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Current Stem Cell Research & Therapy

Editor-in-Chief

ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

Research Article

Bone Marrow Mesenchymal Stem Cell Extracellular Vesicle-derived miR-27b- 3p activates the Wnt/Β-catenin Pathway by Targeting SMAD4 and Aggravates Hepatic Ischemia-reperfusion Injury

Author(s): Hongnan Li, Weidong Lin, Yunlei Li, Jiayang Zhang, Runsheng Liu, Minghai Qu, Ruihua Wang, Xiaomin Kang and Xuekun Xing*

Volume 19, Issue 5, 2024

Published on: 05 October, 2023

Page: [755 - 766] Pages: 12

DOI: 10.2174/1574888X19666230901140628

Price: $65

Abstract

Background: To investigate the roles of extracellular vesicles (EVs) secreted from bone marrow mesenchymal stem cells (BMSCs) and miR-27 (highly expressed in BMSC EVs) in hepatic ischemia‒ reperfusion injury (HIRI).

Approaches and Results: We constructed a HIRI mouse model and pretreated it with an injection of agomir-miR-27-3p, agomir-NC, BMSC-EVs or control normal PBS into the abdominal cavity. Compared with the HIRI group, HIRI mice preinjected with BMSC-EVs had significantly decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and alleviated liver necrosis (P<0.05). However, compared with HIRI+NC mice, HIRI+miR-27b mice had significantly increased ALT and AST levels, aggravated liver necrosis, and increased apoptosis-related protein expression (P<0.05). The proliferation and apoptosis of AML-12 cells transfected with miR-27 were significantly higher than the proliferation and apoptosis of AML-12 cells in the mimic NC group (P<0.01) after hypoxia induction. SMAD4 was proven to be a miR-27 target gene. Furthermore, compared to HIRI+NC mice, HIRI+miR-27 mice displayed extremely reduced SMAD4 expression and increased levels of wnt1, β-catenin, c-Myc, and Cyclin D1.

Conclusion: Our findings reveal the role and mechanism of miR-27 in HIRI and provide novel insights for the prevention and treatment of HIRI; for example, EVs derived from BMSCs transfected with antimiR- 27 might demonstrate better protection against HIRI.

Graphical Abstract

[1]
Czigany Z, Lurje I, Schmelzle M, et al. Ischemia-reperfusion injury in marginal liver grafts and the role of hypothermic machine perfusion: Molecular mechanisms and clinical implications. J Clin Med 2020; 9(3): 846.
[http://dx.doi.org/10.3390/jcm9030846] [PMID: 32244972]
[2]
Guan Y, Yao W, Yi K, et al. Nanotheranostics for the management of hepatic ischemia‐reperfusion injury. Small 2021; 17(23): 2007727.
[http://dx.doi.org/10.1002/smll.202007727] [PMID: 33852769]
[3]
Du Y, Li D, Han C, et al. Exosomes from human-induced pluripotent stem cell–derived mesenchymal stromal cells (hiPSC-MSCs) protect liver against hepatic ischemia/reperfusion injury via activating sphingosine kinase and sphingosine-1-phosphate signaling pathway. Cell Physiol Biochem 2017; 43(2): 611-25.
[http://dx.doi.org/10.1159/000480533] [PMID: 28934733]
[4]
Witwer KW, Van Balkom BWM, Bruno S, et al. Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications. J Extracell Vesicles 2019; 8(1): 1609206.
[http://dx.doi.org/10.1080/20013078.2019.1609206] [PMID: 31069028]
[5]
Cheng C, Chen X, Wang Y, et al. MSCs derived exosomes attenuate ischemia-reperfusion brain injury and inhibit microglia apoptosis might via exosomal miR-26a-5p mediated suppression of CDK6. Mol Med 2021; 27(1): 67.
[http://dx.doi.org/10.1186/s10020-021-00324-0] [PMID: 34215174]
[6]
Farzamfar S, Hasanpour A, Nazeri N, et al. Extracellular micro/nanovesicles rescue kidney from ischemia‐reperfusion injury. J Cell Physiol 2019; 234(8): 12290-300.
[http://dx.doi.org/10.1002/jcp.27998] [PMID: 30609022]
[7]
Liu J, Chen T, Lei P, Tang X, Huang P. Exosomes released by bone marrow mesenchymal stem cells attenuate lung injury induced by intestinal ischemia reperfusion via the TLR4/NF-κB pathway. Int J Med Sci 2019; 16(9): 1238-44.
[http://dx.doi.org/10.7150/ijms.35369] [PMID: 31588189]
[8]
Shen D, He Z. Mesenchymal stem cell-derived exosomes regulate the polarization and inflammatory response of macrophages via miR-21-5p to promote repair after myocardial reperfusion injury. Ann Transl Med 2021; 9(16): 1323.
[http://dx.doi.org/10.21037/atm-21-3557] [PMID: 34532460]
[9]
Chen Q, Kong L, Xu X, Geng Q, Tang W, Jiang W. Down-regulation of microRNA-146a in the early stage of liver ischemia-reperfusion injury. Transplant Proc 2013; 45(2): 492-6.
[http://dx.doi.org/10.1016/j.transproceed.2012.10.045] [PMID: 23498784]
[10]
Farid WRR, Pan Q, van der Meer AJP, et al. Hepatocyte-derived microRNAs as serum biomarkers of hepatic injury and rejection after liver transplantation. Liver Transpl 2012; 18(3): 290-7.
[http://dx.doi.org/10.1002/lt.22438] [PMID: 21932376]
[11]
Li X, Yi S, Deng Y, et al. miR-124 protects human hepatic L02 cells from H2O2-induced apoptosis by targeting Rab38 gene. Biochem Biophys Res Commun 2014; 450(1): 148-53.
[http://dx.doi.org/10.1016/j.bbrc.2014.05.085] [PMID: 24875359]
[12]
Li L, Li G, Yu C, et al. A role of microRNA-370 in hepatic ischaemia-reperfusion injury by targeting transforming growth factor-β receptor II. Liver Int 2015; 35(4): 1124-32.
[http://dx.doi.org/10.1111/liv.12441] [PMID: 24351048]
[13]
Sun J, Sun X, Chen J, et al. microRNA-27b shuttled by mesenchymal stem cell-derived exosomes prevents sepsis by targeting JMJD3 and downregulating NF-κB signaling pathway. Stem Cell Res Ther 2021; 12(1): 14.
[http://dx.doi.org/10.1186/s13287-020-02068-w] [PMID: 33397467]
[14]
Wu R, Zhao B, Ren X, et al. miR-27a-3p targeting GSK3β promotes triple-negative breast cancer proliferation and migration through Wnt/β-catenin pathway. Cancer Manag Res 2020; 12: 6241-9.
[http://dx.doi.org/10.2147/CMAR.S255419] [PMID: 32801869]
[15]
Kong LY, Xue M, Zhang QC, Su CF. In vivo and in vitro effects of microRNA-27a on proliferation, migration and invasion of breast cancer cells through targeting of SFRP1 gene via Wnt/β-catenin signaling pathway. Oncotarget 2017; 8(9): 15507-19.
[http://dx.doi.org/10.18632/oncotarget.14662] [PMID: 28099945]
[16]
Zhuang Y-S, Liao YY, Liu BY, et al. MicroRNA-27a mediates the Wnt/β-catenin pathway to affect the myocardial fibrosis in rats with chronic heart failure. Cardiovasc Ther 2018; e12468.
[PMID: 30238685]
[17]
Liu T. Human periodontal ligament stem cell-derived exosomes promote bone regeneration by altering microRNA profiles. Stem Cells Int 2020; 2020: 8852307.
[http://dx.doi.org/10.1155/2020/8852307]
[18]
Théry C, Witwer KW, Aikawa E, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 2018; 7(1): 1535750.
[http://dx.doi.org/10.1080/20013078.2018.1535750] [PMID: 30637094]
[19]
Su S, Luo D, Liu X, et al. miR-494 up-regulates the PI3K/Akt pathway via targetting PTEN and attenuates hepatic ischemia/reperfusion injury in a rat model. Biosci Rep 2017; 37(5): BSR20170798.
[http://dx.doi.org/10.1042/BSR20170798] [PMID: 28842516]
[20]
Suzuki S, Nakamura S, Koizumi T, et al. The beneficial effect of a prostaglandin I2 analog on ischemic rat liver. Transplantation 1991; 52(6): 979-83.
[http://dx.doi.org/10.1097/00007890-199112000-00008] [PMID: 1750084]
[21]
Annabi B, Lee YT, Turcotte S, et al. Hypoxia promotes murine bone-marrow-derived stromal cell migration and tube formation. Stem Cells 2003; 21(3): 337-47.
[http://dx.doi.org/10.1634/stemcells.21-3-337] [PMID: 12743328]
[22]
Xu Q, Tong JL, Zhang CP, Xiao Q, Lin XL, Xiao XY. miR-27a induced by colon cancer cells in HLECs promotes lymphangiogenesis by targeting SMAD4. PLoS One 2017; 12(10): e0186718.
[http://dx.doi.org/10.1371/journal.pone.0186718] [PMID: 29065177]
[23]
Liu Q, Song B, Xu M, An Y, Zhao Y, Yue F. miR-25 exerts cardioprotective effect in a rat model of myocardial ischemia-reperfusion injury by targeting high-mobility group box 1. J Chin Med Assoc 2020; 83(1): 25-31.
[http://dx.doi.org/10.1097/JCMA.0000000000000229] [PMID: 31809304]
[24]
Zhang J, Shi L, Zhang L, et al. MicroRNA-25 negatively regulates cerebral ischemia/reperfusion injury-induced cell apoptosis through Fas/FasL pathway. J Mol Neurosci 2016; 58(4): 507-16.
[http://dx.doi.org/10.1007/s12031-016-0712-0] [PMID: 26768135]
[25]
Kaplowitz N. Mechanisms of liver cell injury. J Hepatol 2000; 32(1): 39-47.
[http://dx.doi.org/10.1016/S0168-8278(00)80414-6] [PMID: 10728793]
[26]
Kaplowitz N. Cell death at the millennium. Implications for liver diseases. Clin Liver Dis 2000; 4(1): 1-23. v.
[http://dx.doi.org/10.1016/S1089-3261(05)70094-5] [PMID: 11232179]
[27]
Zhang S, Rao S, Yang M, Ma C, Hong F, Yang S. Role of mitochondrial pathways in cell apoptosis during He-patic ischemia/reperfusion injury. Int J Mol Sci 2022; 23(4): 2357.
[http://dx.doi.org/10.3390/ijms23042357] [PMID: 35216473]
[28]
Pankajakshan D, Agrawal DK. Mesenchymal stem cell paracrine factors in vascular repair and regeneration. J Biomed Technol Res 2014; 1(1)
[http://dx.doi.org/10.19104/jbtr.2014.107] [PMID: 28890954]
[29]
Hade MD, Suire CN, Suo Z. Mesenchymal stem cell-derived exosomes: Applications in regenerative medicine. Cells 2021; 10(8): 1959.
[http://dx.doi.org/10.3390/cells10081959] [PMID: 34440728]
[30]
Chevillet JR, Kang Q, Ruf IK, et al. Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc Natl Acad Sci 2014; 111(41): 14888-93.
[http://dx.doi.org/10.1073/pnas.1408301111] [PMID: 25267620]
[31]
Albanese M, Chen YFA, Hüls C, et al. MicroRNAs are minor constituents of extracellular vesicles that are rarely delivered to target cells. PLoS Genet 2021; 17(12): e1009951.
[http://dx.doi.org/10.1371/journal.pgen.1009951] [PMID: 34871319]
[32]
Toh WS, Lai RC, Zhang B, Lim SK. MSC exosome works through a protein-based mechanism of action. Biochem Soc Trans 2018; 46(4): 843-53.
[http://dx.doi.org/10.1042/BST20180079] [PMID: 29986939]
[33]
Li D, Zhang J, Liu Z, Gong Y, Zheng Z. Human umbilical cord mesenchymal stem cell-derived exosomal miR-27b attenuates subretinal fibrosis via suppressing epithelial–mesenchymal transition by targeting HOXC6. Stem Cell Res Ther 2021; 12(1): 24.
[http://dx.doi.org/10.1186/s13287-020-02064-0] [PMID: 33413548]
[34]
Loor G, Schumacker PT. Role of hypoxia-inducible factor in cell survival during myocardial ischemia–reperfusion. Cell Death Differ 2008; 15(4): 686-90.
[http://dx.doi.org/10.1038/cdd.2008.13] [PMID: 18259200]
[35]
Eltzschig HK, Collard CD. Vascular ischaemia and reperfusion injury. Br Med Bull 2004; 70(1): 71-86.
[http://dx.doi.org/10.1093/bmb/ldh025] [PMID: 15494470]
[36]
Huang Q, Li F, Liu X, et al. Caspase 3–mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat Med 2011; 17(7): 860-6.
[http://dx.doi.org/10.1038/nm.2385] [PMID: 21725296]
[37]
Zhao X, Yang L, Hu J. Down-regulation of miR-27a might inhibit proliferation and drug resistance of gastric cancer cells. J Exp Clin Cancer Res 2011; 30(1): 55.
[http://dx.doi.org/10.1186/1756-9966-30-55] [PMID: 21569481]
[38]
Peng H, Wang X, Zhang P, Sun T, Ren X, Xia Z. miR-27a promotes cell proliferation and metastasis in renal cell carcinoma. Int J Clin Exp Pathol 2015; 8(2): 2259-66.
[PMID: 25973137]
[39]
Moustakas A, Heldin CH. From mono- to oligo-Smads: The heart of the matter in TGF-β signal transduction. Genes Dev 2002; 16(15): 1867-71.
[http://dx.doi.org/10.1101/gad.1016802] [PMID: 12154118]
[40]
Chen L, Zhong J, Liu JH, et al. Pokemon inhibits transforming growth factor β-smad4-related cell proliferation arrest in breast cancer through specificity protein 1. J Breast Cancer 2019; 22(1): 15-28.
[http://dx.doi.org/10.4048/jbc.2019.22.e11] [PMID: 30941230]
[41]
Zhao Y, Wang L, Wang Y, et al. Astragaloside IV inhibits cell proliferation in vulvar squamous cell carcinoma through the TGF-β/Smad signaling pathway. Dermatol Ther 2019; 32(4): e12802.
[PMID: 30536730]
[42]
Du X, Li Q, Yang L, Liu L, Cao Q, Li Q. SMAD4 activates Wnt signaling pathway to inhibit granulosa cell apoptosis. Cell Death Dis 2020; 11(5): 373.
[http://dx.doi.org/10.1038/s41419-020-2578-x] [PMID: 32415058]
[43]
Moon YJ, Yun CY, Choi H, et al. Smad4 controls bone homeostasis through regulation of osteoblast/osteocyte viability. Exp Mol Med 2016; 48(9): e256-6.
[http://dx.doi.org/10.1038/emm.2016.75] [PMID: 27585718]
[44]
Freeman TJ, Smith JJ, Chen X, et al. Smad4-mediated signaling inhibits intestinal neoplasia by inhibiting expression of β-catenin. Gastroenterology 2012; 142(3): 562-571.e2.
[http://dx.doi.org/10.1053/j.gastro.2011.11.026] [PMID: 22115830]
[45]
Nayak L, Bhattacharyya NP, De RK. Wnt signal transduction pathways: Modules, development and evolution. BMC Syst Biol 2016; 10(S2): 44.
[http://dx.doi.org/10.1186/s12918-016-0299-7] [PMID: 27490822]
[46]
Lei S, Chen G, Deng L, He J. Upregulation of miR-27b facilitates apoptosis of TNF-α-stimulated fibroblast-like synoviocytes. Yonsei Med J 2019; 60(6): 585-91.
[http://dx.doi.org/10.3349/ymj.2019.60.6.585] [PMID: 31124343]
[47]
Miao W, Li N, Gu B, Yi G, Su Z, Cheng H. miR-27b-3p suppresses glioma development via targeting YAP1. Biochem Cell Biol 2020; 98(4): 466-73.
[http://dx.doi.org/10.1139/bcb-2019-0300] [PMID: 32567955]
[48]
He C, Zheng S, Luo Y, Wang B. Exosome theranostics: Biology and translational medicine. Theranostics 2018; 8(1): 237-55.
[http://dx.doi.org/10.7150/thno.21945] [PMID: 29290805]
[49]
Yu W, Li S, Guan X, et al. Higher yield and enhanced therapeutic effects of exosomes derived from MSCs in hydrogel-assisted 3D culture system for bone regeneration. Biomater Advances 2022; 133: 112646.
[http://dx.doi.org/10.1016/j.msec.2022.112646] [PMID: 35067433]

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