Mesenchymal Stem Cells for the Treatment of Acetic Acid-Induced Ulcerative Colitis in Rats

Thoria Ahmed Omar; Eman Sweed; Dina Sweed; Rawhia Hassan  Eledel; Dalia Hosny Abou-Elela; Gehad Hikal

doi:10.3889/oamjms.2022.10686

Authors

Thoria Ahmed Omar Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt
Eman Sweed Department of Clinical Pharmacology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt https://orcid.org/0000-0003-3689-2648
Dina Sweed Department of Pathology, National Liver Institute, Menoufia University, Shebin Elkom, Menoufia, Egypt
Rawhia Hassan Eledel Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt
Dalia Hosny Abou-Elela Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt
Gehad Hikal Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt

DOI:

https://doi.org/10.3889/oamjms.2022.10686

Keywords:

Inflammatory bowel diseases, Ulcerative colitis, Acetic acid, Mesenchymal stem cells, Immunomodulatory, Anti-inflammatory

Abstract

Background: Ulcerative colitis (UC) is an autoimmune inflammatory bowel disease, characterized by chronic and relapsing inflammation of the intestinal mucosa. Clinical treatments fail to reduce inflammation and induce side effects in nearly 30% of patients. Mesenchymal stem cells (MSCs) are immunomodulatory agents that can encourage tissue repair and regeneration.

Aim: To investigate the ability of MSCs to differentiate into enterocytes under the mediation of activin a, fibroblastic growth factor 2, and epidermal growth factors and to study the effect of administering MSCs to rats with acetic acid (AA)-induced UC.

Methods: MSCs isolated from the umbilical cord were induced to differentiate into enterocytes. The induced cells were morphologically evaluated by flow cytometry and immunocytochemistry. Forty rats were divided into four groups: control, AA-induced UC, differentiated, and undifferentiated MSC treated groups. The acute UC in rats was induced by 3% AA transrectal administration. Body weight changes, disease activity index (DAI), and histopathological and immunohistochemical CD105 and CD34 staining were recorded. IL-17, IL-10, and TGF- β levels were measured as well.

Results: In Both differentiated and undifferentiated MSCs, induced MSCs improved the DAI score and significantly recovered the pathological changes. The favorable effect of MSCs was significantly linked to CD105 overexpression and CD34 low expression. IL-10 and TGF-β levels increased while IL-17 levels decreased.

Conclusion: Both differentiated and undifferentiated MSCs showed anti-inflammatory and immunomodulatory effects in our study. Based on our results, MSCs could become potentially useful for regenerative medicine and the clinical treatment of UC.

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References

Moein S, Vaghari-Tabari M, Qujeq D, Majidinia M, Nabavi SM, Yousefi B. MiRNAs and inflammatory bowel disease: An interesting new story. J Cell Physiol. 2019;234(4):3277-93. https://doi.org/10.1002/jcp.27173 PMid:30417350 DOI: https://doi.org/10.1002/jcp.27173

Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448(7152):427-34. https://doi.org/10.1038/nature06005 PMid:17653185 DOI: https://doi.org/10.1038/nature06005

Terry R, Chintanaboina J, Patel D, Lippert B, Haner M, Price K, et al. Expression of WIF-1 in inflammatory bowel disease. Histol Histopathol. 2019;34(2):149-57. https://doi.org/10.14670/HH-18-031 PMid:30051904

Neurath MF. Current and emerging therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol. 2017;14(5):269-78. https://doi.org/10.1038/nrgastro.2016.208 PMid:28144028 DOI: https://doi.org/10.1038/nrgastro.2016.208

Safarpour AR, Hosseini SV, Mehrabani D. Epidemiology of inflammatory bowel diseases in iran and Asia; a mini review. Iran J Med Sci. 2013;38(Suppl 2):140-9 PMid:24031103

Mehrabani D, Khajehahmadi Z, Tajik P, Tamadon A, Rahmanifar F, Ashraf M, et al. Regenerative effect of bone marrow-derived mesenchymal stem cells in thioacetamide-induced liver fibrosis of rats. Arch Razi Inst. 2019;74(3):279-86. https://doi.org/10.22092/ari.2018.110029.1120

Mehrabani D, Mehrabani G, Zare S, Manafi A. Adipose-derived stem cells (ADSC) and aesthetic surgery: A mini review. World J Plast Surg. 2013;2(2):65-70. PMid:25489507

Iwao T, Toyota M, Miyagawa Y, Okita H, Kiyokawa N, Akutsu H, et al. Differentiation of human induced pluripotent stem cells into functional enterocyte-like cells using a simple method. Drug Metab Pharmacokinet. 2014;29(1):44-51. https://doi.org/10.2133/dmpk.dmpk-13-rg-005 PMid:23822979 DOI: https://doi.org/10.2133/dmpk.DMPK-13-RG-005

Ogaki S, Shiraki N, Kume K, Kume S. Wnt and Notch signals guide embryonic stem cell differentiation into the intestinal lineages. Stem Cells. 2013;31(6):1086-96. https://doi.org/10.1002/stem.1344 PMid:23378042 DOI: https://doi.org/10.1002/stem.1344

El-Akabawy G, El-Sherif NM. Zeaxanthin exerts protective effects on acetic acid-induced colitis in rats via modulation of pro-inflammatory cytokines and oxidative stress. Biomed Pharmacother. 2019;111:841-51. https://doi.org/10.1016/j.biopha.2019.01.001 PMid:30616083 DOI: https://doi.org/10.1016/j.biopha.2019.01.001

Charan J, Kantharia ND. How to calculate sample size in animal studies? J Pharmacol Pharmacother. 2013;4(4):303-6. https://doi.org/10.4103/0976-500X.119726 PMid:24250214 DOI: https://doi.org/10.4103/0976-500X.119726

Soontararak S, Chow L, Johnson V, Coy J, Wheat W, Regan D, et al. Mesenchymal stem cells (MSC) derived from induced pluripotent stem cells (iPSC) equivalent to adipose-derived MSC in promoting intestinal healing and microbiome normalization in mouse inflammatory bowel disease model. Stem Cells Transl Med. 2018;7(6):456-67. https://doi.org/10.1002/sctm.17-0305 PMid:29635868 DOI: https://doi.org/10.1002/sctm.17-0305

Lopez-Santalla M, Hervas-Salcedo R, Fernandez-Garcia M, Bueren JA, Garin MI. Cell therapy with mesenchymal stem cells induces an innate immune memory response that attenuates experimental colitis in the long term. J Crohns Colitis. 2020;14(10):1424-35. https://doi.org/10.1093/ecco-jcc/jjaa079 PMid:32318720 DOI: https://doi.org/10.1093/ecco-jcc/jjaa079

Pandurangan AK, Mohebali N, Norhaizan ME, Looi CY. Gallic acid attenuates dextran sulfate sodium-induced experimental colitis in BALB/c mice. Drug Des Devel Ther. 2015;9:3923-34. https://doi.org/10.2147/DDDT.S86345 PMid:26251571 DOI: https://doi.org/10.2147/DDDT.S86345

Helal OK, Metwaly HG, Abo Gazia MM, El Desoki R, El Ashmouny N. The possible therapeutic effect of mesenchymal stem cells and Vitamin E on experimentally induced ulcerative colitis in adult male albino rats: Histological and immunohistochemical study. Benha Med J. 2021;38(1):294-321. https://doi.org/10.21608/BMFJ.2021.24068.1215 DOI: https://doi.org/10.21608/bmfj.2021.24068.1215

Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Löfberg R. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut. 2000;47(3):404-9. https://doi.org/10.1136/gut.47.3.404 PMid:10940279 DOI: https://doi.org/10.1136/gut.47.3.404

Araki Y, Mukaisyo K, Sugihara H, Fujiyama Y, Hattori T. Increased apoptosis and decreased proliferation of colonic epithelium in dextran sulfate sodium-induced colitis in mice. Oncol Rep. 2010;24(4):869-74. https://doi.org/10.3892/or.2010.869 PMid:20811666 DOI: https://doi.org/10.3892/or.2010.869

Tampakis A, Weixler B, Rast S, Tampaki EC, Cremonesi E, Kancherla V, et al. Nestin and CD34 expression in colorectal cancer predicts improved overall survival. Acta Oncol. 2021;60(6):727-34. https://doi.org/10.1080/0284186X.2021.1891280 PMid:33734917 DOI: https://doi.org/10.1080/0284186X.2021.1891280

Matsuoka K, Kobayashi T, Ueno F, Matsui T, Hirai F, Inoue N, et al. Evidence-based clinical practice guidelines for inflammatory bowel disease. J Gastroenterol. 2018;53(3):305-53. https://doi.org/10.1007/s00535-018-1439-1 PMid:29429045 DOI: https://doi.org/10.1007/s00535-018-1439-1

Nakahashi-Oda C, Udayanga KG, Nakamura Y, Nakazawa Y, Totsuka N, Miki H, et al. Apoptotic epithelial cells control the abundance of Treg cells at barrier surfaces. Nat Immunol. 2016;17(4):441-50. https://doi.org/10.1038/ni.3345 PMid:26855029 DOI: https://doi.org/10.1038/ni.3345

He XW, He XS, Lian L, Wu XJ, Lan P. Systemic infusion of bone marrow-derived mesenchymal stem cells for treatment of experimental colitis in mice. Dig Dis Sci. 2012;57(12):3136-44. https://doi.org/10.1007/s10620-012-2290-5 PMid:22752635 DOI: https://doi.org/10.1007/s10620-012-2290-5

Song WJ, Li Q, Ryu MO, Ahn JO, Bhang DH, Jung YC, et al. TSG-6 released from intraperitoneally injected canine adipose tissue-derived mesenchymal stem cells ameliorate inflammatory bowel disease by inducing M2 macrophage switch in mice. Stem Cell Res Ther. 2018;9(1):91. https://doi.org/10.1186/s13287-018-0841-1 PMid:29625582 DOI: https://doi.org/10.1186/s13287-018-0841-1

Lin Y, Lin L, Wang Q, Jin Y, Zhang Y, Cao Y, et al. Transplantation of human umbilical mesenchymal stem cells attenuates dextran sulfate sodium-induced colitis in mice. Clin Exp Pharmacol Physiol. 2015;42(1):76-86. https://doi.org/10.1111/1440-1681.12321 PMid:25311720 DOI: https://doi.org/10.1111/1440-1681.12321

Shi G, Wang G, Lu S, Li X, Zhang B, Xu X, et al. PD-L1 is required for human endometrial regenerative cells-associated attenuation of experimental colitis in mice. Am J Transl Res. 2019;11(8):4696-712. PMid:31497192

Zhang D, Zheng L, Shi H, Chen X, Wan Y, Zhang H, et al. Suppression of peritoneal tumorigenesis by placenta-derived mesenchymal stem cells expressing endostatin on colorectal cancer. Int J Med Sci. 2014;11(9):870-9. https://doi.org/10.7150/ijms.8758 PMid:25013366 DOI: https://doi.org/10.7150/ijms.8758

Yui S, Nakamura T, Sato T, Nemoto Y, Mizutani T, Zheng X, et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5⁺ stem cell. Nat Med. 2012;18(4):618-23. https://doi.org/10.1038/nm.2695 PMid:22406745 DOI: https://doi.org/10.1038/nm.2695

Miyamoto S, Ohnishi S, Onishi R, Tsuchiya I, Hosono H, Katsurada T, et al. Therapeutic effects of human amnion-derived mesenchymal stem cell transplantation and conditioned medium enema in rats with trinitrobenzene sulfonic acid-induced colitis. Am J Transl Res. 2017;9(3):940-52. PMid:28386323

Legaki E, Roubelakis MG, Theodoropoulos GE, Lazaris A, Kollia A, Karamanolis G, et al. Therapeutic potential of secreted molecules derived from human amniotic fluid mesenchymal stem/stroma cells in a mice model of colitis. Stem Cell Rev Rep. 2016;12(5):604-12. https://doi.org/10.1007/s12015-016-9677-1 PMid:27503204 DOI: https://doi.org/10.1007/s12015-016-9677-1

Lee KE, Jung SA, Joo YH, Song EM, Moon CM, Kim SE, et al. The efficacy of conditioned medium released by tonsil-derived mesenchymal stem cells in a chronic murine colitis model. PLoS One. 2019;14(12):e0225739. https://doi.org/10.1371/journal.pone.0225739 PMid:31790467 DOI: https://doi.org/10.1371/journal.pone.0225739

Wang M, Liang C, Hu H, Zhou L, Xu B, Wang X, et al. Intraperitoneal injection (IP), Intravenous injection (IV) or anal injection (AI)? Best way for mesenchymal stem cells transplantation for colitis. Sci Rep. 2016;6:30696. https://doi.org/10.1038/srep30696 PMid:27488951 DOI: https://doi.org/10.1038/srep30696

Hoshino A, Hashimoto H, Arihiro S, Hori M, Tajiri H, Kusakabe M. Su1896 Tenascin-C mediates the suppressive effects on inflammation by the mesenchymal stem cell in dextran sulfate sodium induced colitis. Gastroenterology. 2015;148(4):S-547. https://doi.org/10.1016/S0016-5085(15)31832-1 DOI: https://doi.org/10.1016/S0016-5085(15)31832-1

Borzou B, Mehrabani D, Zare S, Zamani-Pereshkaft M, Acker JP. The effect of age and type of media on growth kinetics of human amniotic fluid stem cells. Biopreserv Biobank. 2020;18(5):389-94. https://doi.org/10.1089/bio.2019.0103 PMid:32799559 DOI: https://doi.org/10.1089/bio.2019.0103

Al Naem M, Bourebaba L, Kucharczyk K, Röcken M, Marycz K. Therapeutic mesenchymal stromal stem cells: Isolation, characterization and role in equine regenerative medicine and metabolic disorders. Stem Cell Rev Rep. 2020;16(2):301-22. https://doi.org/10.1007/s12015-019-09932-0 PMid:31797146 DOI: https://doi.org/10.1007/s12015-019-09932-0

Yu F, Lu Z, Huang K, Wang X, Xu Z, Chen B, et al. MicroRNA- 17-5p-activated Wnt/β-catenin pathway contributes to the progression of liver fibrosis. Oncotarget. 2016;7(1):81-93. https://doi.org/10.18632/oncotarget.6447 PMid:26637809 DOI: https://doi.org/10.18632/oncotarget.6447

Qiu S, Kabeya T, Ogawa I, Anno S, Hayashi H, Kanaki T, et al. Gellan gum promotes the differentiation of enterocytes from human induced pluripotent stem cells. Pharmaceutics. 2020;12(10):951. https://doi.org/10.3390/pharmaceutics12100951 PMid:33050367 DOI: https://doi.org/10.3390/pharmaceutics12100951

Li S, Huang Q, Mao J, Li Q. FGF signaling mediates definitive endoderm formation by regulating epithelial-to-mesenchymal transition and cell proliferation. Int J Dev Biol. 2020;64(10-11- 12):471-7. https://doi.org/10.1387/ijdb.190372ql PMid:33336709 DOI: https://doi.org/10.1387/ijdb.190372ql

Ye L, Sun LX, Wu MH, Wang J, Ding X, Shi H, et al. A Simple system for differentiation of functional intestinal stem cell-like cells from bone marrow mesenchymal stem cells. Mol Ther Nucleic Acids. 2018;13:110-20. https://doi.org/10.1016/j.omtn.2018.08.017 PMid:30268688 DOI: https://doi.org/10.1016/j.omtn.2018.08.017

Wang Y, Liu XP, Zhao ZB, Chen JH, Yu CG. Expression of CD4+ forkhead box P3 (FOXP3)+ regulatory T cells in inflammatory bowel disease. J Dig Dis. 2011;12(4):286-94. https://doi.org/10.1111/j.1751-2980.2011.00505.x PMid:21791023 DOI: https://doi.org/10.1111/j.1751-2980.2011.00505.x

Kim HS, Shin TH, Lee BC, Yu KR, Seo Y, Lee S, et al. Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2. Gastroenterology. 2013;145(6):1392-403. e8. https://doi.org/10.1053/j.gastro.2013.08.033 PMid:23973922 DOI: https://doi.org/10.1053/j.gastro.2013.08.033