间充质干细胞移植治疗肝脏疾病的研究进展

doi:10.16352/j.issn.1001-6325.2023.01.0012

摘要/Abstract

摘要： 肝脏疾病严重危害人类健康,然而目前对于肝硬化和肝衰竭等终末期肝脏疾病的内科治疗方法疗效欠佳。间充质干细胞(MSCs)因其具有多向分化潜能和免疫调节功能,有望在临床上用于治疗各种病因所致的肝硬化、慢加急性肝衰竭、慢性肝衰竭以及肝移植后的并发症等。MSCs可通过直接分化为肝细胞样细胞,间接分泌可溶性因子以产生抗氧化、抗调节性细胞死亡、抗纤维化、抑制炎性反应、抑制免疫反应等作用,从而减轻肝脏损伤和提高生存率。完善的质量标准评价体系和更加深入的机制探索是未来MSCs用于临床治疗肝脏疾病的前提。

关键词: 肝脏疾病, 间充质干细胞, 临床治疗, 作用机制

Abstract: Liver disease is a serious threat to human health. However, there is still no effective medical treatment for end-stage liver diseases such as cirrhosis and liver failure. Mesenchymal stem cells (MSCs) are expected to be used clinically for liver cirrhosis caused by various etiologies, acute-on-chronic liver failure, chronic liver failure, and complications post-liver transplantation by their multi-directional differentiation and immunomodulatory abilities. MSCs can directly differentiate into hepatocyte-like cells and indirectly secrete soluble factors to achieve goals such as antioxidant, anti-regulated cell death, anti-fibrosis, inhibiting inflammation, inhibiting immune response, etc., so to reduce liver damage and improve survival rate. A sound quality standard evaluation system and a more in-depth mechanism exploration are the prerequisites for MSCs to be used in the clinical treatment of liver diseases in the future.

Key words: liver disease, mesenchymal stem cells, clinical treatment, mechanism

中图分类号:

R575.3

周嘉航, 陈鋆瑶, 曹红翠. 间充质干细胞移植治疗肝脏疾病的研究进展[J]. 基础医学与临床, 2023, 43(1): 12-20.

ZHOU Jiahang, CHEN Junyao, CAO Hongcui. Research progress of mesenchymal stem cells in the treatment of liver disease[J]. Basic & Clinical Medicine, 2023, 43(1): 12-20.

参考文献

[1] Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease[J]. Nat Rev Immunol, 2008, 8: 726-736.
[2] Lazarus HM, Haynesworth SE, Gerson SL, et al. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use.[J]. Bone Marrow Transplant, 1995, 16: 557-564.
[3] Arroyo V, Moreau R, Kamath PS, et al. Acute-on-chronic liver failure in cirrhosis[J]. Nat Rev Dis Prim, 2016, 2: 1-18.
[4] 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: 725-731.
[5] 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: 209-219.
[6] 中华医学会感染病学分会肝衰竭与人工肝学组,中华医学会肝病学分会重型肝病与人工肝学组. 肝衰竭诊治指南(2018 年版)[J]. 临床肝胆病杂志, 2019, 35: 38-44.
[7] 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: 820-828.
[8] 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: 1620-1628.
[9] 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: 1490-1496.
[10] 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: 112-120.
[11] 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: 774-780.
[12] 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: 1431-1441.
[13] Amer MEM, 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: 936-941.
[14] Amin MA, Sabry D, Rashed LA, et al. Short-term evaluation of autologous transplantation of bone marrow-derived mesenchymal stem cells in patients with cirrhosis: Egyptian study[J]. Clin Transplant, 2013, 27: 607-612.
[15] El-Ansary M, Abdel-Aziz I, Mogawer S, et al. Phase II trial: undifferentiated versus differentiated autologous mesen-chymal stem cells transplantation in Egyptian patients with HCV induced liver cirrhosis[J]. Stem Cell Rev Reports, 2012, 8: 972-981.
[16] Salama H, Zekri ARN, 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: 70.
[17] 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: 33-41.
[18] Saadatmand S, Vos JR, Hooning MJ, et al. Transplanta-tion with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial[J]. Hepatology, 2016, 64: 2185-2197.
[19] Wang L, Han Q, Chen H, et al. Allogeneic bone marrow mesenchymal stem cell transplantation in patients with UDCA-resistant primary biliary cirrhosis[J]. Stem Cells Dev, 2014, 23: 2482-2489.
[20] Wang L, Li J, Liu H, et al. A pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis[J]. J Gastroenterol Hepatol, 2013, 28: 85-92.
[21] 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: 1219-1226.
[22] Schacher FC, Martins Pezzi Da Silva A, Silla LMDR, et al. Bone marrow mesenchymal stem cells in acute-on-chronic liver failure grades 2 and 3: a phase I-II randomized clinical trial[J]. Can J Gastroenterol Hepatol, 2021, 2021: 3662776.
[23] Kantarciogğlu M, Demirci H, Avcu F, et al. Efficacy of autologous mesenchymal stem cell transplantation in patients with liver cirrhosis[J]. Turkish J Gastroenterol, 2015, 26: 244-250.
[24] Kharaziha P, Hellström PM, Noorinayer B, et al. Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial[J]. Eur J Gastroenterol Hepatol, 2009, 21: 1199-1205.
[25] Sakai Y, Takamura M, Seki A, et al. Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell[J]. Regen Ther, 2017, 6: 52-64.
[26] Zhang YC, Liu W, Fu BS, et al. Therapeutic potentials of umbilical cord-derived mesenchymal stromal cells for ischemic-type biliary lesions following liver transplantation[J]. Cytotherapy, 2017, 19: 194-199.
[27] Zhang Y, Zhang J, Yi H, et al. A novel MSC-based immune induction strategy for ABO-incompatible liver transplantation: a phase I/II randomized, open-label, controlled trial[J]. Stem Cell Res Ther, 2021, 12: 1-15.
[28] Shi M, Liu Z, Wang Y, et al. A pilot study of mesenchymal stem cell therapy for acute liver allograft rejection[J]. Stem Cells Transl Med, 2017, 6: 2053-2061.
[29] Casiraghi F, Perico N, Podestà MA, et al. Third-party bone marrow-derived mesenchymal stromal cell infusion before liver transplantation: a randomized controlled trial[J]. Am J Transplant, 2021, 21: 2795-2809.
[30] Detry O, Vandermeulen M, Delbouille MH, et al. Infusion of mesenchymal stromal cells after deceased liver transplantation: a phase I-II, open-label, clinical study[J]. J Hepatol, 2017, 67: 47-55.
[31] Alizadeh E, Eslaminejad MRB, Akbarzadeh A, et al. Upregulation of miR-122 via trichostatin A treatments in hepatocyte-like cells derived from mesenchymal stem cells[J]. Chem Biol Drug Des, 2016, 87: 296-305.
[32] Xu F, Liu J, Deng J, et al. Rapid and high-efficiency generation of mature functional hepatocyte-like cells from adipose-derived stem cells by a three-step protocol[J]. Stem Cell Res Ther, 2015, 6: 1-10.
[33] Zhao Q, Ren H, Li X, et al. Differentiation of human umbilical cord mesenchymal stromal cells into low immunogenic hepatocyte-like cells[J]. Cytotherapy, 2009, 11: 414-426.
[34] An SY, Han J, Lim HJ, et al. Valproic acid promotes differentiation of hepatocyte-like cells from whole human umbilical cord-derived mesenchymal stem cells[J]. Tissue Cell, 2014, 46: 127-135.
[35] Li H, Zhu L, Chen H, et al. Generation of functional hepatocytes from human adipose-derived MYC⁺ KLF4⁺ GMNN⁺ stem cells analyzed by single-cell RNA-seq profiling[J]. Stem Cells Transl Med, 2018, 7: 792-805.
[36] Li J, Yang Y, Fan J, et al. Long noncoding RNA ANCR inhibits the differentiation of mesenchymal stem cells toward definitive endoderm by facilitating the association of PTBP1 with ID2[J]. Cell Death Dis, 2019, 10: 492.
[37] Sato Y, Araki H, Kato J, et al. Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion[J]. Blood, 2005, 106: 756-763.
[38] Cao H, Yang J, Yu J, et al. Therapeutic potential of transplanted placental mesenchymal stem cells in treating Chinese miniature pigs with acute liver failure[J]. BMC Med, 2012, 10: 56.
[39] Aurich H, Sgodda M, Kaltwasser P, et al. Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo[J]. Gut, 2009, 58: 570-581.
[40] Campard D, Lysy PA, Najimi M, et al. Native umbilical cord matrix stem cells express hepatic markers and differentiate into hepatocyte-like cells[J]. Gastroenterology, 2008, 134: 833-848.
[41] Gentile P, Garcovich S, Bielli A. Human menstrual blood-derived stem cells ameliorate liver fibrosis in mice by targeting hepatic stellate cells via paracrine mediators[J]. Stem Cells Transl Med, 2017, 6: 272-284.
[42] Quintanilha LF, Takami T, Hirose Y, et al. Canine mesenchymal stem cells show antioxidant properties against thioacetamide-induced liver injury in vitro and in vivo[J]. Hepatol Res, 2014, 44: E206-E217.
[43] Cho K, Woo S, Seoh J, et al. Mesenchymal stem cells restore CCl4-induced liver injury by an antioxidative process[J]. Cell Biol Int, 2012, 36: 1267-1274.
[44] Tang D, Kang R, Berghe TV, et al. The molecular machinery of regulated cell death[J]. Cell Res, 2019, 29: 347-364.
[45] Van Poll D, Parekkadan B, Cho CH, et al. Mesenchymal stem cell-derived molecules directly modulate hepato-cellular death and regeneration in vitro and in vivo[J]. Hepatology, 2008, 47: 1634-1643.
[46] Lin F, Chen W, Zhou J, et al. Mesenchymal stem cells protect against ferroptosis via exosome-mediated stabiliza-tion of SLC7A11 in acute liver injury[J]. Cell Death Dis, 2022, 13: 271.
[47] An SY, Jang YJ, Lim HJ, et al. Milk fat globule-EGF factor 8, secreted by mesenchymal stem cells, protects against liver fibrosis in mice[J]. Gastroenterology, 2017, 152: 1174-1186.
[48] Wang S, Kim J, Lee C, et al. Tumor necrosis factor-inducible gene 6 reprograms hepatic stellate cells into stem-like cells, which ameliorates liver damage in mouse[J]. Biomaterials, 2019, 219: 119375.
[49] Wang M, Zhang M, Fu L, et al. Liver-targeted delivery of TSG-6 by calcium phosphate nanoparticles for the management of liver fibrosis[J]. Theranostics, 2020, 10: 36-49.
[50] Milosavljevic N, Gazdic M, Simovic Markovic B, et al. Mesenchymal stem cells attenuate liver fibrosis by suppressing Th17 cells-an experimental study[J]. Transpl Int, 2018, 31: 102-115.
[51] 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: 1405-1412.
[52] Li C, Jin Y, Wei S, et al. Hippo signaling controls NLR family pyrin domain containing 3 activation and governs immunoregulation of mesenchymal stem cells in mouse liver injury[J]. Hepatology, 2019, 70: 1714-1731.
[53] Wang J, Liu Y, Ding H, et al. Mesenchymal stem cell-secreted prostaglandin E2 ameliorates acute liver failure via attenuation of cell death and regulation of macrophage polarization[J]. Stem Cell Res Ther, 2021, 12: 1-13.
[54] Zhou J, Feng X, Zhu J, et al. Mesenchymal stem cell treatment restores liver macrophages homeostasis to alleviate mouse acute liver injury revealed by single-cell analysis[J]. Pharmacol Res, 2022, 179: 106229.
[55] Meisel R, Zibert A, Laryea M, et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation[J]. Blood, 2004, 103: 4619-4621.
[56] Plumas J, Chaperot L, Richard MJ, et al. Mesenchymal stem cells induce apoptosis of activated T cells[J]. Leukemia, 2005, 19: 1597-1604.
[57] Sato K, Ozaki K, Oh I, et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells[J]. Blood, 2007, 109: 228-234.
[58] Ren G, Zhang L, Zhao X, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide[J]. Cell Stem Cell, 2008, 2: 141-150.