Mesenchymal Stem Cell Therapy for Liver Cirrhosis

Summary

MSCs have been studied for the treatment of liver diseases as well as non-liver diseases. MSCs have been successful in treating conditions like acute steroid-resistant GVHD in hematopoietic stem cell transplanted patients and also have shown to improve the MELD score in end-stage liver disease. There were no severe side effects observed in using autologous MSCs as a treatment option. The outcome of the studies done so far have been positive and it is encouraged to study the use of MSCs as cell therapy for treating liver diseases. The estimated rate of cirrhosis in HBV patients in Singapore is about 1.6% per year, rate of hepatocellular carcinoma is about 0.8% per year overall and 3.0% per year in cirrhotic patients. Knowing that there are not many options currently available for Liver Cirrhosis patients and that they have a poor prognosis with an average life expectancy of \< 12 months, this study uses autologous MSCs to treat Liver Cirrhosis patients in Singapore. The objective of the study is to demonstrate that autologous bone marrow is safe to be used in patients with liver cirrhosis as well as demonstrate that bone marrow MSC may improve liver function and prolong patient survival.

Timeline

Start

2018-08-18

Primary completion

2021-10-22

Completion

2021-10-22

Publications

• Background Poh Z, Goh BB, Chang PE, Tan CK. Rates of cirrhosis and hepatocellular carcinoma in chronic hepatitis B and the role of surveillance: a 10-year follow-up of 673 patients. Eur J Gastroenterol Hepatol. 2015 Jun;27(6):638-43. doi: 10.1097/MEG.0000000000000341.
• Background Lyra AC, Soares MB, da Silva LF, Fortes MF, Silva AG, Mota AC, Oliveira SA, Braga EL, de Carvalho WA, Genser B, dos Santos RR, Lyra LG. Feasibility and safety of autologous bone marrow mononuclear cell transplantation in patients with advanced chronic liver disease. World J Gastroenterol. 2007 Feb 21;13(7):1067-73. doi: 10.3748/wjg.v13.i7.1067.
• Background Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, Yokoyama Y, Uchida K, Yamasaki T, Fujii Y, Okita K, Sakaida I. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells. 2006 Oct;24(10):2292-8. doi: 10.1634/stemcells.2005-0542. Epub 2006 Jun 15.
• Background Peng L, Xie DY, Lin BL, Liu J, Zhu HP, Xie C, Zheng YB, Gao ZL. Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: short-term and long-term outcomes. Hepatology. 2011 Sep 2;54(3):820-8. doi: 10.1002/hep.24434. Epub 2011 Jul 14.
• Background Zhao DC, Lei JX, Chen R, Yu WH, Zhang XM, Li SN, Xiang P. Bone marrow-derived mesenchymal stem cells protect against experimental liver fibrosis in rats. World J Gastroenterol. 2005 Jun 14;11(22):3431-40. doi: 10.3748/wjg.v11.i22.3431.
• Background Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8407-11. doi: 10.1073/pnas.1432929100. Epub 2003 Jun 18.
• Background Meier RP, Muller YD, Morel P, Gonelle-Gispert C, Buhler LH. Transplantation of mesenchymal stem cells for the treatment of liver diseases, is there enough evidence? Stem Cell Res. 2013 Nov;11(3):1348-64. doi: 10.1016/j.scr.2013.08.011. Epub 2013 Aug 29.
• Background Amorin B, Alegretti AP, Valim V, Pezzi A, Laureano AM, da Silva MA, Wieck A, Silla L. Mesenchymal stem cell therapy and acute graft-versus-host disease: a review. Hum Cell. 2014 Oct;27(4):137-50. doi: 10.1007/s13577-014-0095-x. Epub 2014 Jun 6.
• Background Jacobs SA, Roobrouck VD, Verfaillie CM, Van Gool SW. Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells. Immunol Cell Biol. 2013 Jan;91(1):32-9. doi: 10.1038/icb.2012.64.
• Background Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008 Sep;8(9):726-36. doi: 10.1038/nri2395.
• Background Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002 May 15;99(10):3838-43. doi: 10.1182/blood.v99.10.3838.
• Background Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood. 2003 May 1;101(9):3722-9. doi: 10.1182/blood-2002-07-2104. Epub 2002 Dec 27.
• Background Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood. 2004 Jun 15;103(12):4619-21. doi: 10.1182/blood-2003-11-3909. Epub 2004 Mar 4.
• Background Suva D, Passweg J, Arnaudeau S, Hoffmeyer P, Kindler V. In vitro activated human T lymphocytes very efficiently attach to allogenic multipotent mesenchymal stromal cells and transmigrate under them. J Cell Physiol. 2008 Mar;214(3):588-94. doi: 10.1002/jcp.21244.
• Background Kisseleva T, Cong M, Paik Y, Scholten D, Jiang C, Benner C, Iwaisako K, Moore-Morris T, Scott B, Tsukamoto H, Evans SM, Dillmann W, Glass CK, Brenner DA. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9448-53. doi: 10.1073/pnas.1201840109. Epub 2012 May 7.
• Background Sheng H, Wang Y, Jin Y, Zhang Q, Zhang Y, Wang L, Shen B, Yin S, Liu W, Cui L, Li N. A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res. 2008 Aug;18(8):846-57. doi: 10.1038/cr.2008.80.
• Background Dmitrewski J, Olliff S, Buckels JA. Obstructive jaundice associated with polycystic liver disease. HPB Surg. 1996;10(2):117-20. doi: 10.1155/1996/83547.
• Background Manousou P, Arvaniti V, Tsochatzis E, Isgro G, Jones K, Shirling G, Dhillon AP, O'Beirne J, Patch D, Burroughs AK. Primary biliary cirrhosis after liver transplantation: influence of immunosuppression and human leukocyte antigen locus disparity. Liver Transpl. 2010 Jan;16(1):64-73. doi: 10.1002/lt.21960.
• Background Mohamadnejad M, Malekzadeh R, Nasseri-Moghaddam S, Hagh-Azali S, Rakhshani N, Tavangar SM, Sedaghat M, Alimohamadi SM. Impact of immunosuppressive treatment on liver fibrosis in autoimmune hepatitis. Dig Dis Sci. 2005 Mar;50(3):547-51. doi: 10.1007/s10620-005-2472-5.
• Background Yang ZF, Ho DW, Ngai P, Lau CK, Zhao Y, Poon RT, Fan ST. Antiinflammatory properties of IL-10 rescue small-for-size liver grafts. Liver Transpl. 2007 Apr;13(4):558-65. doi: 10.1002/lt.21094.
• Background Sgroi A, Gonelle-Gispert C, Morel P, Baertschiger RM, Niclauss N, Mentha G, Majno P, Serre-Beinier V, Buhler L. Interleukin-1 receptor antagonist modulates the early phase of liver regeneration after partial hepatectomy in mice. PLoS One. 2011;6(9):e25442. doi: 10.1371/journal.pone.0025442. Epub 2011 Sep 27.
• Background Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, Hardy W, Devine S, Ucker D, Deans R, Moseley A, Hoffman R. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002 Jan;30(1):42-8. doi: 10.1016/s0301-472x(01)00769-x.
• Background Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F, Mancardi G, Uccelli A. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood. 2005 Sep 1;106(5):1755-61. doi: 10.1182/blood-2005-04-1496. Epub 2005 May 19.
• Background Gerdoni E, Gallo B, Casazza S, Musio S, Bonanni I, Pedemonte E, Mantegazza R, Frassoni F, Mancardi G, Pedotti R, Uccelli A. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol. 2007 Mar;61(3):219-27. doi: 10.1002/ana.21076.
• Background Augello A, Tasso R, Negrini SM, Cancedda R, Pennesi G. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum. 2007 Apr;56(4):1175-86. doi: 10.1002/art.22511.
• Background Urban VS, Kiss J, Kovacs J, Gocza E, Vas V, Monostori E, Uher F. Mesenchymal stem cells cooperate with bone marrow cells in therapy of diabetes. Stem Cells. 2008 Jan;26(1):244-53. doi: 10.1634/stemcells.2007-0267. Epub 2007 Oct 11.
• Background Lee KD, Kuo TK, Whang-Peng J, Chung YF, Lin CT, Chou SH, Chen JR, Chen YP, Lee OK. In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology. 2004 Dec;40(6):1275-84. doi: 10.1002/hep.20469.
• Background Li J, Tao R, Wu W, Cao H, Xin J, Li J, Guo J, Jiang L, Gao C, Demetriou AA, Farkas DL, Li L. 3D PLGA scaffolds improve differentiation and function of bone marrow mesenchymal stem cell-derived hepatocytes. Stem Cells Dev. 2010 Sep;19(9):1427-36. doi: 10.1089/scd.2009.0415.
• Background Ong SY, Dai H, Leong KW. Inducing hepatic differentiation of human mesenchymal stem cells in pellet culture. Biomaterials. 2006 Aug;27(22):4087-97. doi: 10.1016/j.biomaterials.2006.03.022. Epub 2006 Apr 17.
• Background Sato Y, Araki H, Kato J, Nakamura K, Kawano Y, Kobune M, Sato T, Miyanishi K, Takayama T, Takahashi M, Takimoto R, Iyama S, Matsunaga T, Ohtani S, Matsuura A, Hamada H, Niitsu Y. Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. Blood. 2005 Jul 15;106(2):756-63. doi: 10.1182/blood-2005-02-0572. Epub 2005 Apr 7.
• Background Kuo TK, Hung SP, Chuang CH, Chen CT, Shih YR, Fang SC, Yang VW, Lee OK. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology. 2008 Jun;134(7):2111-21, 2121.e1-3. doi: 10.1053/j.gastro.2008.03.015. Epub 2008 Mar 12.
• Background Seo MJ, Suh SY, Bae YC, Jung JS. Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo. Biochem Biophys Res Commun. 2005 Mar 4;328(1):258-64. doi: 10.1016/j.bbrc.2004.12.158.
• Background Chamberlain J, Yamagami T, Colletti E, Theise ND, Desai J, Frias A, Pixley J, Zanjani ED, Porada CD, Almeida-Porada G. Efficient generation of human hepatocytes by the intrahepatic delivery of clonal human mesenchymal stem cells in fetal sheep. Hepatology. 2007 Dec;46(6):1935-45. doi: 10.1002/hep.21899.
• Background Natarajan A, Wagner B, Sibilia M. The EGF receptor is required for efficient liver regeneration. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17081-6. doi: 10.1073/pnas.0704126104. Epub 2007 Oct 16.
• Background Parekkadan B, van Poll D, Megeed Z, Kobayashi N, Tilles AW, Berthiaume F, Yarmush ML. Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells. Biochem Biophys Res Commun. 2007 Nov 16;363(2):247-52. doi: 10.1016/j.bbrc.2007.05.150. Epub 2007 May 30.
• Background Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K, Phinney DG. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11002-7. doi: 10.1073/pnas.0704421104. Epub 2007 Jun 14.
• Background Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden O; 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 May 10;371(9624):1579-86. doi: 10.1016/S0140-6736(08)60690-X.
• Background Deeg HJ. How I treat refractory acute GVHD. Blood. 2007 May 15;109(10):4119-26. doi: 10.1182/blood-2006-12-041889. Epub 2007 Jan 18.
• Background Tobin LM, Healy ME, English K, Mahon BP. Human mesenchymal stem cells suppress donor CD4(+) T cell proliferation and reduce pathology in a humanized mouse model of acute graft-versus-host disease. Clin Exp Immunol. 2013 May;172(2):333-48. doi: 10.1111/cei.12056.
• Background Mohamadnejad M, Namiri M, Bagheri M, Hashemi SM, Ghanaati H, Zare Mehrjardi N, Kazemi Ashtiani S, Malekzadeh R, Baharvand H. Phase 1 human trial of autologous bone marrow-hematopoietic stem cell transplantation in patients with decompensated cirrhosis. World J Gastroenterol. 2007 Jun 28;13(24):3359-63. doi: 10.3748/wjg.v13.i24.3359.
• Background Kharaziha P, Hellstrom PM, Noorinayer B, Farzaneh F, Aghajani K, Jafari F, Telkabadi M, Atashi A, Honardoost M, Zali MR, Soleimani M. Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial. Eur J Gastroenterol Hepatol. 2009 Oct;21(10):1199-205. doi: 10.1097/MEG.0b013e32832a1f6c.
• Background Amer ME, El-Sayed SZ, El-Kheir WA, Gabr H, Gomaa AA, El-Noomani N, Hegazy M. Clinical and laboratory evaluation of patients with end-stage liver cell failure injected with bone marrow-derived hepatocyte-like cells. Eur J Gastroenterol Hepatol. 2011 Oct;23(10):936-41. doi: 10.1097/MEG.0b013e3283488b00.
• Background Zhang Z, Lin H, Shi M, Xu R, Fu J, Lv J, Chen L, Lv S, Li Y, Yu S, Geng H, Jin L, Lau GK, Wang FS. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients. J Gastroenterol Hepatol. 2012 Mar;27 Suppl 2:112-20. doi: 10.1111/j.1440-1746.2011.07024.x.
• Background Gholamrezanezhad A, Mirpour S, Bagheri M, Mohamadnejad M, Alimoghaddam K, Abdolahzadeh L, Saghari M, Malekzadeh R. In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis. Nucl Med Biol. 2011 Oct;38(7):961-7. doi: 10.1016/j.nucmedbio.2011.03.008. Epub 2011 Jun 22.
• Background Baertschiger RM, Serre-Beinier V, Morel P, Bosco D, Peyrou M, Clement S, Sgroi A, Kaelin A, Buhler LH, Gonelle-Gispert C. Fibrogenic potential of human multipotent mesenchymal stromal cells in injured liver. PLoS One. 2009 Aug 17;4(8):e6657. doi: 10.1371/journal.pone.0006657.
• Background Forbes SJ, Russo FP, Rey V, Burra P, Rugge M, Wright NA, Alison MR. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology. 2004 Apr;126(4):955-63. doi: 10.1053/j.gastro.2004.02.025.
• Background Casiraghi F, Remuzzi G, Abbate M, Perico N. Multipotent mesenchymal stromal cell therapy and risk of malignancies. Stem Cell Rev Rep. 2013 Feb;9(1):65-79. doi: 10.1007/s12015-011-9345-4.
• Background Sundin M, Lindblom A, Orvell C, Barrett AJ, Sundberg B, Watz E, Wikman A, Broliden K, Le Blanc K. Persistence of human parvovirus B19 in multipotent mesenchymal stromal cells expressing the erythrocyte P antigen: implications for transplantation. Biol Blood Marrow Transplant. 2008 Oct;14(10):1172-1179. doi: 10.1016/j.bbmt.2008.08.003.
• Background Sundin M, Orvell C, Rasmusson I, Sundberg B, Ringden O, Le Blanc K. Mesenchymal stem cells are susceptible to human herpesviruses, but viral DNA cannot be detected in the healthy seropositive individual. Bone Marrow Transplant. 2006 Jun;37(11):1051-9. doi: 10.1038/sj.bmt.1705368.
• Background Zhou YF, Bosch-Marce M, Okuyama H, Krishnamachary B, Kimura H, Zhang L, Huso DL, Semenza GL. Spontaneous transformation of cultured mouse bone marrow-derived stromal cells. Cancer Res. 2006 Nov 15;66(22):10849-54. doi: 10.1158/0008-5472.CAN-06-2146.
• Background Miura M, Miura Y, Padilla-Nash HM, Molinolo AA, Fu B, Patel V, Seo BM, Sonoyama W, Zheng JJ, Baker CC, Chen W, Ried T, Shi S. Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation. Stem Cells. 2006 Apr;24(4):1095-103. doi: 10.1634/stemcells.2005-0403. Epub 2005 Nov 10.
• Background Dahl JA, Duggal S, Coulston N, Millar D, Melki J, Shahdadfar A, Brinchmann JE, Collas P. Genetic and epigenetic instability of human bone marrow mesenchymal stem cells expanded in autologous serum or fetal bovine serum. Int J Dev Biol. 2008;52(8):1033-42. doi: 10.1387/ijdb.082663jd.
• Background Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007 Oct 4;449(7162):557-63. doi: 10.1038/nature06188.
• Background Rollin R, Alvarez-Lafuente R, Marco F, Jover JA, Hernandez-Garcia C, Rodriguez-Navas C, Lopez-Duran L, Fernandez-Gutierrez B. Human parvovirus B19, varicella zoster virus, and human herpesvirus-6 in mesenchymal stem cells of patients with osteoarthritis: analysis with quantitative real-time polymerase chain reaction. Osteoarthritis Cartilage. 2007 Apr;15(4):475-8. doi: 10.1016/j.joca.2006.11.007. Epub 2007 Jan 3.
• Background Salama H, Zekri AR, Medhat E, Al Alim SA, Ahmed OS, Bahnassy AA, Lotfy MM, Ahmed R, Musa S. Peripheral vein infusion of autologous mesenchymal stem cells in Egyptian HCV-positive patients with end-stage liver disease. Stem Cell Res Ther. 2014 May 28;5(3):70. doi: 10.1186/scrt459.
• Background Neagu M, Suciu E, Ordodi V, Unescu VP. Human Mesenchymal Stem Cells As Basic Tools for Tissue Engineering : Isolation and Culture. October. 2005;15(October):29-34.

Drugs

Indications