Current Stem Cell Research & TherapyCurrent Stem Cell Research & TherapyCurrent Stem Cell Research & Therapy1574-888X2212-3946Bentham Science64576910.2174/1574888X18666230512112735MedicineResearch ArticleHuman Mesenchymal Stem Cells Improve Angiogenesis and Bone Formation in Severed Finger Rats through SIRT1/Nrf2 SignalingWuHaoinfo@benthamscience.netSunWeixueinfo@benthamscience.netChengGonginfo@benthamscience.netZhengMingdiinfo@benthamscience.netZhaoYuchiinfo@benthamscience.netCaoZhilininfo@benthamscience.netDepartment of Sports Medicine, Yantaishan HospitalDepartment of Arthrology Surgery, Yantai Yuhuangding HospitalDepartment of Articulation Surgery, Yantaishan Hospital0103202419338939911012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1574-888X/article/view/645769

Background:This study employed a severed finger rat model to analyze the effects of human mesenchymal stem cells (MSCs) on angiogenesis, inflammatory response, apoptosis, and oxidative stress, to evaluate the possible mechanism of the repair effect of MSCs on severed finger (SF) rats.

Methods:Sixty Sprague-Dawley (SD) rats were categorized into five groups (n = 12). The pathological changes of severed finger tissues were investigated by Hematoxylin and eosin (H&E) staining on day 14 after the rats were sacrificed. The levels of inflammatory factors and oxidative stress factors were detected by ELISA. Terminal Deoxynucleotidyl Transferase (TdT) dUTP Nick End Labeling (TUNEL) was employed to assess the apoptosis of chondrocytes in severed finger tissues. The expression of osteocalcin (OCN), osteopontin (OPN), Collagen I (Col-1), and CD31 were detected by immunohistochemistry or immunofluorescence assay, respectively. The expression levels of related proteins were determined by western blot.

Result:Our study presented evidence that MSCs treatment improved pathological changes of skin and bone tissue, diminished the inflammatory response, prevented oxidative stress injury, suppressed chondrocyte apoptosis, and promoted angiogenesis, and bone formation compared to the model group. In addition, EX527 treatment attenuated the effect of MSCs, SRT1720 and ML385 co-treatment also attenuated the effect of MSCs. Importantly, the MSCs treatment increased the expression of Sirtuin 1(SIRT1)/Nuclear factor erythroid2-related factor 2(Nrf2) relate proteins.

Conclusion:Our study indicated that the mechanism of the effect of MSCs on a severed finger was related to the SIRT1/ Nrf2 signaling pathway.

Angiogenesischondrocyte apoptosisOCNoxidative stress injurySIRT1Nrf2.Yan Y, Goodman JM, Moore DD, Solla SA, Bensmaia SJ. Unexpected complexity of everyday manual behaviors. Nat Commun 2020; 11(1): 3564. doi: 10.1038/s41467-020-17404-0 PMID: 32678102Eming SA, Wynn TA, Martin P. Inflammation and metabolism in tissue repair and regeneration. Science 2017; 356(6342): 1026-30. doi: 10.1126/science.aam7928 PMID: 28596335Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol 2008; 8(9): 726-36. doi: 10.1038/nri2395 PMID: 19172693Lindsay SL, Barnett SC. Therapeutic potential of niche-specific mesenchymal stromal cells for spinal cord injury repair. Cells 2021; 10(4): 901. doi: 10.3390/cells10040901 PMID: 33919910Kim M, Bae YK, Um S, et al. A small-sized population of human umbilical cord blood-derived mesenchymal stem cells shows high stemness properties and therapeutic benefit. Stem Cells Int 2020; 2020: 1-17. doi: 10.1155/2020/5924983 PMID: 32399043Samsonraj RM, Raghunath M, Nurcombe V, Hui JH, van Wijnen AJ, Cool SM. Concise review: Multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med 2017; 6(12): 2173-85. doi: 10.1002/sctm.17-0129 PMID: 29076267Singh CK, Chhabra G, Ndiaye MA, Garcia-Peterson LM, Mack NJ, Ahmad N. The role of sirtuins in antioxidant and redox signaling. Antioxid Redox Signal 2018; 28(8): 643-61. doi: 10.1089/ars.2017.7290 PMID: 28891317Zhang Q, Liu J, Duan H, Li R, Peng W, Wu C. Activation of Nrf2/HO-1 signaling: An important molecular mechanism of herbal medicine in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress. J Adv Res 2021; 34: 43-63. doi: 10.1016/j.jare.2021.06.023 PMID: 35024180Huang K, Gao X, Wei W. The crosstalk between Sirt1 and Keap1/Nrf2/ARE anti-oxidative pathway forms a positive feedback loop to inhibit FN and TGF-β1 expressions in rat glomerular mesangial cells. Exp Cell Res 2017; 361(1): 63-72. doi: 10.1016/j.yexcr.2017.09.042 PMID: 28986066Gu L, Tao X, Xu Y, et al. Dioscin alleviates BDL- and DMN-induced hepatic fibrosis via Sirt1/Nrf2-mediated inhibition of p38 MAPK pathway. Toxicol Appl Pharmacol 2016; 292: 19-29. doi: 10.1016/j.taap.2015.12.024 PMID: 26747300Yoon DS, Choi Y, Lee JW. Cellular localization of NRF2 determines the self-renewal and osteogenic differentiation potential of human MSCs via the P53–SIRT1 axis. Cell Death Dis 2016; 7(2): e2093. doi: 10.1038/cddis.2016.3 PMID: 26866273Xia DY, Yuan JL, Jiang XC, et al. SIRT1 Promotes M2 microglia polarization via reducing ROS-mediated NLRP3 inflammasome signaling after subarachnoid hemorrhage. Front Immunol 2021; 12: 770744. doi: 10.3389/fimmu.2021.770744 PMID: 34899720Shi C, Hou C, Zhu X, et al. SRT1720 ameliorates sodium taurocholate-induced severe acute pancreatitis in rats by suppressing NF-κB signalling. Biomed Pharmacother 2018; 108: 50-7. doi: 10.1016/j.biopha.2018.09.035 PMID: 30216799Gao Z, Sui J, Fan R, Qu W, Dong X, Sun D. Emodin protects against acute pancreatitis-associated lung injury by inhibiting NLPR3 inflammasome activation via Nrf2/HO-1 signaling. Drug Des Devel Ther 2020; 14: 1971-82. doi: 10.2147/DDDT.S247103 PMID: 32546964Kaneshiro Y, Hidaka N, Yano K, Sakanaka H, Hyun S, Takamatsu K. Replantation for multiple digit amputations: A retrospective analysis of the clinical results. J Plast Reconstr Aesthet Surg 2020; 73(11): 1995-2000. doi: 10.1016/j.bjps.2020.08.077 PMID: 32948497Zhao F, Deng J, Yu X, Li D, Shi H, Zhao Y. Protective effects of vascular endothelial growth factor in cultured brain endothelial cells against hypoglycemia. Metab Brain Dis 2015; 30(4): 999-1007. doi: 10.1007/s11011-015-9659-z PMID: 25761767Luo H, Zhang Y, Zhang Z, Jin Y. The protection of MSCs from apoptosis in nerve regeneration by TGFβ1 through reducing inflammation and promoting VEGF-dependent angiogenesis. Biomaterials 2012; 33(17): 4277-87. doi: 10.1016/j.biomaterials.2012.02.042 PMID: 22425554Wiafe B, Adesida AB, Churchill T, Kadam R, Carleton J, Metcalfe PD. Mesenchymal stem cell therapy inhibited inflammatory and profibrotic pathways induced by partial bladder outlet obstruction and prevented high-pressure urine storage. J Pediatr Urol 2019; 15(3): 254.e1-254.e10. doi: 10.1016/j.jpurol.2019.03.003 PMID: 30967358Lundberg IE. The role of cytokines, chemokines, and adhesion molecules in the pathogenesis of idiopathic inflammatory myopathies. Curr Rheumatol Rep 2000; 2(3): 216-24. doi: 10.1007/s11926-000-0082-y PMID: 11123062Yu R, Li Q, Feng Z, Cai L, Xu Q. m6A reader YTHDF2 regulates LPS-induced inflammatory response. Int J Mol Sci 2019; 20(6): 1323. doi: 10.3390/ijms20061323 PMID: 30875984Mo W, Chen Z, Zhang X, et al. N6-Methyladenosine Demethylase FTO (Fat Mass and Obesity-Associated Protein) as a novel mediator of statin effects in human endothelial cells. Arterioscler Thromb Vasc Biol 2022; 42(5): 644-58. doi: 10.1161/ATVBAHA.121.317295 PMID: 35296150Tsikas D. Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: Analytical and biological challenges. Anal Biochem 2017; 524: 13-30. doi: 10.1016/j.ab.2016.10.021 PMID: 27789233Bai H, Yuan R, Zhang Z, et al. Intra-articular injection of baicalein inhibits cartilage catabolism and NLRP3 inflammasome signaling in a posttraumatic OA model. Oxid Med Cell Longev 2021; 2021: 1-11. doi: 10.1155/2021/6116890 PMID: 34512868Chen Y, Zhang F, Wang D, et al. Mesenchymal stem cells attenuate diabetic lung fibrosis via adjusting Sirt3-Mediated stress responses in rats. Oxid Med Cell Longev 2020; 2020: 1-15. doi: 10.1155/2020/8076105 PMID: 32089781Li S, Liu J, Liu S, Jiao W, Wang X. Mesenchymal stem cell-derived extracellular vesicles prevent the development of osteoarthritis via the circHIPK3/miR-124-3p/MYH9 axis. J Nanobiotechnology 2021; 19(1): 194. doi: 10.1186/s12951-021-00940-2 PMID: 34193158Izawa A, Ishihara Y, Mizutani H, et al. Inflammatory bone loss in experimental periodontitis induced by Aggregatibacter actinomycetemcomitans in interleukin-1 receptor antagonist knockout mice. Infect Immun 2014; 82(5): 1904-13. doi: 10.1128/IAI.01618-13 PMID: 24566623Song Y, Tan H, Liu K, et al. Effect of fluoride exposure on bone metabolism indicators ALP, BALP, and BGP. Environ Health Prev Med 2011; 16(3): 158-63. doi: 10.1007/s12199-010-0181-y PMID: 21431799Hosseininia S, Lindberg LR, Dahlberg LE. Cartilage collagen damage in hip osteoarthritis similar to that seen in knee osteoarthritis; a case–control study of relationship between collagen, glycosaminoglycan and cartilage swelling. BMC Musculoskelet Disord 2013; 14(1): 18. doi: 10.1186/1471-2474-14-18 PMID: 23302451Guneta V, Zhou Z, Tan NS, Sugii S, Wong MTC, Choong C. Recellularization of decellularized adipose tissue-derived stem cells: Role of the cell-secreted extracellular matrix in cellular differentiation. Biomater Sci 2018; 6(1): 168-78. doi: 10.1039/C7BM00695K PMID: 29167844Lim KT, Patel DK, Dutta SD, Ganguly K. Fluid flow mechanical stimulation-assisted cartridge device for the osteogenic differentiation of human mesenchymal stem cells. Micromachines 2021; 12(8): 927. doi: 10.3390/mi12080927 PMID: 34442549