中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 39 Issue 5
May  2023
Turn off MathJax
Article Contents

Clinical research advances in mesenchymal stem cells for the treatment of end-stage liver disease

DOI: 10.3969/j.issn.1001-5256.2023.05.003
Research funding:

National Natural Science Foundation of China (82070612);

National Natural Science Foundation of China (81901940);

National Science and Technology Major Project of China (2018ZX10302204);

National Science and Technology Major Project of China (2017ZX10203201003);

Natural Science Foundation of Guangdong Province (2021A1515010306);

Guangzhou Science and Technology Project-Key R & D Plan (2023B03J0154)

More Information
  • Corresponding author: LIN Bingliang, linbingl@mail.sysu.edu.cn. (ORCID: 0000-0003-4069-6287)
  • Received Date: 2023-03-13
  • Accepted Date: 2023-04-13
  • Published Date: 2023-05-20
  • End-stage liver disease (ESLD) includes decompensated liver cirrhosis and liver failure, which usually have dangerous conditions and a poor prognosis. Liver transplantation is the only effective therapy for ESLD, but its clinical application is limited due to shortage of liver donors, immunological rejection, and expensive costs. Mesenchymal stem cells (MSCs) can differentiate into hepatocyte-like cells and alleviate liver fibrosis by regulating immune function through paracrine, and therefore, MSCs have a wide application prospect in the field of ESLD treatment. A number of clinical studies have shown that MSC infusion is safe and effective in the treatment of ESLD during a short period of time, and there is also certain clinical evidence for its long-term safety and efficacy. MSC-derived exosomes (MSC-Exo) do not have a complete cellular structure and can promote hepatocyte regeneration through a variety of mechanisms, and their clinical value has attracted more and more attention, but there are few studies on this issue. Currently, the core mechanism of MSC therapy for ESLD and the standardized process of MSC preparation are the problems needing to be solved urgently.

     

  • loading
  • [1]
    PANDURO A, TIRIBELLI C, CHÁVEZ-TAPIA NC, et al. Renovation of Annals of Hepatology's Scientific Scope: Towards preventing rather than treating end-stage liver disease[J]. Ann Hepatol, 2018, 17(4): 539-540. DOI: 10.5604/01.3001.0012.0913.
    [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]
    RAZEGHIAN E, MARGIANA R, CHUPRADIT S, et al. Mesenchymal stem/stromal cells as a vehicle for cytokine delivery: an emerging approach for tumor immunotherapy[J]. Front Med (Lausanne), 2021, 8: 721174. DOI: 10.3389/fmed.2021.721174.
    [4]
    YAN L, HAN Y, WANG J, et al. Peripheral blood monocytes from the decompensated liver cirrhosis could migrate into nude mouse liver with human hepatocyte-markers expression[J]. Biochem Biophys Res Commun, 2008, 371(4): 635-638. DOI: 10.1016/j.bbrc.2008.04.058.
    [5]
    LI Q, ZHOU X, SHI Y, et al. In vivo tracking and comparison of the therapeutic effects of MSCs and HSCs for liver injury[J]. PLoS One, 2013, 8(4): e62363. DOI: 10.1371/journal.pone.0062363.
    [6]
    YU YB, SONG Y, CHEN Y, et al. Differentiation of umbilical cord mesenchymal stem cells into hepatocytes in comparison with bone marrow mesenchymal stem cells[J]. Mol Med Rep, 2018, 18(2): 2009-2016. DOI: 10.3892/mmr.2018.9181.
    [7]
    FANG X, LIU L, DONG J, et al. A study about immunomodulatory effect and efficacy and prognosis of human umbilical cord mesenchymal stem cells in patients with chronic hepatitis B-induced decompensated liver cirrhosis[J]. J Gastroenterol Hepatol, 2018, 33(4): 774-780. DOI: 10.1111/jgh.14081.
    [8]
    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.
    [9]
    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.
    [10]
    GLENNIE S, SOEIRO I, DYSON PJ, et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells[J]. Blood, 2005, 105(7): 2821-2827. DOI: 10.1182/blood-2004-09-3696.
    [11]
    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.
    [12]
    CORCIONE A, BENVENUTO F, FERRETTI E, et al. Human mesenchymal stem cells modulate B-cell functions[J]. Blood, 2006, 107(1): 367-372. DOI: 10.1182/blood-2005-07-2657.
    [13]
    XUAN J, FENG W, AN ZT, et al. Anti-TGFβ-1 receptor inhibitor mediates the efficacy of the human umbilical cord mesenchymal stem cells against liver fibrosis through TGFβ-1/Smad pathway[J]. Mol Cell Biochem, 2017, 429(1-2): 113-122. DOI: 10.1007/s11010-017-2940-1.
    [14]
    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.
    [15]
    CHEN X, GAN Y, LI W, et al. The interaction between mesenchymal stem cells and steroids during inflammation[J]. Cell Death Dis, 2014, 5(1): e1009. DOI: 10.1038/cddis.2013.537.
    [16]
    KIM MD, KIM SS, CHA HY, et al. Therapeutic effect of hepatocyte growth factor-secreting mesenchymal stem cells in a rat model of liver fibrosis[J]. Exp Mol Med, 2014, 46(8): e110. DOI: 10.1038/emm.2014.49.
    [17]
    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.
    [18]
    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[J]. Cell Physiol Biochem, 2017, 43(2): 611-625. DOI: 10.1159/000480533.
    [19]
    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.
    [20]
    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.
    [21]
    LIN D, CHEN H, XIONG J, et al. Mesenchymal stem cells exosomal let-7a-5p improve autophagic flux and alleviate liver injury in acute-on-chronic liver failure by promoting nuclear expression of TFEB[J]. Cell Death Dis, 2022, 13(10): 865. DOI: 10.1038/s41419-022-05303-9.
    [22]
    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.
    [23]
    SHAO M, XU Q, WU Z, et al. Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate IL-6-induced acute liver injury through miR-455-3p[J]. Stem Cell Res Ther, 2020, 11(1): 37. DOI: 10.1186/s13287-020-1550-0.
    [24]
    ZHANG S, JIANG L, HU H, et al. Pretreatment of exosomes derived from hUCMSCs with TNF-α ameliorates acute liver failure by inhibiting the activation of NLRP3 in macrophage[J]. Life Sci, 2020, 246: 117401. DOI: 10.1016/j.lfs.2020.117401.
    [25]
    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.
    [26]
    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.
    [27]
    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.
    [28]
    SALAMA H, ZEKRI AR, ZERN M, et al. Autologous hematopoietic stem cell transplantation in 48 patients with end-stage chronic liver diseases[J]. Cell Transplant, 2010, 19(11): 1475-1486. DOI: 10.3727/096368910X514314.
    [29]
    GARG V, GARG H, KHAN A, et al. Granulocyte colony-stimulating factor mobilizes CD34(+) cells and improves survival of patients with acute-on-chronic liver failure[J]. Gastroenterology, 2012, 142(3): 505-512. e1. DOI: 10.1053/j.gastro.2011.11.027.
    [30]
    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.
    [31]
    PENG L, XIE DY, LIN BL, et al. Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: short-term and long-term outcomes[J]. Hepatology, 2011, 54(3): 820-828. DOI: 10.1002/hep.24434.
    [32]
    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.
    [33]
    LI YH, XU Y, WU HM, et al. Umbilical cord-derived mesenchymal stem cell transplantation in hepatitis B virus related acute-on-chronic liver failure treated with plasma exchange and entecavir: a 24-month prospective study[J]. Stem Cell Rev Rep, 2016, 12(6): 645-653. DOI: 10.1007/s12015-016-9683-3.
    [34]
    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.
    [35]
    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.
    [36]
    GUO C, GUO G, ZHOU X, et al. Long-term outcomes of autologous peripheral blood stem cell transplantation in patients with cirrhosis[J]. Clin Gastroenterol Hepatol, 2019, 17(6): 1175-1182. e2. DOI: 10.1016/j.cgh.2018.10.034.
    [37]
    KHAN AA, PARVEEN N, MAHABOOB VS, et al. Safety and efficacy of autologous bone marrow stem cell transplantation through hepatic artery for the treatment of chronic liver failure: a preliminary study[J]. Transplant Proc, 2008, 40(4): 1140-1144. DOI: 10.1016/j.transproceed.2008.03.111.
    [38]
    NAKAMURA T, TORIMURA T, IWAMOTO H, et al. CD34(+) cell therapy is safe and effective in slowing the decline of hepatic reserve function in patients with decompensated liver cirrhosis[J]. J Gastroenterol Hepatol, 2014, 29(10): 1830-1838. DOI: 10.1111/jgh.12622.
    [39]
    CAI T, DENG Q, ZHANG S, et al. Peripheral blood stem cell transplantation improves liver functional reserve[J]. Med Sci Monit, 2015, 21: 1381-1386. DOI: 10.12659/MSM.892990.
    [40]
    LANTHIER N, LIN-MARQ N, RUBBIA-BRANDT L, et al. Autologous bone marrow-derived cell transplantation in decompensated alcoholic liver disease: what is the impact on liver histology and gene expression patterns?[J]. Stem Cell Res Ther, 2017, 8(1): 88. DOI: 10.1186/s13287-017-0541-2.
    [41]
    HAN Y, YAN L, HAN G, et al. Controlled trials in hepatitis B virus-related decompensate liver cirrhosis: peripheral blood monocyte transplant versus granulocyte-colony-stimulating factor mobilization therapy[J]. Cytotherapy, 2008, 10(4): 390-396. DOI: 10.1080/14653240802129901.
    [42]
    ZHANG Z, LIN H, SHI M, et al. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients[J]. J Gastroenterol Hepatol, 2012, 27 Suppl 2: 112-120. DOI: 10.1111/j.1440-1746.2011.07024.x.
    [43]
    SHI M, ZHANG Z, XU R, et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients[J]. Stem Cells Transl Med, 2012, 1(10): 725-731. DOI: 10.5966/sctm.2012-0034.
    [44]
    LIN H, ZHANG Z, SHI M, et al. Prospective controlled trial of safety of human umbilical cord derived-mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis[J]. Chin J Hepatol, 2012, 20(7): 487-491. DOI: 10.3760/cma.j.issn.1007-3418.2012.07.002.

    林沪, 张政, 施明, 等. 人脐带间充质干细胞治疗肝硬化腹水患者的安全性[J]. 中华肝脏病杂志, 2012, 20(7): 487-491. DOI: 10.3760/cma.j.issn.1007-3418.2012.07.002.
    [45]
    SHI M, LI YY, XU RN, et al. Mesenchymal stem cell therapy in decompensated liver cirrhosis: a long-term follow-up analysis of the randomized controlled clinical trial[J]. Hepatol Int, 2021, 15(6): 1431-1441. DOI: 10.1007/s12072-021-10199-2.
    [46]
    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.
    [47]
    JANG YO, KIM YJ, BAIK SK, et al. Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a pilot study[J]. Liver Int, 2014, 34(1): 33-41. DOI: 10.1111/liv.12218.
    [48]
    PAI M, ZACHAROULIS D, MILICEVIC MN, et al. Autologous infusion of expanded mobilized adult bone marrow-derived CD34+ cells into patients with alcoholic liver cirrhosis[J]. Am J Gastroenterol, 2008, 103(8): 1952-1958. DOI: 10.1111/j.1572-0241.2008.01993.x.
    [49]
    LIANG J, ZHANG H, ZHAO C, et al. Effects of allogeneic mesenchymal stem cell transplantation in the treatment of liver cirrhosis caused by autoimmune diseases[J]. Int J Rheum Dis, 2017, 20(9): 1219-1226. DOI: 10.1111/1756-185X.13015.
    [50]
    WANG L, LI J, LIU H, et al. Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis[J]. J Gastroenterol Hepatol, 2013, 28 Suppl 1: 85-92. DOI: 10.1111/jgh.12029.
    [51]
    MOHAMADNEJAD M, ALIMOGHADDAM K, MOHYEDDIN-BONAB M, et al. Phase 1 trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis[J]. Arch Iran Med, 2007, 10(4): 459-466.
    [52]
    LYRA AC, SOARES MB, da SILVA LF, et al. Infusion of autologous bone marrow mononuclear cells through hepatic artery results in a short-term improvement of liver function in patients with chronic liver disease: a pilot randomized controlled study[J]. Eur J Gastroenterol Hepatol, 2010, 22(1): 33-42. DOI: 10.1097/MEG.0b013e32832eb69a.
    [53]
    SHARMA M, RAO PN, SASIKALA M, et al. Autologous mobilized peripheral blood CD34(+) cell infusion in non-viral decompensated liver cirrhosis[J]. World J Gastroenterol, 2015, 21(23): 7264-7271. DOI: 10.3748/wjg.v21.i23.7264.
    [54]
    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.
    [55]
    MATSUURA K, TAKAMI T, MAEDA M, et al. Evaluation of the effects of cultured bone marrow mesenchymal stem cell infusion on hepatocarcinogenesis in hepatocarcinogenic mice with liver cirrhosis[J]. Transplant Proc, 2019, 51(3): 925-935. DOI: 10.1016/j.transproceed.2019.03.011.
    [56]
    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.
    [57]
    SAAT TC, VAN DEN ENGEL S, BIJMAN-LACHGER W, et al. Fate and effect of intravenously infused mesenchymal stem cells in a mouse model of hepatic ischemia reperfusion injury and resection[J]. Stem Cells Int, 2016, 2016: 5761487. DOI: 10.1155/2016/5761487.
    [58]
    KHAN AA, SHAIK MV, PARVEEN N, et al. Human fetal liver-derived stem cell transplantation as supportive modality in the management of end-stage decompensated liver cirrhosis[J]. Cell Transplant, 2010, 19(4): 409-418. DOI: 10.3727/096368910X498241.
    [59]
    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.
    [60]
    WANG L, ABHANGE KK, WEN Y, et al. Preparation of engineered extracellular vesicles derived from human umbilical cord mesenchymal stem cells with ultrasonication for skin rejuvenation[J]. ACS Omega, 2019, 4(27): 22638-22645. DOI: 10.1021/acsomega.9b03561.
    [61]
    YAN L, WU X. Exosomes produced from 3D cultures of umbilical cord mesenchymal stem cells in a hollow-fiber bioreactor show improved osteochondral regeneration activity[J]. Cell Biol Toxicol, 2020, 36(2): 165-178. DOI: 10.1007/s10565-019-09504-5.
    [62]
    National Health and Family Planning Commission of the People's Republic of China. Management measures for clinical research of stem cells (Trial)[EB/OL]. (2015-03-27). http://www.nhc.gov.cn/qjjys/s3582/201503/ad9098ef20ba4162bafc743133e799f6.shtml.

    中华人民共和国国家卫生和计划生育委员会. 干细胞临床研究管理办法(试行)[EB/OL]. (2015-03-27). http://www.nhc.gov.cn/qjjys/s3582/201503/ad9098ef20ba4162bafc743133e799f6.shtml.
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Article Metrics

    Article views (409) PDF downloads(126) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return