骨髓间充质干细胞及其外泌体治疗终末期肝病的研究进展
DOI: 10.3969/j.issn.1001-5256.2022.11.041
利益冲突声明:所有作者均声明不存在利益冲突。
作者贡献声明:梁悦负责收集、分析资料,撰写论文;胡永红、刘伟、慕永平参与收集文献,修改论文;陈佳美负责拟定文章框架,指导撰写文章并修改稿件;刘平负责拟定文章思路,指导撰写文章并修改稿件,最后定稿。
Research advances in bone marrow mesenchymal stem cells and its exosomes in treatment of end-stage liver disease
-
摘要: 终末期肝病是各种急慢性肝病的晚期阶段,病死率高,严重危害人民健康。目前有效的治疗方法是肝移植,但囿于供体短缺、费用高昂等因素极大地限制了其临床应用。近年来临床与基础研究表明,骨髓间充质干细胞及其外泌体在治疗终末期肝病上具有良好的临床应用前景。本文就骨髓间充质干细胞及其外泌体在终末期肝病治疗中的作用机制与临床应用研究概况作一综述,期冀为进一步研究提供参考。Abstract: End-stage liver disease is the late stage of various acute and chronic liver diseases with high mortality and seriously threatens people's health. Liver transplantation is currently an effective treatment method for this disease, but its clinical application is greatly limited by the factors such as shortage of donors and high costs. In recent years, clinical and basic studies have shown that bone marrow mesenchymal stem cell and its exosomes have good clinical application prospects in the treatment of end-stage liver disease. This article reviews the mechanism of action and clinical application of bone marrow mesenchymal stem cell and its exosomes in the treatment of end-stage liver disease, so as to provide a reference for further research.
-
Key words:
- End-Stage Liver Disease /
- Mesenchymal Stem Cells /
- Exosomes /
- Therapeutics
-
[1] TRANAH TH, KRONSTEN VT, SHAWCROSS DL. Implications and management of cirrhosis-associated immune dysfunction before and after liver transplantation[J]. Liver Transpl, 2022, 28(4): 700-716. DOI: 10.1002/lt.26353. [2] LI G, ZHANG XA, WANG H, et al. Comparative proteomic analysis of mesenchymal stem cells derived from human bone marrow, umbilical cord, and placenta: implication in the migration[J]. Proteomics, 2009, 9(1): 20-30. DOI: 10.1002/pmic.200701195. [3] TSUCHIYA A, TAKEUCHI S, WATANABE T, et al. Mesenchymal stem cell therapies for liver cirrhosis: MSCs as "conducting cells" for improvement of liver fibrosis and regeneration[J]. Inflamm Regen, 2019, 39: 18. DOI: 10.1186/s41232-019-0107-z. [4] ZHANG YT, XIN L, LI ZS. Research advances in mesenchymal stem cells in treatment of end-stage liver disease and their application and prospect[J]. J Clin Hepatol, 2019, 35(9): 2104-2107. DOI: 10.3969/j.issn.1001-5256.2019.09.049.张熠彤, 辛磊, 李兆申. 间充质干细胞治疗终末期肝病的研究进展及应用前景[J]. 临床肝胆病杂志, 2019, 35(9): 2104-2107. DOI: 10.3969/j.issn.1001-5256.2019.09.049. [5] YANG ZE, ZHAO JK, YU HY. Research status of biological function and tumor regulation of mesenchymal stem cell derived exosomes[J]. Clin J Med Offic, 2020, 48(11): 1386-1388. DOI: 10.16680/j.1671-3826.2020.11.47.杨紫恩, 赵继凯, 于卉影. 间充质干细胞来源外泌体生物学功能及对肿瘤调控作用研究现状[J]. 临床军医杂志, 2020, 48(11): 1386-1388. DOI: 10.16680/j.1671-3826.2020.11.47. [6] PSARAKI A, NTARI L, KARAKOSTAS C, et al. Extracellular vesicles derived from mesenchymal stem/stromal cells: The regenerative impact in liver diseases[J]. Hepatology, 2022, 75(6): 1590-1603. DOI: 10.1002/hep.32129. [7] KALLURI R, LEBLEU VS. The biology, function, and biomedical applications of exosomes[J]. Science, 2020, 367(6478): eaau6977. DOI: 10.1126/science.aau6977. [8] SHAN S, ZHAO LH, MA H, et al. Definition, etiology, and epidemiology of liver cirrhosis[J]. J Clin Hepatol, 2021, 37(1): 14-16. DOI: 10.3969/j.issn.1001-5256.2021.01.003.单姗, 赵连晖, 马红, 等. 肝硬化的定义、病因及流行病学[J]. 临床肝胆病杂志, 2021, 37(1): 14-16. DOI: 10.3969/j.issn.1001-5256.2021.01.003. [9] XU L, GONG Y, WANG B, et al. Randomized trial of autologous bone marrow mesenchymal stem cells transplantation for hepatitis B virus cirrhosis: regulation of Treg/Th17 cells[J]. J Gastroenterol Hepatol, 2014, 29(8): 1620-1628. DOI: 10.1111/jgh.12653. [10] EL-ANSARY M, ABDEL-AZIZ I, MOGAWER S, et al. Phase Ⅱ trial: undifferentiated versus differentiated autologous mesenchymal stem cells transplantation in Egyptian patients with HCV induced liver cirrhosis[J]. Stem Cell Rev Rep, 2012, 8(3): 972-981. DOI: 10.1007/s12015-011-9322-y. [11] SUK KT, YOON JH, KIM MY, et al. Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial[J]. Hepatology, 2016, 64(6): 2185-2197. DOI: 10.1002/hep.28693. [12] MOHAMADNEJAD M, ALIMOGHADDAM K, BAGHERI M, et al. Randomized placebo-controlled trial of mesenchymal stem cell transplantation in decompensated cirrhosis[J]. Liver Int, 2013, 33(10): 1490-1496. DOI: 10.1111/liv.12228. [13] LIN BL, CHEN JF, QIU WH, et al. Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: A randomized controlled trial[J]. Hepatology, 2017, 66(1): 209-219. DOI: 10.1002/hep.29189. [14] SALAMA H, ZEKRI AR, MEDHAT E, et al. Peripheral vein infusion of autologous mesenchymal stem cells in Egyptian HCV-positive patients with end-stage liver disease[J]. Stem Cell Res Ther, 2014, 5(3): 70. DOI: 10.1186/scrt459. [15] AMER ME, EL-SAYED SZ, EL-KHEIR WA, et al. Clinical and laboratory evaluation of patients with end-stage liver cell failure injected with bone marrow-derived hepatocyte-like cells[J]. Eur J Gastroenterol Hepatol, 2011, 23(10): 936-941. DOI: 10.1097/MEG.0b013e3283488b00. [16] ZHANG ZH, ZHU W, REN HZ, et al. Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure[J]. Stem Cell Res Ther, 2017, 8(1): 70. DOI: 10.1186/s13287-017-0524-3. [17] DING HR, WANG JL, TANG ZT, et al. Mesenchymal stem cells improve glycometabolism and liver regeneration in the treatment of post-hepatectomy liver failure[J]. Front Physiol, 2019, 10: 412. DOI: 10.3389/fphys.2019.00412. [18] WANG M, ZHANG X, XIONG XI, et al. Bone marrow mesenchymal stem cells reverse liver damage in a carbon tetrachloride-induced mouse model of chronic liver injury[J]. In Vivo, 2016, 30(3): 187-193. [19] PUTRA A, ROSDIANA I, DARLAN DM, et al. Intravenous administration is the best route of mesenchymal stem cells migration in improving liver function enzyme of acute liver failure[J]. Folia Med (Plovdiv), 2020, 62(1): 52-58. DOI: 10.3897/folmed.e47712. [20] WEN H, YE K, QIAN B, et al. Differentiation of rat bone marrow mesenchymal stem cells into hepatocyte-like cells induced by macrophage-derived colony stimulating factor (M-CSF)[J]. Genom Appl Biol, 2020, 39(2): 763-768. DOI: 10.13417/j.gab.039.000763.文汉, 叶琨, 钱波, 等. M-CSF诱导大鼠骨髓间充质干细胞分化为肝样细胞[J]. 基因组学与应用生物学, 2020, 39(2): 763-768. DOI: 10.13417/j.gab.039.000763. [21] AHN YJ, YUN WS, CHOI JS, et al. Biodistribution of poly clustered superparamagnetic iron oxide nanoparticle labeled mesenchymal stem cells in aminoglycoside induced ototoxic mouse model[J]. Biomed Eng Lett, 2021, 11(1): 39-53. DOI: 10.1007/s13534-020-00181-6. [22] TAMURA R, UEMOTO S, TABATA Y. Immunosuppressive effect of mesenchymal stem cell-derived exosomes on a concanavalin A-induced liver injury model[J]. Inflamm Regen, 2016, 36: 26. DOI: 10.1186/s41232-016-0030-5. [23] ZHAO S, LIU Y, PU Z. Bone marrow mesenchymal stem cell-derived exosomes attenuate D-GaIN/LPS-induced hepatocyte apoptosis by activating autophagy in vitro[J]. Drug Des Devel Ther, 2019, 13: 2887-2897. DOI: 10.2147/DDDT.S220190. [24] TAN CY, LAI RC, WONG W, et al. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models[J]. Stem Cell Res Ther, 2014, 5(3): 76. DOI: 10.1186/scrt465. [25] ZHENG X, LI J, HUANG JK, et al. Experimental study of bone marrow mesenchymal stem cells transplantation for treatment of liver fibrosis in rats with carbon tetrachloride[J]. J Shihezi Uni(Nat Sci), 2019, 37(5): 636-641. DOI: 10.13880/j.cnki.65-1174/n.2019.22.005.郑雪, 李静, 黄俊凯, 等. 骨髓间充质干细胞移植治疗四氯化碳大鼠肝纤维化的实验研究[J]. 石河子大学学报(自然科学版), 2019, 37(5): 636-641. DOI: 10.13880/j.cnki.65-1174/n.2019.22.005. [26] QIAO H, ZHOU Y, QIN X, et al. NADPH oxidase signaling pathway mediates mesenchymal stem cell-induced inhibition of hepatic stellate cell activation[J]. Stem Cells Int, 2018, 2018: 1239143. DOI: 10.1155/2018/1239143. [27] JANG YO, KIM MY, CHO MY, et al. Effect of bone marrow-derived mesenchymal stem cells on hepatic fibrosis in a thioacetamide-induced cirrhotic rat model[J]. BMC Gastroenterol, 2014, 14: 198. DOI: 10.1186/s12876-014-0198-6. [28] KHALIFA YH, MOURAD GM, STEPHANOS WM, et al. Bone marrow-derived mesenchymal stem cell potential regression of dysplasia associating experimental liver fibrosis in albino rats[J]. Biomed Res Int, 2019, 2019: 5376165. DOI: 10.1155/2019/5376165. [29] RONG X, LIU J, YAO X, et al. Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway[J]. Stem Cell Res Ther, 2019, 10(1): 98. DOI: 10.1186/s13287-019-1204-2. [30] MA L, WEI J, ZENG Y, et al. Mesenchymal stem cell-originated exosomal circDIDO1 suppresses hepatic stellate cell activation by miR-141-3p/PTEN/AKT pathway in human liver fibrosis[J]. Drug Deliv, 2022, 29(1): 440-453. DOI: 10.1080/10717544.2022.2030428. [31] LUO XY, MENG XJ, CAO DC, et al. Transplantation of bone marrow mesenchymal stromal cells attenuates liver fibrosis in mice by regulating macrophage subtypes[J]. Stem Cell Res Ther, 2019, 10(1): 16. DOI: 10.1186/s13287-018-1122-8. [32] LEE KC, LIN HC, HUANG YH, et al. Allo-transplantation of mesenchymal stem cells attenuates hepatic injury through IL1Ra dependent macrophage switch in a mouse model of liver disease[J]. J Hepatol, 2015, 63(6): 1405-1412. DOI: 10.1016/j.jhep.2015.07.035. [33] SHENG M, LIN Y, XU D, et al. CD47-mediated Hedgehog/SMO/GLI1 signaling promotes mesenchymal stem cell immunomodulation in mouse liver inflammation[J]. Hepatology, 2021, 74(3): 1560-1577. DOI: 10.1002/hep.31831. [34] WANG FD, HOU RX, LI JQ, et al. Research progress of mesenchymal stem cells on immunomodulatory mechanism of T lymphocytes[J]. Chin J Immunol, 2021, 37(22): 2715-2721. https://www.cnki.com.cn/Article/CJFDTOTAL-ZMXZ202122006.htm王方迪, 侯瑞霞, 李俊琴, 等. 间充质干细胞对T细胞免疫调节机制的研究进展[J]. 中国免疫学杂志, 2021, 37(22): 2715-2721. https://www.cnki.com.cn/Article/CJFDTOTAL-ZMXZ202122006.htm [35] CHEN X, GAN Y, LI W, et al. The interaction between mesenchymal stem cells and steroids during inflammation[J]. Cell Death Dis, 2014, 5: e1009. DOI: 10.1038/cddis.2013.537. [36] WANG HY, LI C, LIU WH, et al. Autophagy inhibition via Becn1 downregulation improves the mesenchymal stem cells antifibrotic potential in experimental liver fibrosis[J]. J Cell Physiol, 2020, 235(3): 2722-2737. DOI: 10.1002/jcp.29176. [37] YAGHOUBI A, AZARPIRA N, KARBALAY-DOUST S, et al. Prednisolone and mesenchymal stem cell preloading protect liver cell migration and mitigate extracellular matrix modification in transplanted decellularized rat liver[J]. Stem Cell Res Ther, 2022, 13(1): 36. DOI: 10.1186/s13287-022-02711-8. [38] ANGIONI R, CALÌ B, VIGNESWARA V, et al. Administration of human MSC-derived extracellular vesicles for the treatment of primary sclerosing cholangitis: preclinical data in MDR2 knockout mice[J]. Int J Mol Sci, 2020, 21(22): 8874. DOI: 10.3390/ijms21228874. [39] CHEN L, LU FB, CHEN DZ, et al. BMSCs-derived miR-223-containing exosomes contribute to liver protection in experimental autoimmune hepatitis[J]. Mol Immunol, 2018, 93: 38-46. DOI: 10.1016/j.molimm.2017.11.008. [40] JUNG Y, BAUER G, NOLTA JA. Concise review: Induced pluripotent stem cell-derived mesenchymal stem cells: progress toward safe clinical products[J]. Stem Cells, 2012, 30(1): 42-47. DOI: 10.1002/stem.727. [41] LYU YH, WU SS, WEN ZX, et al. Study on mechanism of Rougan Huaxian Granules bone marrow mesenchymal stem cells homing to treat liver fibrosis in rats[J]. Chin Arch Tradit Chin Med, 2021, 39(10): 146-149, 278-279. DOI: 10.13193/j.issn.1673-7717.2021.10.035.吕艳杭, 吴姗姗, 温智稀, 等. 柔肝化纤颗粒动员骨髓间充质干细胞归巢治疗肝纤维化大鼠的机制研究[J]. 中华中医药学刊, 2021, 39(10): 146-149, 278-279. DOI: 10.13193/j.issn.1673-7717.2021.10.035. [42] LIU JK, SONG YF, LIU YZ, et al. Cordyceps polysaccharide induces differentiation of adult rat mesenchymal stem cells into a hepatocyte lineage in vitro[J]. Chin J Tissue Engineer Res, 2012, 16(49): 9221-9225. DOI: 10.3969/j.issn.2095-4344.2012.49.01.刘江凯, 宋雅芳, 刘友章, 等. 虫草多糖体外诱导大鼠骨髓间充质干细胞分化为类肝细胞样细胞[J]. 中国组织工程研究, 2012, 16(49): 9221-9225. DOI: 10.3969/j.issn.2095-4344.2012.49.018. [43] LI WH, ZHANG R, CUI XY, et al. Effect mechanism of Yiguanjian combined with bone marrow mesenchymal stem cells on liver fibrosis rats based on RhoA/ROCK1 signaling pathway[J]. World Chin Med, 2022, 17(18): 2563-2568. DOI: 10.3969/j.issn.1673-7202.2022.18.006.李汶航, 张睿, 崔欣怡, 等. 一贯煎联合骨髓间充质干细胞调控RhoA/ROCK1通路抑制大鼠肝纤维化的实验研究[J]. 世界中医药, 2022, 17(18): 2563-2568. DOI: 10.3969/j.issn.1673-7202.2022.18.006. [44] HUANG JJ, WANG XJ, GUO Y, et al. Reverse effects of Biejiajian Pills combined with bone marrow mesenchymal stem cell on liver fibrosis in rats[J]. China J Tradit Chin Med Pharma, 2021, 36(8): 4687-4690. https://www.cnki.com.cn/Article/CJFDTOTAL-BXYY202108066.htm黄晶晶, 王小娇, 郭炎, 等. 鳖甲煎丸联合骨髓间充质干细胞对大鼠肝纤维化的作用[J]. 中华中医药杂志, 2021, 36(8): 4687-4690. https://www.cnki.com.cn/Article/CJFDTOTAL-BXYY202108066.htm [45] ZHOU X, YANG J, LIU Y, et al. Observation of the effect of bone marrow mesenchymal stem cell transplantation by different interventions on cirrhotic rats[J]. Braz J Med Biol Res, 2019, 52(3): e7879. DOI: 10.1590/1414-431X20187879. [46] ZHANG X, DU G, XU Y, et al. Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes[J]. Lab Invest, 2016, 96(3): 350-360. DOI: 10.1038/labinvest.2015.149. [47] ZHANG X, XU Y, CHEN JM, et al. Huang Qi decoction prevents BDL-induced liver fibrosis through inhibition of notch signaling activation[J]. Am J Chin Med, 2017, 45(1): 85-104. DOI: 10.1142/S0192415X17500070. [48] XU W, XU YN, ZHANG X, et al. Hepatic stem cell Numb gene is a potential target of Huang Qi Decoction against cholestatic liver fibrosis[J]. Sci Rep, 2020, 10(1): 17486. DOI: 10.1038/s41598-020-74324-1. [49] BARKHOLT L, FLORY E, JEKERLE V, et al. Risk of tumorigenicity in mesenchymal stromal cell-based therapies—bridging scientific observations and regulatory viewpoints[J]. Cytotherapy, 2013, 15(7): 753-759. DOI: 10.1016/j.jcyt.2013.03.005. [50] ZHAO C, IKEYA M. Generation and applications of induced pluripotent stem cell-derived mesenchymal stem cells[J]. Stem Cells Int, 2018, 2018: 9601623. DOI: 10.1155/2018/9601623. [51] FU X, LIU G, HALIM A, et al. Mesenchymal stem cell migration and tissue repair[J]. Cells, 2019, 8(8): 784. DOI: 10.3390/cells8080784.