Download PDF
Semin Liver Dis 2022; 42(03): 283-292
DOI: 10.1055/s-0042-1755328
Review Article

Mesenchymal Stem Cell Transplantation in Liver Diseases

Frederik Nevens
1   Department of Chronic Diseases, Laboratory of Hepatology, Metabolism and Aging (CHROMETA), University of Leuven, Leuven, Belgium
2   Division of Hepatology, Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Belgium
,
Schalk van der Merwe
1   Department of Chronic Diseases, Laboratory of Hepatology, Metabolism and Aging (CHROMETA), University of Leuven, Leuven, Belgium
2   Division of Hepatology, Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Belgium
› Author Affiliations Funding This study was funded by the C1 project C14/18/087 of KU Leuven, Belgium.
› Further Information
   Permissions and Reprints


Abstract

Promising preclinical data suggested that bone marrow–derived mesenchymal stem cells (BM-MSC) can reduce hepatic fibrosis and stimulate liver regeneration. Preclinical studies moreover suggested that the immunomodulatory and anti-inflammatory functions of MSCs may reduce hepatic inflammation, improve liver function, and decrease infection incidences which are deemed especially important in the case of acute-on-chronic liver failure (ACLF). Studies in patients with decompensated cirrhosis demonstrated that injection of BM-MSC resulted in an improvement of biochemical tests and led to a survival benefit in ACLF. Most of these studies were performed in hepatitis B virus infected patients. However, two adequately powered studies performed in Europe could not confirm these data. A possible alternative to mobilize BM-MSC into the liver is the use of granulocyte colony-stimulating factor (G-CSF) which has proregenerative and immunomodulatory effects. In Indian studies, the use of G-CSF was associated with improvement of survival, although this finding could not be confirmed in European studies. Human allogeneic liver-derived progenitor cell therapy represents a potential treatment for ACLF, of which the main action is paracrine. These human liver–derived MSC can perform various functions, including the downregulation of proinflammatory responses. The clinical beneficial effect of these cells is further explored in patients with alcoholic cirrhosis and ACLF in Europe.

Keywords

liver cirrhosis - ACLF - alcoholic hepatitis - human allogeneic liver progenitor cells


Publication History

Article published online:
01 September 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Arroyo V, Moreau R, Kamath PS. et al. Acute-on-chronic liver failure in cirrhosis. Nat Rev Dis Primers 2016; 2: 16041
    CrossrefPubMedGoogle Scholar
  • 2 Allen AM, Kim WR, Moriarty JP, Shah ND, Larson JJ, Kamath PS. Time trends in the health care burden and mortality of acute on chronic liver failure in the United States. Hepatology 2016; 64 (06) 2165-2172
    CrossrefPubMedGoogle Scholar
  • 3 Meersseman P, Langouche L, du Plessis J. et al. The intensive care unit course and outcome in acute-on-chronic liver failure are comparable to other populations. J Hepatol 2018; 69 (04) 803-809
    CrossrefPubMedGoogle Scholar
  • 4 Mathurin P, Mendenhall CL, Carithers Jr. RL. et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH. J Hepatol 2002; 36 (04) 480-487
    CrossrefPubMedGoogle Scholar
  • 5 Jalan R, Gines P, Olson JC. et al. Acute-on chronic liver failure. J Hepatol 2012; 57 (06) 1336-1348
    CrossrefPubMedGoogle Scholar
  • 6 Moolman FS, Rolfes H, Van der Merwe S, Heydenrych MD. Optimization of perfluorocarbon emulsion properties for enhancing mass transfer in a bio-artificial liver support system. Biochem J 2004; 19 (03) 237-250
    PubMedGoogle Scholar
  • 7 Nieuwoudt M, Kunnike R, Smuts M. et al. Standardization criteria for an ischemic surgical model of acute hepatic failure in pigs. Biomaterials 2006; 27 (20) 3836-3845
    CrossrefPubMedGoogle Scholar
  • 8 Bousingen D. Europe supports moratorium on xenotransplantation. Lancet 1999; 353: 476
    CrossrefPubMedGoogle Scholar
  • 9 van Wenum M, Chamuleau RA, van Gulik TM, Siliakus A, Seppen J, Hoekstra R. Bioartificial livers in vitro and in vivo: tailoring biocomponents to the expanding variety of applications. Expert Opin Biol Ther 2014; 14 (12) 1745-1760
    CrossrefPubMedGoogle Scholar
  • 10 Roelandt P, Pauwelyn KA, Sancho-Bru P. et al. Human embryonic and rat adult stem cells with primitive endoderm-like phenotype can be fated to definitive endoderm, and finally hepatocyte-like cells. PLoS One 2010; 5 (08) e12101
    CrossrefPubMedGoogle Scholar
  • 11 Roelandt P, Obeid S, Paeshuyse J. et al. Human pluripotent stem cell-derived hepatocytes support complete replication of hepatitis C virus. J Hepatol 2012; 57 (02) 246-251
    CrossrefPubMedGoogle Scholar
  • 12 Demetriou AA, Brown Jr. RS, Busuttil RW. et al. Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure. Ann Surg 2004; 239 (05) 660-667 , discussion 667–670
    CrossrefPubMedGoogle Scholar
  • 13 Thompson J, Jones N, Al-Khafaji A. et al; VTI-208 Study Group. Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: a multinational, prospective, controlled, randomized trial. Liver Transpl 2018; 24 (03) 380-393
    CrossrefPubMedGoogle Scholar
  • 14 Rozga J, Williams F, Ro MS. et al. Development of a bioartificial liver: properties and function of a hollow-fiber module inoculated with liver cells. Hepatology 1993; 17 (02) 258-265
    CrossrefPubMedGoogle Scholar
  • 15 Nieuwoudt MJ, Moolman SF, Van Wyk KJ. et al. Hepatocyte function in a radial-flow bioreactor using a perfluorocarbon oxygen carrier. Artif Organs 2005; 29 (11) 915-918
    CrossrefPubMedGoogle Scholar
  • 16 Nevens F, Laleman W. Artificial liver support devices as treatment option for liver failure. Best Pract Res Clin Gastroenterol 2012; 26 (01) 17-26
    CrossrefPubMedGoogle Scholar
  • 17 Bañares R, Nevens F, Larsen FS. et al; RELIEF study group. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology 2013; 57 (03) 1153-1162
    CrossrefPubMedGoogle Scholar
  • 18 Kribben A, Gerken G, Haag S. et al; HELIOS Study Group. Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure. Gastroenterology 2012; 142 (04) 782-789
    CrossrefPubMedGoogle Scholar
  • 19 Bañares R, Ibáñez-Samaniego L, Torner JM. et al. Meta-analysis of individual patient data of albumin dialysis in acute-on-chronic liver failure: focus on treatment intensity. Therap Adv Gastroenterol 2019; 12: 1756284819879565
    CrossrefPubMedGoogle Scholar
  • 20 Larsen FS. Artificial liver support in acute and acute-on-chronic liver failure. Curr Opin Crit Care 2019; 25 (02) 187-191
    CrossrefPubMedGoogle Scholar
  • 21 Larsen FS, Schmidt LE, Bernsmeier C. et al. High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial. J Hepatol 2016; 64 (01) 69-78
    CrossrefPubMedGoogle Scholar
  • 22 Bernsmeier C, van der Merwe S, Périanin A. Innate immune cells in cirrhosis. J Hepatol 2020; 73 (01) 186-201
    CrossrefPubMedGoogle Scholar
  • 23 Albillos A, Martin-Mateos R, Van der Merwe S, Wiest R, Jalan R, Álvarez-Mon M. Cirrhosis-associated immune dysfunction. Nat Rev Gastroenterol Hepatol 2022; 19 (02) 112-134
    CrossrefPubMedGoogle Scholar
  • 24 Jiang Y, Jahagirdar BN, Reinhardt RL. et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418 (6893): 41-49
    CrossrefPubMedGoogle Scholar
  • 25 Rodríguez-Fuentes DE, Fernández-Garza LE, Samia-Meza JA, Barrera-Barrera SA, Caplan AI, Barrera-Saldaña HA. Mesenchymal stem cells current clinical applications: a systematic review. Arch Med Res 2021; 52 (01) 93-101
    CrossrefPubMedGoogle Scholar
  • 26 Di Nicola M, Carlo-Stella C, Magni M. et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99 (10) 3838-3843
    CrossrefPubMedGoogle Scholar
  • 27 Le Blanc K, Rasmusson I, Sundberg B. et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363 (9419): 1439-1441
    CrossrefPubMedGoogle Scholar
  • 28 Crop MJ, Baan CC, Korevaar SS. et al. Donor-derived mesenchymal stem cells suppress alloreactivity of kidney transplant patients. Transplantation 2009; 87 (06) 896-906
    CrossrefPubMedGoogle Scholar
  • 29 Ferrand J, Noël D, Lehours P. et al. Human bone marrow-derived stem cells acquire epithelial characteristics through fusion with gastrointestinal epithelial cells. PLoS One 2011; 6 (05) e19569
    CrossrefPubMedGoogle Scholar
  • 30 Sohni A, Verfaillie CM. Mesenchymal stem cells migration homing and tracking. Stem Cells Int 2013; 2013: 130763
    CrossrefPubMedGoogle Scholar
  • 31 Le Blanc K, Frassoni F, Ball L. et al; Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371 (9624): 1579-1586
    CrossrefPubMedGoogle Scholar
  • 32 Lagasse E, Connors H, Al-Dhalimy M. et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2000; 6 (11) 1229-1234
    CrossrefPubMedGoogle Scholar
  • 33 Sakaida I, Terai S, Yamamoto N. et al. Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology 2004; 40 (06) 1304-1311
    CrossrefPubMedGoogle Scholar
  • 34 Fausto N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 2004; 39 (06) 1477-1487
    CrossrefPubMedGoogle Scholar
  • 35 Wang D, Zhang H, Liang J. et al. Effect of allogeneic bone marrow-derived mesenchymal stem cells transplantation in a polyI:C-induced primary biliary cirrhosis mouse model. Clin Exp Med 2011; 11 (01) 25-32
    CrossrefPubMedGoogle Scholar
  • 36 King A, Houlihan DD, Kavanagh D. et al. Sphingosine-1-phosphate prevents egress of hematopoietic stem cells from liver to reduce fibrosis. Gastroenterology 2017; 153 (01) 233-248
    CrossrefPubMedGoogle Scholar
  • 37 Forbes SJ, Newsome PN. Liver regeneration - mechanisms and models to clinical application. Nat Rev Gastroenterol Hepatol 2016; 13 (08) 473-485
    CrossrefPubMedGoogle Scholar
  • 38 Theise ND, Nimmakayalu M, Gardner R. et al. Liver from bone marrow in humans. Hepatology 2000; 32 (01) 11-16
    CrossrefPubMedGoogle Scholar
  • 39 Körbling M, Katz RL, Khanna A. et al. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med 2002; 346 (10) 738-746
    CrossrefPubMedGoogle Scholar
  • 40 Houlihan DD, Newsome PN. Critical review of clinical trials of bone marrow stem cells in liver disease. Gastroenterology 2008; 135 (02) 438-450
    CrossrefPubMedGoogle Scholar
  • 41 Moore JK, Stutchfield BM, Forbes SJ. Systematic review: the effects of autologous stem cell therapy for patients with liver disease. Aliment Pharmacol Ther 2014; 39 (07) 673-685
    CrossrefPubMedGoogle Scholar
  • 42 Zhao L, Chen S, Shi X, Cao H, Li L. A pooled analysis of mesenchymal stem cell-based therapy for liver disease. Stem Cell Res Ther 2018; 9 (01) 72
    CrossrefPubMedGoogle Scholar
  • 43 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. Eur J Gastroenterol Hepatol 2010; 22 (01) 33-42
    CrossrefPubMedGoogle Scholar
  • 44 Mohamadnejad M, Alimoghaddam K, Bagheri M. et al. Randomized placebo-controlled trial of mesenchymal stem cell transplantation in decompensated cirrhosis. Liver Int 2013; 33 (10) 1490-1496
    CrossrefPubMedGoogle Scholar
  • 45 Bai YQ, Yang YX, Yang YG. et al. Outcomes of autologous bone marrow mononuclear cell transplantation in decompensated liver cirrhosis. World J Gastroenterol 2014; 20 (26) 8660-8666
    CrossrefPubMedGoogle Scholar
  • 46 Suk KT, Yoon JH, Kim MY. et al. Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial. Hepatology 2016; 64 (06) 2185-2197
    CrossrefPubMedGoogle Scholar
  • 47 Andreone P, Catani L, Margini C. et al. Reinfusion of highly purified CD133+ bone marrow-derived stem/progenitor cells in patients with end-stage liver disease: A phase I clinical trial. Dig Liver Dis 2015; 47 (12) 1059-1066
    CrossrefPubMedGoogle Scholar
  • 48 Philips CA, Augustine P. Still 'dwelling in the possibility' - critical update on stem cell therapy for acute on chronic liver failure. World J Stem Cells 2020; 12 (10) 1124-1132
    CrossrefPubMedGoogle Scholar
  • 49 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. Stem Cells Transl Med 2012; 1 (10) 725-731
    CrossrefPubMedGoogle Scholar
  • 50 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. Hepatology 2017; 66 (01) 209-219
    CrossrefPubMedGoogle Scholar
  • 51 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. Hepatology 2011; 54 (03) 820-828
    CrossrefPubMedGoogle Scholar
  • 52 Fujii K, Ishimaru F, Kozuka T. et al. Elevation of serum hepatocyte growth factor during granulocyte colony-stimulating factor-induced peripheral blood stem cell mobilization. Br J Haematol 2004; 124 (02) 190-194
    CrossrefPubMedGoogle Scholar
  • 53 Piscaglia AC, Shupe TD, Oh SH, Gasbarrini A, Petersen BE. Granulocyte-colony stimulating factor promotes liver repair and induces oval cell migration and proliferation in rats. Gastroenterology 2007; 133 (02) 619-631
    CrossrefPubMedGoogle Scholar
  • 54 Spahr L, Lambert JF, Rubbia-Brandt L. et al. Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial. Hepatology 2008; 48 (01) 221-229
    CrossrefPubMedGoogle Scholar
  • 55 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. Gastroenterology 2012; 142 (03) 505-512
    CrossrefPubMedGoogle Scholar
  • 56 Duan XZ, Liu FF, Tong JJ. et al. Granulocyte-colony stimulating factor therapy improves survival in patients with hepatitis B virus-associated acute-on-chronic liver failure. World J Gastroenterol 2013; 19 (07) 1104-1110
    CrossrefPubMedGoogle Scholar
  • 57 Singh V, Sharma AK, Narasimhan RL, Bhalla A, Sharma N, Sharma R. Granulocyte colony-stimulating factor in severe alcoholic hepatitis: a randomized pilot study. Am J Gastroenterol 2014; 109 (09) 1417-1423
    CrossrefPubMedGoogle Scholar
  • 58 Kedarisetty CK, Anand L, Bhardwaj A. et al. Combination of granulocyte colony-stimulating factor and erythropoietin improves outcomes of patients with decompensated cirrhosis. Gastroenterology 2015; 148 (07) 1362-1370
    CrossrefPubMedGoogle Scholar
  • 59 Prajapati R, Arora A, Sharma P, Bansal N, Singla V, Kumar A. Granulocyte colony-stimulating factor improves survival of patients with decompensated cirrhosis: a randomized-controlled trial. Eur J Gastroenterol Hepatol 2017; 29 (04) 448-455
    CrossrefPubMedGoogle Scholar
  • 60 Verma N, Kaur A, Sharma R. et al. Outcomes after multiple courses of granulocyte colony-stimulating factor and growth hormone in decompensated cirrhosis: a randomized trial. Hepatology 2018; 68 (04) 1559-1573
    CrossrefPubMedGoogle Scholar
  • 61 De A, Kumari S, Singh A. et al. Multiple cycles of granulocyte colony-stimulating factor increase survival times of patients with decompensated cirrhosis in a randomized trial. Clin Gastroenterol Hepatol 2021; 19 (02) 375-383
    CrossrefPubMedGoogle Scholar
  • 62 Philips CA, Augustine P, Rajesh S. et al. Granulocyte colony-stimulating factor use in decompensated cirrhosis: lack of survival benefit. J Clin Exp Hepatol 2020; 10 (02) 124-134
    CrossrefPubMedGoogle Scholar
  • 63 Donaghy A, Ross R, Wicks C. et al. Growth hormone therapy in patients with cirrhosis: a pilot study of efficacy and safety. Gastroenterology 1997; 113 (05) 1617-1622
    CrossrefPubMedGoogle Scholar
  • 64 Anand L, Bihari C, Kedarisetty CK. et al. Early cirrhosis and a preserved bone marrow niche favour regenerative response to growth factors in decompensated cirrhosis. Liver Int 2019; 39 (01) 115-126
    CrossrefPubMedGoogle Scholar
  • 65 Engelmann C, Herber A, Franke A. et al. Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: a multicenter randomized trial (GRAFT study). J Hepatol 2021; 75 (06) 1346-1354
    CrossrefPubMedGoogle Scholar
  • 66 Marot A, Singal AK, Moreno C, Deltenre P. Granulocyte colony-stimulating factor for alcoholic hepatitis: a systematic review and meta-analysis of randomised controlled trials. JHEP Rep 2020; 2 (05) 100139
    CrossrefPubMedGoogle Scholar
  • 67 Engelmann C, Martino VD, Kerbert AJC. et al. The current status of granulocyte-colony stimulating factor to treat acute-on-chronic liver failure. Semin Liver Dis 2021; 41 (03) 298-307
    Article in Thieme ConnectPubMedGoogle Scholar
  • 68 Spahr L, Chalandon Y, Terraz S. et al. Autologous bone marrow mononuclear cell transplantation in patients with decompensated alcoholic liver disease: a randomized controlled trial. PLoS One 2013; 8 (01) e53719
    CrossrefPubMedGoogle Scholar
  • 69 Newsome PN, Fox R, King AL. et al. Granulocyte colony-stimulating factor and autologous CD133-positive stem-cell therapy in liver cirrhosis (REALISTIC): an open-label, randomised, controlled phase 2 trial. Lancet Gastroenterol Hepatol 2018; 3 (01) 25-36
    CrossrefPubMedGoogle Scholar
  • 70 Thomas JA, Pope C, Wojtacha D. et al. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology 2011; 53 (06) 2003-2015
    CrossrefPubMedGoogle Scholar
  • 71 Korf H, du Plessis J, van Pelt J. et al. Inhibition of glutamine synthetase in monocytes from patients with acute-on-chronic liver failure resuscitates their antibacterial and inflammatory capacity. Gut 2019; 68 (10) 1872-1883
    CrossrefPubMedGoogle Scholar
  • 72 Van der Merwe S, Chokshi S, Bernsmeier C, Albillos A. The multifactorial mechanisms of bacterial infection in decompensated cirrhosis. J Hepatol 2021; 75 (suppl 1): S82-S100
    CrossrefPubMedGoogle Scholar
  • 73 Du Plessis J, Vanheel H, Janssen CE. et al. Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function. J Hepatol 2013; 58 (06) 1125-1132
    CrossrefPubMedGoogle Scholar
  • 74 Najimi M, Khuu DN, Lysy PA. et al. Adult-derived human liver mesenchymal-like cells as a potential progenitor reservoir of hepatocytes?. Cell Transplant 2007; 16 (07) 717-728
    CrossrefPubMedGoogle Scholar
  • 75 Sokal EM, Lombard CA, Roelants V. et al. Biodistribution of liver-derived mesenchymal stem cells after peripheral injection in a hemophilia a patient. Transplantation 2017; 101 (08) 1845-1851
    CrossrefPubMedGoogle Scholar
  • 76 Najar M, Crompot E, Raicevic G, Sokal EM, Najimi M, Lagneaux L. Cytokinome of adult-derived human liver stem/progenitor cells: immunological and inflammatory features. Hepatobiliary Surg Nutr 2018; 7 (05) 331-344
    CrossrefPubMedGoogle Scholar
  • 77 Lombard CA, Sana G, LeMaoult J. et al. Human hepatocytes and differentiated adult-derived human liver stem/progenitor cells display in vitro immunosuppressive properties mediated, at least in part, through the nonclassical HLA Class I molecule HLA-G. J Immunol Res 2019; 2019: 8250584
    CrossrefPubMedGoogle Scholar
  • 78 El-Kehdy H, Sargiacomo C, Fayyad-Kazan M. et al. Immunoprofiling of adult-derived human liver stem/progenitor cells: impact of hepatogenic differentiation and inflammation. Stem Cells Int 2017; 2017: 2679518
    CrossrefPubMedGoogle Scholar
  • 79 Najimi M, Berardis S, El-Kehdy H. et al. Human liver mesenchymal stem/progenitor cells inhibit hepatic stellate cell activation: in vitro and in vivo evaluation. Stem Cell Res Ther 2017; 8 (01) 131
    CrossrefPubMedGoogle Scholar
  • 80 Roskams TA, Libbrecht L, Desmet VJ. Progenitor cells in diseased human liver. Semin Liver Dis 2003; 23 (04) 385-396
    Article in Thieme ConnectPubMedGoogle Scholar
  • 81 Katoonizadeh A, Nevens F, Verslype C, Pirenne J, Roskams T. Liver regeneration in acute severe liver impairment: a clinicopathological correlation study. Liver Int 2006; 26 (10) 1225-1233
    CrossrefPubMedGoogle Scholar
  • 82 Sancho-Bru P, Altamirano J, Rodrigo-Torres D. et al. Liver progenitor cell markers correlate with liver damage and predict short-term mortality in patients with alcoholic hepatitis. Hepatology 2012; 55 (06) 1931-1941
    CrossrefPubMedGoogle Scholar
  • 83 Caplan AI. Mesenchymal stem cells: time to change the name!. Stem Cells Transl Med 2017; 6 (06) 1445-1451
    CrossrefPubMedGoogle Scholar
  • 84 Smets F, Dobbelaere D, McKiernan P. et al. Phase I/II trial of liver-derived mesenchymal stem cells in pediatric liver-based metabolic disorders: a prospective, open label, multicenter, partially randomized, safety study of one cycle of Heterologous Human Adult Liver-derived Progenitor Cells (HepaStem) in urea cycle disorders and Crigler-Najjar syndrome patients. Transplantation 2019; 103 (09) 1903-1915
    CrossrefPubMedGoogle Scholar
  • 85 Scheers I, Maerckx C, Khuu DN. et al. Adult-derived human liver progenitor cells in long-term culture maintain appropriate gatekeeper mechanisms against transformation. Cell Transplant 2012; 21 (10) 2241-2255
    CrossrefPubMedGoogle Scholar
  • 86 Katoonizadeh A, Laleman W, Verslype C. et al. Early features of acute-on-chronic alcoholic liver failure: a prospective cohort study. Gut 2010; 59 (11) 1561-1569
    CrossrefPubMedGoogle Scholar
  • 87 Nevens F, Gustot T, Laterre PF. et al. A phase II study of human allogeneic liver-derived progenitor cell therapy for acute-on-chronic liver failure and acute decompensation. JHEP Rep 2021; 3 (04) 100291
    CrossrefPubMedGoogle Scholar