotz Y, Nathan C (1992) Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J Biol Chem 267(32):23301–23308. (PMID: 10.1016/S0021-9258(18)50091-01429677)
Cabrera-Pastor A, Balzano T, Hernández-Rabaza V, Malaguarnera M, Llansola M, Felipo V (2018) Increasing extracellular cGMP in cerebellum in vivo reduces neuroinflammation, GABAergic tone and motor in-coordination in hyperammonemic rats. Brain Behav Immun 69:386–398. https://doi.org/10.1016/j.bbi.2017.12.013. (PMID: 10.1016/j.bbi.2017.12.01329288802)
Cabrera-Pastor A, Llansola M, Montoliu C et al (2019) Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: underlying mechanisms and therapeutic implications. Acta Physiol (Oxf) 226(2):e13270. https://doi.org/10.1111/apha.13270. (PMID: 10.1111/apha.1327030830722)
Castro B, Martinez-Redondo D, Gartzia I, Alonso-Varona A, Garrido P, Palomares T (2019) Cryopreserved H2O2 -preconditioned human adipose-derived stem cells exhibit fast post-thaw recovery and enhanced bioactivity against oxidative stress. J Tissue Eng Regen Med 2019(132):328–341. https://doi.org/10.1002/term.2797. (PMID: 10.1002/term.2797)
Cauli O, Mansouri MT, Agusti A, Felipo V (2009) Hyperammonemia increases GABAergic tone in the cerebellum but decreases it in the rat cortex. Gastroenterology 136(4):1359–1367 e1-2. https://doi.org/10.1053/j.gastro.2008.12.057. (PMID: 10.1053/j.gastro.2008.12.05719245864)
Chandok N, Watt KD (2010) Pain management in the cirrhotic patient: the clinical challenge. Mayo Clin Proc 85(5):451–458. https://doi.org/10.4065/mcp.2009.0534. (PMID: 10.4065/mcp.2009.0534203572772861975)
Cheng X, Jiang M, Long L, Meng J (2021) Potential roles of mesenchymal stem cells and their exosomes in the treatment of COVID-19. Front Biosci (Landmark Ed) 26(10):948–961. https://doi.org/10.52586/4999. (PMID: 10.52586/499934719217)
Cossetti C, Iraci N, Mercer TR et al (2014) Extracellular vesicles from neural stem cells transfer IFN-γ via Ifngr1 to activate Stat1 signaling in target cells. Mol Cell 56(2):193–204. https://doi.org/10.1016/j.molcel.2014.08.020. (PMID: 10.1016/j.molcel.2014.08.020252421464578249)
Elia CA, Losurdo M, Malosio ML, Coco S (2019) Extracellular vesicles from mesenchymal stem cells exert Pleiotropic effects on Amyloid-β, inflammation, and regeneration: a spark of Hope for Alzheimer’s disease from tiny structures? BioEssays 41(4):e1800199. https://doi.org/10.1002/bies.201800199. (PMID: 10.1002/bies.20180019930919493)
Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101(4):890–898. https://doi.org/10.1172/JCI1112. (PMID: 10.1172/JCI11129466984508637)
Felipo V (2013) Hepatic encephalopathy: effects of liver failure on brain function. Nat Rev Neurosci 14(12):851–858. https://doi.org/10.1038/nrn3587. (PMID: 10.1038/nrn358724149188)
Felipo V, Miñana MD, Grisolía S (1988) Long term ingestion of ammonium increases acetylglutamate and urea levels without affecting the amount of carbamyl phosphate synthase. Eur J Biochem 176(3):567–571. https://doi.org/10.1111/j.1432-1033.1988.tb14315.x. (PMID: 10.1111/j.1432-1033.1988.tb14315.x3169014)
Felipo V, Urios A, Montesinos E et al (2012) Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. Metab Brain Dis 27:51–58. https://doi.org/10.1007/s11011-011-9269-3. (PMID: 10.1007/s11011-011-9269-322072427)
Gluud LL, Vilstrup H, Morgan MY (2016) Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 6(5):CD003044. https://doi.org/10.1002/14651858. (PMID: 10.1002/14651858)
Gonzalez-Usano A, Cauli O, Agusti A, Felipo V (2014) Pregnenolone sulfate restores the glutamate-nitric-oxide-cGMP pathway and extracellular GABA in cerebellum and learning and motor coordination in hyperammonemic rats. ACS Chem Neurosci 5(2):100–105. https://doi.org/10.1021/cn400168y. (PMID: 10.1021/cn400168y24256194)
Häussinger D, Dhiman RK, Felipo V et al (2022) Hepatic encephalopathy. Nat Rev Dis Primers 8(1):43. https://doi.org/10.1038/s41572-022-00366-6. (PMID: 10.1038/s41572-022-00366-635739133)
Islam A, Choudhury ME, Kigami Y et al (2018) Sustained anti-inflammatory effects of TGF-β1 on microglia/macrophages. Biochim Biophys Acta Mol Basis Dis 1864(3):721–734. https://doi.org/10.1016/j.bbadis.2017.12.022. (PMID: 10.1016/j.bbadis.2017.12.02229269050)
Izquierdo-Altarejos P, Cabrera-Pastor A, Martínez-García M, Sánchez-Huertas C, Hernández A, Moreno-Manzano V, Felipo V (2023) Extracellular vesicles from mesenchymal stem cells reduce neuroinflammation in hippocampus and restore cognitive function in hyperammonemic rats. J Neuroinflamm 20(1):1. https://doi.org/10.1186/s12974-022-02688-4. (PMID: 10.1186/s12974-022-02688-4)
Izquierdo-Altarejos P, Cabrera-Pastor A, Gonzalez-King H, Montoliu C, Felipo V Extracellular vesicles from Hyperammonemic rats induce Neuroinflammation and Motor Incoordination in Control rats. Cells 2020, 9(3), 572. https://doi.org/10.3390/cells9030572.
Jafarinia M, Alsahebfosoul F, Salehi H, Eskandari N, Azimzadeh M, Mahmoodi M, Asgary S, Ganjalikhani Hakemi M (2020) Therapeutic effects of extracellular vesicles from human adipose-derived mesenchymal stem cells on chronic experimental autoimmune encephalomyelitis. J Cell Physiol 235(11):8779–8790. https://doi.org/10.1002/jcp.29721. (PMID: 10.1002/jcp.2972132329062)
Jiang M, Wang H, Jin M, Yang X, Ji H, Jiang Y, Zhang H, Wu F, Wu G, Lai X, Cai L, Hu R, Xu L, Li L (2018) Exosomes from MiR-30d-5p-ADSCs reverse Acute Ischemic Stroke-Induced, autophagy-mediated Brain Injury by promoting M2 Microglial/Macrophage polarization. Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology. 47(2):864–878. https://doi.org/10.1159/000490078.
Kirkham AM, Monaghan M, Bailey AJM et al (2021) Mesenchymal stromal cells as a therapeutic intervention for COVID-19: a living systematic review and meta-analysis protocol. Syst Rev 10(1):249. https://doi.org/10.1186/s13643-021-01803-5. (PMID: 10.1186/s13643-021-01803-5345261238441251)
Lai P, Weng J, Guo L, Chen X, Du X (2019) Novel insights into MSC-EVs therapy for immune diseases. Biomark Res 7:6. https://doi.org/10.1186/s40364-019-0156-0. (PMID: 10.1186/s40364-019-0156-0309236176423844)
Lee M, Liu T, Im W, Kim M (2016) Exosomes from adipose-derived stem cells ameliorate phenotype of Huntington’s disease in vitro model. Eur J Neurosci 44(4):2114–2119. https://doi.org/10.1111/ejn.13275. (PMID: 10.1111/ejn.1327527177616)
Long Q, Upadhya D, Hattiangady B et al (2017) Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus. Proc Natl Acad Sci U S A 114(17):E3536–E3545. https://doi.org/10.1073/pnas.1703920114. (PMID: 10.1073/pnas.1703920114283964355410779)
Ma X, Huang M, Zheng M, Dai C, Song Q, Zhang Q, Li Q, Gu X, Chen H, Jiang G (2020) ADSCs-derived extracellular vesicles alleviate neuronal damage, promote neurogenesis and rescue memory loss in mice with Alzheimer’s disease. J Control Release 327:688–702. https://doi.org/10.1016/j.jconrel.2020.09.019. (PMID: 10.1016/j.jconrel.2020.09.01932931898)
Malaguarnera M, Balzano T, Castro MC, Llansola M, Felipo V (2021) The dual role of the GABAA receptor in Peripheral inflammation and neuroinflammation: a study in hyperammonemic rats. Int J Mol Sci 22(13):6772. https://doi.org/10.3390/ijms22136772. (PMID: 10.3390/ijms22136772342025168268725)
McMillin M, Grant S, Frampton G, Petrescu AD, Williams E, Jefferson B, Thomas A, Brahmaroutu A, DeMorrow S Elevated circulating TGFβ1 during acute liver failure activates TGFβR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice, 2019. J Neuroinflamm, 16(1), 69. https://doi.org/10.1186/s12974-019-1455-y.
Mincheva G, Gimenez-Garzo C, Izquierdo-Altarejos P et al (2022 Jul) Golexanolone, a GABAA receptor modulating steroid antagonist, restores motor coordination and cognitive function in hyperammonemic rats by dual effects on peripheral inflammation and neuroinflammation. CNS Neurosci Ther 26. https://doi.org/10.1111/cns.13926 Epub ahead of print.
Noh MY, Lim SM, Oh KW et al (2016) Mesenchymal stem cells modulate the Functional properties of Microglia via TGF-β secretion. Stem Cells Transl Med 5(11):1538–1549. https://doi.org/10.5966/sctm.2015-0217. (PMID: 10.5966/sctm.2015-0217274007955070497)
Otero-Ortega L, Gómez de Frutos MC, Laso-García F et al (2018) Exosomes promote restoration after an experimental animal model of intracerebral hemorrhage. J Cereb Blood Flow Metab 38(5):767–779. https://doi.org/10.1177/0271678X17708917. (PMID: 10.1177/0271678X1770891728524762)
Perez-Hernandez J, Redon J, Cortes R (2017) Extracellular vesicles as therapeutic agents in systemic Lupus Erythematosus. Int J Mol Sci 18(4):717. https://doi.org/10.3390/ijms18040717. (PMID: 10.3390/ijms18040717283503235412303)
Phinney DG, Di Giuseppe M, Njah J et al (2015) Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun 6:8472. https://doi.org/10.1038/ncomms9472. (PMID: 10.1038/ncomms947226442449)
Rodrigo R, Cauli O, Gomez-Pinedo U et al (2010) Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology 139(2):675–684. https://doi.org/10.1053/j.gastro.2010.03.040. (PMID: 10.1053/j.gastro.2010.03.04020303348)
Rubinson DA, Dillon CP, Kwiatkowski AV et al (2003) A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat Genet 33(3):401–406. https://doi.org/10.1038/ng1117. (PMID: 10.1038/ng111712590264)
Ryu KY, Cho GS, Piao HZ, Kim WK (2012) Role of TGF-β in Survival of Phagocytizing Microglia: Autocrine suppression of TNF-α production and oxidative stress. Exp Neurobiol 21(4):151–157. https://doi.org/10.5607/en.2012.21.4.151. (PMID: 10.5607/en.2012.21.4.151233198753538179)
Salem HK, Thiemermann C (2010) Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 28(3):585–596. https://doi.org/10.1002/stem.269 PMID: 19967788; PMCID: PMC2962904. (PMID: 10.1002/stem.26919967788)
Salvi V, Sozio F, Sozzani S, Del Prete A (2017) Role of atypical chemokine receptors in Microglial activation and polarization. Front Aging Neurosci 9:148. https://doi.org/10.3389/fnagi.2017.00148. (PMID: 10.3389/fnagi.2017.00148286034935445112)
Shawcross DL, Wright G, Olde Damink SW et al (2007) Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis 22:125–138. https://doi.org/10.1007/s11011-006-9042-1. (PMID: 10.1007/s11011-006-9042-117260161)
Teixeira FG, Carvalho MM, Panchalingam KM et al (2017) Impact of the secretome of human mesenchymal stem cells on Brain structure and animal behavior in a rat model of Parkinson’s Disease. Stem Cells Transl Med 6(2):634–646. https://doi.org/10.5966/sctm.2016-0071. (PMID: 10.5966/sctm.2016-007128191785)
Tsuda M, Inoue K (2016) Neuron-microglia interaction by purinergic signaling in neuropathic pain following neurodegeneration. Neuropharmacology 104:76–81. https://doi.org/10.1016/j.neuropharm.2015.08.042. (PMID: 10.1016/j.neuropharm.2015.08.04226327676)
Vilaça-Faria H, Salgado AJ, Teixeira FG (2019) Mesenchymal stem cells-derived exosomes: a new possible therapeutic strategy for Parkinson’s Disease? Cells 8(2):118. https://doi.org/10.3390/cells8020118. (PMID: 10.3390/cells8020118307174296406999)
Wang Y, Han B, Wang Y et al (2020) Mesenchymal stem cell-secreted extracellular vesicles carrying TGF-β1 up-regulate miR-132 and promote mouse M2 macrophage polarization. J Cell Mol Med 24(21):12750–12764. https://doi.org/10.1111/jcmm.15860. (PMID: 10.1111/jcmm.15860329657727686990)
Weiss JM, Cuff CA, Berman JW (1999) TGF-beta downmodulates cytokine-induced monocyte chemoattractant protein (MCP)-1 expression in human endothelial cells. A putative role for TGF-beta in the modulation of TNF receptor expression. Endothelium 6(4):291–302. https://doi.org/10.3109/10623329909078496. (PMID: 10.3109/1062332990907849610475092)
Wen D, Peng Y, Liu D, Weizmann Y, Mahato RI (2016) Mesenchymal stem cell and derived exosome as small RNA carrier and immunomodulator to improve islet transplantation. J Control Release 238:166–175. https://doi.org/10.1016/j.jconrel.2016.07.044. (PMID: 10.1016/j.jconrel.2016.07.04427475298)
Werner F, Jain MK, Feinberg MW et al (2000) Transforming growth factor-beta 1 inhibition of macrophage activation is mediated via Smad3. J Biol Chem 275(47):36653–36658. https://doi.org/10.1074/jbc.M004536200. (PMID: 10.1074/jbc.M00453620010973958)
Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M (2013) Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab 33(11):1711–1715. https://doi.org/10.1038/jcbfm.2013.152. (PMID: 10.1038/jcbfm.2013.152239633713824189)
Zappia E, Casazza S, Pedemonte E et al (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106(5):1755–1761. https://doi.org/10.1182/blood-2005-04-1496. (PMID: 10.1182/blood-2005-04-149615905186)
Zhang Y, Chopp M, Zhang ZG et al (2017) Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury. Neurochem Int 111:69–81. https://doi.org/10.1016/j.neuint.2016.08.003. (PMID: 10.1016/j.neuint.2016.08.00327539657)
Zhou X, Zöller T, Krieglstein K, Spittau B (2015) TGFβ1 inhibits IFNγ-mediated microglia activation and protects mDA neurons from IFNγ-driven neurotoxicity. J Neurochem 134(1):125–134. https://doi.org/10.1111/jnc.13111. (PMID: 10.1111/jnc.1311125827682)
Zhu Y, Wang Y, Zhao B et al (2017) Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis. Stem Cell Res Ther 8(1):64. https://doi.org/10.1186/s13287-017-0510-9. (PMID: 10.1186/s13287-017-0510-9282791885345222)

FPU17/01698 Ministerio de Ciencia, Innovación y Universidades; FPU17/01698 Ministerio de Ciencia, Innovación y Universidades; PID2020-113388RB-I00-AEI/10.13039/501100011033 Ministerio de Ciencia e Innovación; PID2020-113388RB-I00-AEI/10.13039/501100011033 Ministerio de Ciencia e Innovación; PROMETEOII/2018/051 and CIPROM 2021/082 Conselleria de Educación de la Generalitat Valenciana; OP ERDF of Comunitat Valenciana 2014-2020 Generalitat Valenciana

Keywords: Extracellular vesicles; GABAergic neurotransmission; Hepatic encephalopathy; Mesenchymal stem cells; Motor coordination; Neuroinflammation

Date Created: 20241009 Date Completed: 20241009 Latest Revision: 20241009

20241009

10.1007/s11481-024-10153-7

39382610