Mesenchymal stem cells and their conditioned medium as potential therapeutic strategies in managing comorbid anxiety in rat sepsis induced by cecal ligation and puncture

Document Type : Original Article

Authors

1 Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

3 Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

4 Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

5 Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

6 MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

7 Department of Immunology, School of Medicine, Iranshahr University of Medical Sciences, Iranshahr, Iran

Abstract

Objective(s): Sepsis-associated encephalopathy (SAE) is a common brain dysfunction following sepsis. Due to the beneficial effects of mesenchymal stem cells (MSCs) therapy on anxiety, an extreme and early manifestation of SAE, we hypothesized that MSCs-derived conditioned medium (CM) may be able to attenuate anxiety in cecal ligation and puncture (CLP)-induced sepsis.
Materials and Methods: Rats were assigned into 4 groups: sham, CLP, MSC, and CM. All animals, except in the sham group, underwent the CLP procedure to induce sepsis. Two hours after sepsis induction, the rats in MSC and CM groups, received 1×106 MSCs and CM derived from the same number of cells, respectively. 48 hr after the treatments, anxiety-related behaviors were assessed, and brain and right hippocampal tissues were collected.
Results: MSCs and CM enhanced the percentages of open arm entries and time spent in the open arms of the elevated plus-maze and the time spent in the light side of the light-dark box. MSCs and CM decreased the Evans blue content and decreased the IL-6 and TNF-α levels in the brain tissue samples. Reductions in the expression of 5-HT2A receptors and phosphorylation of ERK1/2 and an increase in the expression of 5-HT1A receptors in the hippocampal tissue samples were observed in the MSC and CM groups.
Conclusion: MSCs and MSCs-derived CM attenuated anxiety-related behaviors to an equal extent by reducing inflammation, modifying 5-HT receptor expression changes, and inhibiting the ERK pathway. Therefore, MSCs-derived CM may be considered a promising therapy for comorbid anxiety in septic patients.

Keywords

References

1. Angus DC, Van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013; 369:840-851.
2. Gofton TE, Young GB. Sepsis-associated encephalopathy. Nat Rev Neurol 2012; 8:557-566.
3. Chung H-Y, Wickel J, Brunkhorst FM, Geis C. Sepsis-associated encephalopathy: From delirium to dementia? J Clin Med 2020; 9:703.
4. Mazeraud A, Righy C, Bouchereau E, Benghanem S, Bozza FA, Sharshar T. Septic-associated encephalopathy: a comprehensive review. Neurotherapeutics 2020; 17:392-403.
5. Dantzer R. Cytokine-induced sickness behaviour: A neuroimmune response to activation of innate immunity. Eur J Pharmacol 2004; 500:399-411.
6. Heming N, Mazeraud A, Verdonk F, Bozza FA, Chretien F, Sharshar T. Neuroanatomy of sepsis-associated encephalopathy. Critical Care 2017; 21:65.
7. Danielski LG, Della Giustina A, Badawy M, Barichello T, Quevedo J, Dal-Pizzol F, et al. Brain barrier breakdown as a cause and consequence of neuroinflammation in sepsis. Mol Neurobiol 2018; 55:1045-1053.
8. Du Z, Ma L, Zhen L, Sun M, Dong X, An H. Research progress on the mechanism of 5-hydroxytryptamine in sepsis. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 20019; 31:662-664.
9. Heisler LK, Chu H-M, Brennan TJ, Danao JA, Bajwa P, Parsons LH, et al. Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci USA 1998; 95:15049-15054.
10. Ursano RJ, Zhang L, Li H, Johnson L, Carlton J, Fullerton CS, et al. PTSD and traumatic stress: from gene to community and bench to bedside. Brain Res 2009; 1293:2-12.
11. Xiang M, Jiang Y, Hu Z, Yang Y, Du X, Botchway BO, et al. Serotonin receptors 2A and 1A modulate anxiety-like behavior in post-traumatic stress disordered mice. Am J Transl Res 2019; 11:2288-2303.
12. Gugjoo MB, Sharma GT. Equine mesenchymal stem cells: properties, sources, characterization, and potential therapeutic applications. J Equine Vet Sci 2019; 72:16-27.
13. Viswanathan S, Shi Y, Galipeau J, Krampera M, Leblanc K, Martin I, et al. Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy (ISCT®) Mesenchymal Stromal Cell committee position statement on nomenclature. Cytotherapy 2019; 21:1019-1024.
14. Wang L, Yang M, Zhang Y, Yuan R, Kang H. Application of mesenchymal stem cells in sepsis. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2019; 31:505-508.
15. Zhang Y, Deng Z, Li Y, Yuan R, Yang M, Zhao Y, et al. Mesenchymal stem cells provide neuroprotection by regulating heat stroke-induced brain inflammation. Front Neurol 2020; 11:372.
16. Chae H-K, Song W-J, Ahn J-O, Li Q, Lee B-Y, Kweon K, et al. Immunomodulatory effects of soluble factors secreted by feline adipose tissue-derived mesenchymal stem cells. Vet Immunol Immunopathol 2017; 191:22-29.
17. Silva AY, Amorim EA, Barbosa-Silva MC, Lima MN, Oliveira HA, Granja MG, et al. Mesenchymal stromal cells protect the blood-brain barrier, reduce astrogliosis, and prevent cognitive and behavioral alterations in surviving septic mice. Crit Care Med 2020; 48:e290-e298.
18. Abdolmohammadi K, Mahmoudi T, Nojehdehi S, Tayebi L, Hashemi SM, Noorbakhsh F, et al. Effect of hypoxia preconditioned adipose-derived mesenchymal stem cell conditioned medium on cerulein-induced acute pancreatitis in mice. Adv Pharm Bull 2020; 10:297-306.
19. Pouya S, Heidari M, Baghaei K, Aghdaei HA, Moradi A, Namaki S, et al. Study the effects of mesenchymal stem cell conditioned medium injection in mouse model of acute colitis. Int Immunopharmacol 2018; 54:86-94.
20. Kianian F, Seifi B, Kadkhodaee M, Sajedizadeh A, Ahghari P. Protective effects of celecoxib on ischemia reperfusion–induced acute kidney injury: comparing between male and female rats. Iran J Basic Med Sci 2019; 22:43-48.
21. Lorian K, Kadkhodaee M, Kianian F, Abdi A, Seifi B. Administration of sodium hydrosulfide reduces remote organ injury by an anti-oxidant mechanism in a rat model of varicocele. Iran J Basic Med Sci 2020; 23:236-243.
22. Pourmirzaei F, Ranjbaran M, Kadkhodaee M, Kianian F, Lorian K, Abdi A, et al. Sperm and testicular dysfunction during cecal ligation and puncture-induced sepsis in male rats and effects of tannic acid through reducing testicular oxidative stress and inflammation. Iran J Basic Med Sci 2021; 24:1554-1560.
23. Akdemir FN, Tanyeli A. The antioxidant effect of fraxin against acute organ damage in polymicrobial sepsis model induced by cecal ligation and puncture. Turk J Med Sci 2019; 4:22-29.
24. Tanyeli A, Akdemir FN, Eraslan E, Guler MC, Sebin SO, Comakli S, et al. The possible useful effectiveness of sinapic acid sepsis-induced secondary organ damage in rats. Clin Exp Health Sci 2022; 12:134-140.
25. Kianian F, Sadeghipour HR, Karimian SM, Kadkhodaee M, Seifi B. Protective effects of hydrogen sulfide on anxiety in ovalbumin-induced chronic asthma. Physiology and Pharmacology 2019; 23:208-214.
26. Belayev L, Busto R, Ikeda M, Rubin LL, Kajiwara A, Morgan L, et al. Protection against blood–brain barrier disruption in focal cerebral ischemia by the type IV phosphodiesterase inhibitor BBB022: a quantitative study. Brain Res 1998; 787:277-285.
27. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72:248-254.
28. Seemann S, Zohles F, Lupp A. Comprehensive comparison of three different animal models for systemic inflammation. J Biomed Sci 2017; 24:60.
29. Jin P, Deng S, Tian M, Lenahan C, Wei P, Wang Y, et al. INT-777 prevents cognitive impairment through activating Takeda G protein-coupled receptor 5 (TGR5) by attenuating neuroinflammation via cAMP/PKA/CREB signaling axis in a rat model of sepsis. Exp Neurol 2021; 335:113504.
30. Zaghloul N, Addorisio ME, Silverman HA, Patel HL, Valdes-Ferrer SI, Ayasolla KR, et al. Forebrain cholinergic dysfunction and systemic and brain inflammation in murine sepsis survivors. Front Immunol 2017; 8:1673.
31. Gonzalez H, Elgueta D, Montoya A, Pacheco R. Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases. J Neuroimmunol 2014; 274:1-13.
32. Eyre H, Baune BT. Neuroplastic changes in depression: a role for the immune system. Psychoneuroendocrinology 2012; 37:1397-1416.
33. Calsavara AJ, Costa PA, Nobre V, Teixeira AL. Factors associated with short and long term cognitive changes in patients with sepsis. Sci Rep 2018; 8:4509.
34. Vogelzangs N, De Jonge P, Smit J, Bahn S, Penninx B. Cytokine production capacity in depression and anxiety. Transl Psychiatry 2016; 6:e825.
35. Skelly DT, Hennessy E, Dansereau M-A, Cunningham C. A systematic analysis of the peripheral and CNS effects of systemic LPS, IL-1β, TNF-α and IL-6 challenges in C57BL/6 mice. PLoS One 2013; 8:e69123.
36. Salazar A, Gonzalez-Rivera BL, Redus L, Parrott JM, OConnor JC. Indoleamine 2, 3-dioxygenase mediates anhedonia and anxiety-like behaviors caused by peripheral lipopolysaccharide immune challenge. Horm Behav 2012; 62:202-209.
37. Tian J, Tai Y, Shi M, Zhao C, Xu W, Ge X, et al. Atorvastatin relieves cognitive disorder after sepsis through reverting inflammatory cytokines, oxidative stress, and neuronal apoptosis in hippocampus. Cell Mol Neurobiol 2020; 40:521-530.
38. Bordukalo-Niksic T, Mokrovic G, Stefulj J, Zivin M, Jernej B, Cicin-Sain L. 5HT-1A receptors and anxiety-like behaviours: studies in rats with constitutionally upregulated/downregulated serotonin transporter. Behav Brain Res 2010; 213:238-245.
39. McKittrick CR, Blanchard DC, Blanchard RJ, McEwen BS, Sakai RR. Serotonin receptor binding in a colony model of chronic social stress. Biol Psychiatry 1995; 37:383-393.
40. Adamec R, Creamer K, Bartoszyk GD, Burton P. Prophylactic and therapeutic effects of acute systemic injections of EMD 281014, a selective serotonin 2A receptor antagonist on anxiety induced by predator stress in rats. Eur J Pharmacol 2004; 504:79-96.
41. Oufkir T, Vaillancourt C. Phosphorylation of JAK2 by serotonin 5-HT2A receptor activates both STAT3 and ERK1/2 pathways and increases growth of JEG-3 human placental choriocarcinoma cell. Placenta 2011; 32:1033-1040.
42. Kurrasch‐Orbaugh DM, Parrish JC, Watts VJ, Nichols DE. A complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation: the involvement of MAP kinases. J Neurochem 2003; 86:980-991.
43. Franklin JM, Carrasco GA. Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5‐HT2A) receptor activity via ERK1/2 signaling. Synapse 2013; 67:145-159.
44. Liu C, Zhang X, Zhou JX, Wei W, Liu DH, Ke P, et al. The protective action of ketanserin against lipopolysaccharide-induced shock in mice is mediated by inhibiting inducible NO synthase expression via the MEK/ERK pathway. Free Radic Biol Med 2013; 65:658-666.
45. Pati S, Gerber MH, Menge TD, Wataha KA, Zhao Y, Baumgartner JA, et al. Bone marrow derived mesenchymal stem cells inhibit inflammation and preserve vascular endothelial integrity in the lungs after hemorrhagic shock. PLoS One 2011; 6:e25171.
46. Ivanova-Todorova E, Bochev I, Mourdjeva M, Dimitrov R, Bukarev D, Kyurkchiev S, et al. Adipose tissue-derived mesenchymal stem cells are more potent suppressors of dendritic cells differentiation compared to bone marrow-derived mesenchymal stem cells. Immunol Lett 2009; 126:37-42.
47. Chang Cl, Leu S, Sung HC, Zhen YY, Cho CL, Chen A, et al. Impact of apoptotic adipose-derived mesenchymal stem cells on attenuating organ damage and reducing mortality in rat sepsis syndrome induced by cecal puncture and ligation. J Transl Med 2012; 10:244.
48. Akhondzadeh F, Kadkhodaee M, Seifi B, Ashabi G, Kianian F, Abdolmohammadi K, et al. Adipose-derived mesenchymal stem cells and conditioned medium attenuate the memory retrieval impairment during sepsis in rats. Mol Neurobiol 2020; 57:3633-3645.
49. Yousefi F, Ebtekar M, Soudi S, Soleimani M, Hashemi SM. In vivo immunomodulatory effects of adipose-derived mesenchymal stem cells conditioned medium in experimental autoimmune encephalomyelitis. Immunol Lett 2016; 172:94-105.
Iranian Journal of Basic Medical Sciences
Volume 25, Issue 6
June 2022
Pages 690-697

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