https://doi.org/10.4081/ejh.2025.4158
Adipose-derived stem cells promote the recovery of intestinal barrier function by inhibiting the p38 MAPK signaling pathway
Submitted: 5 November 2024
Accepted: 13 December 2024
Published: 21 January 2025
Accepted: 13 December 2024
Abstract Views: 19
PDF: 11
Supplementary Figure: 2
Supplementary Figure: 2
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
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Intestinal barrier damage causes an imbalance in the intestinal flora and microbial environment, promoting a variety of gastrointestinal diseases. This study aimed to explore the mechanism by which adipose-derived stem cells (ADSCs) repair intestinal barrier damage. The human colon adenocarcinoma cell line Caco-2 and rats were treated with lipopolysaccharide (LPS) to establish in vitro and in vivo models, respectively, of intestinal barrier damage. The expression of inflammatory cytokines (TNF-α, HMGB1, IL-1β and IL-6), antioxidant enzymes (iNOS, SOD and CAT), and oxidative products (MDA and 8-iso-PGF2α) was detected using ELISA kits and related reagent kits. Apoptosis-related proteins (Bcl-2, Bax, Caspase-3 and Caspase-9), tight junction proteins (ZO-1, Occludin, E-cadherin, and Claudin-1) and p38 MAPK pathway-associated protein were detected by Western blotting. In addition, cell viability and apoptosis was determined by a CCK-8 kit and flow cytometry, respectively. Cell permeability was assayed by the transepithelial electrical resistance value and FITC-dextran concentration. The homing effect of ADSCs was detected by fluorescence labeling, and intestinal barrier tissue was observed by HE staining. After ADSC treatment, the level of phosphorylated p38 MAPK protein decreased, the expression of inflammatory factors, oxidative stress and cell apoptosis decreased, the expression of tight junction proteins increased, and cell permeability decreased in Caco-2 cells stimulated with LPS. In rats, ADSCs are directionally recruited to damaged intestinal tissue. ADSCs significantly decreased the levels of D-lactate, diamine oxidase (DAO) and FITC-dextran induced by LPS. ADSCs promoted tight junction proteins and inhibited oxidative stress in intestinal tissue. These effects were reversed after the use of a p38 MAPK activator. ADSCs can be directionally recruited to intestinal tissue, upregulate tight junction proteins, and reduce apoptosis and oxidative stress by inhibiting the p38MAPK signaling pathway. This study provides novel insights into the treatment of intestinal injury.
1. Sandoval-Ramirez BA, Catalan U, Pedret A, Valls RM, Motilva MJ, Rubio L, et al. Exploring the effects of phenolic compounds to reduce intestinal damage and improve the intestinal barrier integrity: A systematic review of in vivo animal studies. Clin Nutr 2021;40:1719-32.
DOI: https://doi.org/10.1016/j.clnu.2020.09.027
2. McKenna ZJ, Gorini PF, Gillum TL, Amorim FT, Deyhle MR, Mermier CM. High-altitude exposures and intestinal barrier dysfunction. Am J Physiol-Reg I 2022;322:R192-203.
DOI: https://doi.org/10.1152/ajpregu.00270.2021
3. Cao Z, Mu S, Wang M, Zhang Y, Zou G, Yuan X, et al. Succinate pretreatment attenuates intestinal ischemia-reperfusion injury by inhibiting necroptosis and inflammation via upregulating Klf4. Int Immunopharmacol 2023;120:110425.
DOI: https://doi.org/10.1016/j.intimp.2023.110425
4. Scaldaferri F, Pizzoferrato M, Gerardi V, Lopetuso L, Gasbarrini A. The gut barrier: new acquisitions and therapeutic approaches. J Clin Gastroenterol 2012;46 Suppl:S12-7.
DOI: https://doi.org/10.1097/MCG.0b013e31826ae849
5. Liu J, Huang L, Luo M, Xia X. Bacterial translocation in acute pancreatitis. Crit Rev Microbiol 2019;45:539-47.
DOI: https://doi.org/10.1080/1040841X.2019.1621795
6. Ono K, Han J. The p38 signal transduction pathway: activation and function. Cell Signal 2000;12:1-13.
DOI: https://doi.org/10.1016/S0898-6568(99)00071-6
7. Henson SM, Lanna A, Riddell NE, Franzese O, Macaulay R, Griffiths SJ, et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8(+) T cells. J Clin Invest 2014;124:4004-16.
DOI: https://doi.org/10.1172/JCI75051
8. Li Y, Xu B, Xu M, Chen D, Xiong Y, Lian M, et al. 6-Gingerol protects intestinal barrier from ischemia/reperfusion-induced damage via inhibition of p38 MAPK to NF-kappaB signalling. Pharmacol Res 2017;119:137-48.
DOI: https://doi.org/10.1016/j.phrs.2017.01.026
9. Xiong W, Huang J, Li X, Zhang Z, Jin M, Wang J, et al. Icariin and its phosphorylated derivatives alleviate intestinal epithelial barrier disruption caused by enterotoxigenic Escherichia coli through modulate p38 MAPK in vivo and in vitro. Faseb J 2020;34:1783-801.
DOI: https://doi.org/10.1096/fj.201902265R
10. Ouyang J, Zhang ZH, Zhou YX, Niu WC, Zhou F, Shen CB, et al. Up-regulation of tight-junction proteins by p38 mitogen-activated protein kinase/p53 inhibition leads to a reduction of injury to the intestinal mucosal barrier in severe acute pancreatitis. Pancreas 2016;45:1136-44.
DOI: https://doi.org/10.1097/MPA.0000000000000656
11. Song Y, You Y, Xu X, Lu J, Huang X, Zhang J, et al. Adipose-derived mesenchymal stem cell-derived exosomes biopotentiated extracellular matrix hydrogels accelerate diabetic wound healing and skin regeneration. Adv Sci 2023;10:e2304023.
DOI: https://doi.org/10.1002/advs.202304023
12. Jin J, Shi Y, Gong J, Zhao L, Li Y, He Q, et al. Exosome secreted from adipose-derived stem cells attenuates diabetic nephropathy by promoting autophagy flux and inhibiting apoptosis in podocyte. Stem Cell Res Ther 2019;10:95.
DOI: https://doi.org/10.1186/s13287-019-1177-1
13. Nishikawa T, Maeda K, Nakamura M, Yamamura T, Sawada T, Mizutani Y, et al. Filtrated adipose tissue-derived mesenchymal stem cell lysate ameliorates experimental acute colitis in mice. Digest Dis Sci 2021;66:1034-44.
DOI: https://doi.org/10.1007/s10620-020-06359-3
14. Yu H, Yang X, Xiao X, Xu M, Yang Y, Xue C, et al. Human adipose mesenchymal stem cell-derived exosomes protect mice from DSS-induced inflammatory bowel disease by promoting intestinal-stem-cell and epithelial regeneration. Aging Dis 2021;12:1423-37.
DOI: https://doi.org/10.14336/AD.2021.0601
15. Wang X, Wang Y, Zhou X, Liu F. Conditioned medium from adipose-derived stem cell inhibits Jurkat cell proliferation through TGF-beta1 and p38/MAPK pathway. Anal Cell Pathol 2019;2019:2107414.
DOI: https://doi.org/10.1155/2019/2107414
16. Gan L, Zheng L, Yao L, Lei L, Huang Y, Zeng Z, et al. Exosomes from adipose-derived mesenchymal stem cells improve liver fibrosis by regulating the miR-20a-5p/TGFBR2 axis to affect the p38 MAPK/NF-kappaB pathway. Cytokine 2023;172:156386.
DOI: https://doi.org/10.1016/j.cyto.2023.156386
17. Li Y, Zhang W, Gao J, Liu J, Wang H, Li J, et al. Adipose tissue-derived stem cells suppress hypertrophic scar fibrosis via the p38/MAPK signaling pathway. Stem Cell Res Ther 2016;7:102.
DOI: https://doi.org/10.1186/s13287-016-0356-6
18. Panaro MA, Carofiglio V, Acquafredda A, Cavallo P, Cianciulli A. Anti-inflammatory effects of resveratrol occur via inhibition of lipopolysaccharide-induced NF-kappaB activation in Caco-2 and SW480 human colon cancer cells. Brit J Nutr 2012;108:1623-32.
DOI: https://doi.org/10.1017/S0007114511007227
19. Bolte LA, Vich VA, Imhann F, Collij V, Gacesa R, Peters V, et al. Long-term dietary patterns are associated with pro-inflammatory and anti-inflammatory features of the gut microbiome. Gut 2021;70:1287-98.
DOI: https://doi.org/10.1136/gutjnl-2020-322670
20. Flemming S, Luissint AC, Kusters D, Raya-Sandino A, Fan S, Zhou DW, et al. Desmocollin-2 promotes intestinal mucosal repair by controlling integrin-dependent cell adhesion and migration. Mol Biol Cell 2020;31:407-18.
DOI: https://doi.org/10.1091/mbc.E19-12-0692
21. Barichello T, Generoso JS, Singer M, Dal-Pizzol F. Biomarkers for sepsis: more than just fever and leukocytosis-a narrative review. Crit Care 2022;26:14.
DOI: https://doi.org/10.1186/s13054-021-03862-5
22. Ge P, Luo Y, Okoye CS, Chen H, Liu J, Zhang G, et al. Intestinal barrier damage, systemic inflammatory response syndrome, and acute lung injury: A troublesome trio for acute pancreatitis. Biomed Pharmacother 2020;132:110770.
DOI: https://doi.org/10.1016/j.biopha.2020.110770
23. Lin Z, Lin D, Lin D. The mechanisms of adipose stem cell-derived exosomes promote wound healing and regeneration. Aesthet Plast Surg 2024;48:2730-7.
DOI: https://doi.org/10.1007/s00266-024-03871-z
24. Ni H, Zhao Y, Ji Y, Shen J, Xiang M, Xie Y. Adipose-derived stem cells contribute to cardiovascular remodeling. Aging (Albany NY) 2019;11:11756-69.
DOI: https://doi.org/10.18632/aging.102491
25. Al-Ghadban S, Bunnell BA. Adipose tissue-derived stem cells: immunomodulatory effects and therapeutic potential. Physiology 2020;35:125-33.
DOI: https://doi.org/10.1152/physiol.00021.2019
26. Im GI. Adipose stem cells and skeletal repair. Histol Histopathol 2013;28:557-64.
27. Shingyochi Y, Orbay H, Mizuno H. Adipose-derived stem cells for wound repair and regeneration. Expert Opin Biol Th 2015;15:1285-92.
DOI: https://doi.org/10.1517/14712598.2015.1053867
28. Liu S, Zhang H, Zhang X, Lu W, Huang X, Xie H, et al. Synergistic angiogenesis promoting effects of extracellular matrix scaffolds and adipose-derived stem cells during wound repair. Tissue Eng Pt A 2011;17:725-39.
DOI: https://doi.org/10.1089/ten.tea.2010.0331
29. Bhattacharyya A, Chattopadhyay R, Mitra S, Crowe SE. Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiol Rev 2014;94:329-54.
DOI: https://doi.org/10.1152/physrev.00040.2012
30. Yu C, Wang Z, Tan S, Wang Q, Zhou C, Kang X, et al. Chronic kidney disease induced intestinal mucosal barrier damage associated with intestinal oxidative stress injury. Gastroent Res Pract 2016;2016:6720575.
DOI: https://doi.org/10.1155/2016/6720575
31. Jin Y, Zhai Z, Jia H, Lai J, Si X, Wu Z. Kaempferol attenuates diquat-induced oxidative damage and apoptosis in intestinal porcine epithelial cells. Food Funct 2021;12:6889-99.
DOI: https://doi.org/10.1039/D1FO00402F
32. Zhou Q, Xiang H, Liu H, Qi B, Shi X, Guo W, et al. Emodin alleviates intestinal barrier dysfunction by inhibiting apoptosis and regulating the immune response in severe acute pancreatitis. Pancreas 2021;50:1202-11.
DOI: https://doi.org/10.1097/MPA.0000000000001894
33. Kuo WT, Zuo L, Odenwald MA, Madha S, Singh G, Gurniak CB, et al. The tight junction protein ZO-1 is dispensable for barrier function but critical for effective mucosal repair. Gastroenterology 2021;161:1924-39.
DOI: https://doi.org/10.1053/j.gastro.2021.08.047
34. Jiang Y, Song J, Xu Y, Liu C, Qian W, Bai T, et al. Piezo1 regulates intestinal epithelial function by affecting the tight junction protein claudin-1 via the ROCK pathway. Life Sci 2021;275:119254.
DOI: https://doi.org/10.1016/j.lfs.2021.119254
35. Zhou D, Pan Q, Xin FZ, Zhang RN, He CX, Chen GY, et al. Sodium butyrate attenuates high-fat diet-induced steatohepatitis in mice by improving gut microbiota and gastrointestinal barrier. World J Gastroentero 2017;23:60-75.
DOI: https://doi.org/10.3748/wjg.v23.i1.60
36. Zhang C, Zhu H, Jie H, Ding H, Sun H. Arbutin ameliorated ulcerative colitis of mice induced by dextran sodium sulfate (DSS). Bioengineered 2021;12:11707-15.
DOI: https://doi.org/10.1080/21655979.2021.2005746
37. Bai B, Ji Z, Wang F, Qin C, Zhou H, Li D, et al. CTRP12 ameliorates post-myocardial infarction heart failure through down-regulation of cardiac apoptosis, oxidative stress and inflammation by influencing the TAK1-p38 MAPK/JNK pathway. Inflamm Res 2023;72:1375-90.
DOI: https://doi.org/10.1007/s00011-023-01758-4
38. Zhao Y, Wang J, Liu X. TRPV4 induces apoptosis via p38 MAPK in human lung cancer cells. Braz J Med Biol Res 2021;54:e10867.
DOI: https://doi.org/10.1590/1414-431x2021e10867
39. Foerster EG, Mukherjee T, Cabral-Fernandes L, Rocha J, Girardin SE, Philpott DJ. How autophagy controls the intestinal epithelial barrier. Autophagy 2022;18:86-103.
DOI: https://doi.org/10.1080/15548627.2021.1909406
40. Ma TM, Xu N, Ma XD, Bai ZH, Tao X, Yan HC. Moxibustion regulates inflammatory mediators and colonic mucosal barrier in ulcerative colitis rats. World J Gastroenterol 2016;22:2566-75.
DOI: https://doi.org/10.3748/wjg.v22.i8.2566
Ethics Approval
this study was approved by the Animal Ethics Committee of Kunming Medical University Animal CenterSupporting Agencies
Yunnan Provincial Science and Technology Plan ProjectHow to Cite
Yang, M., Xu, W., Yue, C., Li, R., Huang, X., Yan, Y., … Li, Q. (2025). Adipose-derived stem cells promote the recovery of intestinal barrier function by inhibiting the p38 MAPK signaling pathway. European Journal of Histochemistry, 69(1). https://doi.org/10.4081/ejh.2025.4158
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