Regulatory effect of human umbilical cord mesenchymal stem cells on intestinal barrier function in diabetic nephropathy rats

doi:10.12307/2024.158

Abstract

Abstract: BACKGROUND: Diabetic nephropathy is an important cause of end-stage renal disease, and intestinal barrier damage plays an important role in the occurrence and development of diabetic nephropathy.
OBJECTIVE: To observe the protective effect of human umbilical cord mesenchymal stem cells on the intestinal barrier in rats with diabetic nephropathy.
METHODS: Thirty 8-week-old male SD rats were randomly assigned to healthy control group, model group and human umbilical cord mesenchymal stem cell group, with 10 rats in each group. Rats in the human umbilical cord mesenchymal stem cell group were injected with 1×106 human umbilical cord mesenchymal stem cells through the tail vein once a week for 4 weeks after the model establishment of diabetic nephropathy. Rats in the healthy control group and the model group were injected with an equal volume of PBS at the same time. 1 week after the last injection, the histomorphological changes in the kidney and colon were observed under a light microscope. The expressions of ZO-1 and Occludin in the colon tissue of rats were detected by immunohistochemistry. Serum D-lactic acid and lipopolysaccharide levels were detected by ELISA. In addition, the distribution of human umbilical cord mesenchymal stem cells labeled with DiR dye in rats was observed by in vivo imaging system. The expression of human mesenchymal stem cell surface marker antigens CD44 and CD90 in colon tissue was detected by immunohistochemistry.
RESULTS AND CONCLUSION: (1) Compared with the model group, human umbilical cord mesenchymal stem cell transplantation significantly inhibited the increase of urea nitrogen, serum creatinine, 24-hour urine protein level and urinary albumin/creatinine ratio in diabetic nephropathy rats (all P < 0.05). (2) The expression of human mesenchymal stem cell surface markers CD44 and CD90 was found in the colon of diabetic nephropathy rats. (3) Compared with the healthy control group, the expression levels of tight junction proteins Occludin and ZO-1 in the colon tissue of the model group were significantly reduced, while the expressions of Occludin and ZO-1 were significantly increased after treatment with human umbilical cord mesenchymal stem cells. (4) Compared with the model group, human umbilical cord mesenchymal stem cell transplantation significantly reduced serum D-lactic acid and lipopolysaccharide levels in diabetic nephropathy rats. (5) The results suggest that human umbilical cord mesenchymal stem cells may protect the intestinal barrier function by enhancing the expression of intestinal tight junction proteins in diabetic nephropathy rats.

Key words: human umbilical cord mesenchymal stem cell, diabetic nephropathy, intestinal barrier, ZO-1, Occludin

CLC Number:

Wu Yaru, Mi Yan, Wei Kaiyue, Gao Heping, Zhang Dingyu, Wang Caili. Regulatory effect of human umbilical cord mesenchymal stem cells on intestinal barrier function in diabetic nephropathy rats[J]. Chinese Journal of Tissue Engineering Research, 2024, 28(19): 2967-2973.

Figures/Tables 6

References

[1] NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet. 2016;387(10027):1513-1530.
[2] ZIMMET PZ, MAGLIANO DJ, HERMAN WH, et al. Diabetes: a 21st century challenge. Lancet Diabetes Endocrinol. 2014;2(1):56-64.
[3] SUN H, SAEEDI P, KARURANGA S, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119.
[4] KATO M, NATARAJAN R. Diabetic nephropathy--emerging epigenetic mechanisms. Nat Rev Nephrol. 2014;10(9):517-530.
[5] MENG XM, NIKOLIC-PATERSON DJ, LAN HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12(6):325-338.
[6] RICO-FONTALVO J, AROCA G, CABRALES J, et al. Molecular Mechanisms of Diabetic Kidney Disease. Int J Mol Sci. 2022;23(15):8668.
[7] CHUNG S, BARNES JL, ASTROTH KS. Gastrointestinal Microbiota in Patients with Chronic Kidney Disease: A Systematic Review. Adv Nutr. 2019;10(5): 888-901.
[8] MEIJERS B, EVENEPOEL P, ANDERS HJ. Intestinal microbiome and fitness in kidney disease. Nat Rev Nephrol. 2019;15(9):531-545.
[9] WANG X, YANG S, LI S, et al. Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents. Gut. 2020; 69(12):2131-2142.
[10] WANG Y, ZHAO J, QIN Y, et al. The Specific Alteration of Gut Microbiota in Diabetic Kidney Diseases-A Systematic Review and Meta-Analysis. Front Immunol. 2022;13:908219.
[11] HAN S, CHEN M, CHENG P, et al. A systematic review and meta-analysis of gut microbiota in diabetic kidney disease: Comparisons with diabetes mellitus, non-diabetic kidney disease, and healthy individuals. Front Endocrinol. 2022;13:1018093.
[12] TANG G, DU Y, GUAN H, et al. Butyrate ameliorates skeletal muscle atrophy in diabetic nephropathy by enhancing gut barrier function and FFA2-mediated PI3K/Akt/mTOR signals. Br J Pharmacol. 2022;179(1):159-178.
[13] LIN W, LI HY, YANG Q, et al. Administration of mesenchymal stem cells in diabetic kidney disease: a systematic review and meta-analysis. Stem Cell Res Ther. 2021;12(1):43.
[14] YIN S, LIU W, JI C, et al. hucMSC-sEVs-Derived 14-3-3ζ Serves as a Bridge between YAP and Autophagy in Diabetic Kidney Disease. Oxid Med Cell Longev. 2022;2022:3281896.
[15] SALA E, GENUA M, PETTI L, et al. Mesenchymal Stem Cells Reduce Colitis in Mice via Release of TSG6, Independently of Their Localization to the Intestine. Gastroenterology. 2015;149(1):163-176.
[16] YANG S, LIANG X, SONG J, et al. A novel therapeutic approach for inflammatory bowel disease by exosomes derived from human umbilical cord mesenchymal stem cells to repair intestinal barrier via TSG-6. Stem Cell Res Ther. 2021;12(1):315.
[17] BOSI E, MOLTENI L, RADAELLI MG, et al. Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia. 2006;49(12): 2824-2827.
[18] ZHONG HJ, YUAN Y, XIE WR, et al. Type 2 Diabetes Mellitus Is Associated with More Serious Small Intestinal Mucosal Injuries. PloS one. 2016;11(9): e0162354.
[19] SCHOULTZ I, KEITA ÅV. The Intestinal Barrier and Current Techniques for the Assessment of Gut Permeability. Cells. 2020;9(8):1909.
[20] YAN JT, SUN Q, ZHANG XL, et al. Methods for the evaluation of intestinal mucosal permeability. Sheng Li Xue Bao. 2022;74(4):596-608.
[21] MONACO A, OVRYN B, AXIS J, et al. The Epithelial Cell Leak Pathway. Int J Mol Sci. 2021;22(14):7677.
[22] SHEN L, WEBER CR, RALEIGH DR, et al. Tight junction pore and leak pathways: a dynamic duo. Annu Rev Physiol. 2011;73:283-309.
[23] DENG L, YANG Y, XU G. Empagliflozin ameliorates type 2 diabetes mellitus-related diabetic nephropathy via altering the gut microbiota. Biochim Biophys Acta Mol Cell Biol Lipids. 2022;1867(12):159234.
[24] 霍丽霞,朱鸣,王霄一,等. 早期糖尿病肾病患者肠道菌群结构特征及菌群移位的研究[Z]. 湖州市第一人民医院. 2020.
[25] FRIDENSHTEĬN AIA, PETRAKOVA KV, KURALESOVA AI, et al. Precursor cells for osteogenic and hemopoietic tissues. Analysis of heterotopic transplants of bone marrow. Tsitologiia. 1968;10(5):557-567.
[26] LI T, XIA M, GAO Y, et al. Human umbilical cord mesenchymal stem cells: an overview of their potential in cell-based therapy. Expert Opin Biol Ther. 2015;15(9):1293-1306.
[27] EL OMAR R, BEROUD J, STOLTZ JF, et al. Umbilical cord mesenchymal stem cells: the new gold standard for mesenchymal stem cell-based therapies? Tissue Eng Part B Rev. 2014;20(5):523-544.
[28] CHEN L, XIANG E, LI C, et al. Umbilical Cord-Derived Mesenchymal Stem Cells Ameliorate Nephrocyte Injury and Proteinuria in a Diabetic Nephropathy Rat Model. J Diabetes Res. 2020;2020:8035853.
[29] SZYDLAK R. Biological, chemical and mechanical factors regulating migration and homing of mesenchymal stem cells. World J Stem Cells. 2021;13(6):619-631.
[30] ULLAH M, LIU DD, THAKOR AS. Mesenchymal Stromal Cell Homing: Mechanisms and Strategies for Improvement. iScience. 2019;15:421-438.
[31] WANG S, BAO L, FU W, et al. Protective effect of exosomes derived from bone marrow mesenchymal stem cells on rats with diabetic nephropathy and its possible mechanism. Am J Transl Res. 2021;13(6):6423-6430.
[32] MAO R, SHEN J, HU X. BMSCs-derived exosomal microRNA-let-7a plays a protective role in diabetic nephropathy via inhibition of USP22 expression. Life Sci. 2021;268:118937.
[33] LIN Y, YANG Q, WANG J, et al. An overview of the efficacy and signaling pathways activated by stem cell-derived extracellular vesicles in diabetic kidney disease. Front Endocrinol (Lausanne). 2022;13:962635.
[34] YUE Y, YEH JN, CHIANG JY, et al. Intrarenal arterial administration of human umbilical cord-derived mesenchymal stem cells effectively preserved the residual renal function of diabetic kidney disease in rat. Stem Cell Res Ther. 2022;13(1):186.
[35] YU S, CHENG Y, ZHANG L, et al. Treatment with adipose tissue-derived mesenchymal stem cells exerts anti-diabetic effects, improves long-term complications, and attenuates inflammation in type 2 diabetic rats. Stem Cell Res Ther. 2019;10(1):333.
[36] RAFIEE Z, ORAZIZADEH M, NEJAD DEHBASHI F, et al. Mesenchymal stem cells derived from the kidney can ameliorate diabetic nephropathy through the TGF-β/Smad signaling pathway. Environ Sci Pollut Res Int. 2022;29(35): 53212-53224.
[37] LIU Q, LV S, LIU J, et al. Mesenchymal stem cells modified with angiotensin-converting enzyme 2 are superior for amelioration of glomerular fibrosis in diabetic nephropathy. Diabetes Res Clin Pract. 2020;162:108093.
[38] LEE SE, JANG JE, KIM HS, et al. Mesenchymal stem cells prevent the progression of diabetic nephropathy by improving mitochondrial function in tubular epithelial cells. Exp Mol Med. 2019;51(7):1-14.
[39] ZHANG F, WANG C, WEN X, et al. Mesenchymal stem cells alleviate rat diabetic nephropathy by suppressing CD103+ DCs-mediated CD8+ T cell responses. J Cell Mol Med. 2020;24(10):5817-5831.
[40] LV W, GRAVES DT, HE L, et al. Depletion of the diabetic gut microbiota resistance enhances stem cells therapy in type 1 diabetes mellitus. Theranostics. 2020;10(14):6500-6516.