Mesenchymal stem cell-derived hepatocytes for functional liver replacement

Frontiers in Immunology

Volumn 3, Issue JUN, 2012, Pages

  Christ, Bruno ^a,b   Stock, Peggy ^a  

^a Applied Molecular Hepatology Laboratory   (Germany)

^b Translational Centre for Regenerative Medicine   (Germany)

Author keywords

Cell transplantation; Hepatocyte; Liver; Mesenchymal stem cells

Indexed keywords

EID: 84874180965     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2012.00168     Document Type: Review

References (156)

1. Abdel Aziz, M. T., Atta, H. M., Mah- fouz, S., Fouad, H. H., Roshdy, N. K., Ahmed, H. H., Rashed, L. A., Sabry, D., Hassouna, A. A., and Hasan, N. M. (2007). Therapeutic potential of bone marrow-derived mesenchy- mal stem cells on experimental liver fibrosis. Clin. Biochem. 40, 893-899
2. Aggarwal,S.,and Pittenger,M. F. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105, 1815-1822.
3. Ailles, L. E., and Weissman, I. L. (2007). Cancer stem cells in solid tumors. Curr. Opin. Biotechnol. 18, 460-466
4. Akay, I., Oxmann, D., Helfenstein, A., Mentlein, R., Schünke, M., Has- senpflug, J., and Kurz, B. (2010). Tumor risk by tissue engineer- ing: cartilaginous differentiation of mesenchymal stem cells reduces tumor growth. Osteoarthr. Cartil. 18, 389-396.
5. Alison, M., Islam, S., and Lim, S. (2009). Stem cells in liver regener- ation, fibrosis and cancer: the good, the bad and the ugly. J. Pathol. 217, 282-298.
6. Alison, M. R., Poulsom, R., Jeffery, R., Dhillon, A. P., Quaglia, A., Jacob, J., Novelli, M., Prentice, G., Williamson, J., and Wright, N. A. (2000). Hepatocytes from non- hepatic adult stem cells. Nature 406, 257.
7. Almeida-Porada, G., and Zanjani, E. D. (2004). A large animal noninjury model for study of human stem cell plasticity. Blood Cells Mol. Dis. 32, 77-81.
8. Alvarez-Dolado, M., Pardal, R., Garcia- Verdugo, J. M., Fike, J. R., Lee, H. O., Pfeffer, K., Lois, C., Mor- rison, S. J., and Alvarez-Buylla, A. (2003). Fusion of bone-marrow- derived cells with Purkinje neu- rons, cardiomyocytes and hepato- cytes. Nature 425, 968-973.
9. Amer, M. -. E. M., El-Sayed, S. Z., El-Kheir, W. A., Gabr, H., Gomaa, A. A., El-Noomani, N., and Hegazy, M. (2011). Clinical and laboratory evaluation of patients with end- stage liver cell failure injected with bone marrow-derived hepatocyte- like cells. Eur. J. Gastroenterol. Hepa- tol. 23, 936-941.
10. Anjos-Afonso, F., Siapati, E. K., and Bonnet, D. (2004). In vivo contribu- tion of murine mesenchymal stem cells into multiple cell-types under minimal damage conditions. J. Cell. Sci. 117, 5655-5664.
11. Aurich, H., König, S., Schneider, C., Walldorf, J., Krause, P., Fleig, W. E., and Christ, B. (2005). Functional characterization of serum-free cultured rat hepatocytes for downstream transplantation applications. Cell Transplant. 14, 497-506.
12. Aurich, H., Sgodda, M., Kaltwasser, P., Vetter, M., Weise, A., Liehr, T., Brul- port, M., Hengstler, J. G., Dollinger, M. M., Fleig, W. E., and Christ, B. (2009). Hepatocyte differentia- tion of mesenchymal stem cells from human adipose tissue in vitro pro- motes hepatic integration in vivo. Gut 58, 570-581.
13. Aurich, I., Mueller, L. P., Aurich, H., Luetzkendorf, J., Tisljar, K., Dollinger, M. M., Schormann, W., Walldorf, J., Hengstler, J. G., Fleig, W. E., and Christ, B. (2007). Func- tional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers. Gut 56, 405-415.
14. Banas, A., Teratani, T., Yamamoto, Y., Tokuhara, M., Takeshita, F., Osaki, M., Kawamata, M., Kato, T., Okochi, H., Ochiya, T. (2008). IFATS series: in vivo therapeutic potential of human adipose tis- sue mesenchymal stem cells (at- mscs) after transplantation into mice with liver injury. Stem Cells 26, 2705-2712.
15. Banas, A., Teratani, T., Yamamoto, Y., Tokuhara, M., Takeshita, F., Quinn, G., Okochi, H., and Ochiya, T. (2007). Adipose tissue-derived mes- enchymal stem cells as a source of human hepatocytes. Hepatology 46, 219-228.
16. Bartholomew,A., Sturgeon, C., Siatskas, M., Ferrer, K., McIntosh, K., Patil, S., Hardy, W., Devine, S., Ucker, D., Deans, R., Moseley, A., and Hoff- man, R. (2002). Mesenchymal stem cells suppress lymphocyte prolifera- tion in vitro and prolong skin graft survival in vivo. Exp. Hematol. 30, 42-48.
17. Beyth, S., Borovsky, Z., Mevorach, D., Liebergall, M., Gazit, Z., Aslan, H., Galun, E., and Rachmilewitz, J. (2005). Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unre- sponsiveness. Blood 105, 2214-2219
18. Bilic, J., and Belmonte, J. C. I. (2012). Concise review: induced pluripotent stem cells versus embryonic stem cells: close enough or yet too far apart? Stem Cells 30, 33-41.
19. Birnbaum, T., Roider, J., Schankin, C. J., Padovan, C. S., Schichor, C., Gold- brunner, R., and A, S. (2007). Malig- nant gliomas actively recruit bone marrow stromal cells by secreting angiogenic cytokines. J. Neurooncol. 83, 241-247.
20. Boulter,L.,Govaere,O.,Bird,T. G.,Rad- ulescu, S., Ramachandran, P., Pel- licoro, A., Ridgway, R. A., Seo, S. S., Spee, B., Van Rooijen, N., San- som, O. J., Iredale, J. P., Lowell, S., Roskams, T., and Forbes, S. J. (2012). Macrophage-derived wnt opposes notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat. Med. 18, 572-579.
21. Burke, Z. D., Shen, C. N., Ralphs, K. L., and Tosh, D. (2006). Characteriza- tion of liver function in transdiffer- entiated hepatocytes. J. Cell. Physiol. 206, 147-159.
22. Camargo, F. D., Finegold, M., and Goodell, M. A. (2004). Hematopoi- etic myelomonocytic cells are the major source of hepatocyte fusion partners. J. Clin. Invest. 113, 1266-1270.
23. Casado, J. G., Gomez-Mauricio, G., Alvarez, V., Mijares, J., Tarazona, R., Bernad, A., and Sanchez- Margallo, F. M. (2012). Compar- ative phenotypic and molecular characterization of porcine mes- enchymal stem cells from different sources for translational studies in a large animal model. Vet. Immunol. Immunopathol. 147, 104-112.
24. Chabannes, D., Hill, M., Merieau, E., Rossignol, J., Brion, R., Soulillou, J. P., Anegon, I., and Cuturi, M. C. (2007). A role for heme oxygenase- 1 in the immunosuppressive effect of adult rat and human mes- enchymal stem cells. Blood 110, 3691-3694.
25. Chamberlain, J., Yamagami, T., Colletti, E., Theise, N. D., Desai, J., Frias, A., Pixley, J., Zanjani, E. D., Porada, C. D., and Almeida-Porada, G. (2007). Efficient generation of human hepa- tocytes by the intrahepatic delivery of clonal human mesenchymal stem cells in fetal sheep. Hepatology 46, 1935-1945.
26. Chan, J. L., Tang, K. C., Patel, A. P., Bonilla, L. M., Pierobon, N., Ponzio, N. M., and Rameshwar, P. (2006).Antigen-presentingproperty of mesenchymal stem cells occurs during a narrow window at low lev- els of interferon-gamma. Blood 107, 4817-4824.
27. Chen, X., McClurg, A., Zhou, G.- Q., McCaigue, M., Armstrong, M. A., and Li, G. (2007). Chon- drogenic differentiation alters the immunosuppressive property of bone marrow-derived mesenchymal stem cells, and the effect is par- tially due to the upregulated expres- sion of B7 molecules. Stem Cells 25, 364-370.
28. Christ, B. (2006). "Latest experimen- tal models in hepatocyte transplan- tation," in Artificial Liver Support, Series: Falk Symposium, Vol. 145,ed. D. Henne-Bruns, K. Buttenschön, M. Fuchs, and A. Lohse (New York: Springer), 79-90.
29. Christ, B., and Brückner, S. (2012). Rodent animal models for surro- gate analysis of cell therapy in acute liver failure. Front. Physiol. 3:78. doi:10.3389/fphys.2012.00078
30. Covas, D. T., Panepucci, R. A., Fontes, A. M., Silva, W. A. Jr, Orel- lana, M. D., Freitas, M. C., Neder, L., Santos, A. R., Peres, L. C., Jamur, M. C., Zago, M. A. (2008). Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional proper- ties and gene-expression profile with CD146 + perivascular cells and fibroblasts. Exp. Hematol. 36, 642-654.
31. Devine, S. M., Cobbs, C., Jennings, M., Bartholomew, A., and Hoff- man, R. (2003). Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood 101, 2999-3001.
32. Di Nicola, M., Carlo-Stella, C., Magni, M., Milanesi, M., Longoni, P. D., Matteucci, P., Grisanti, S., and Gianni, A. M. (2002). Human bone marrow stromal cells suppress T- lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99, 3838-3843.
33. Djouad, F., Plence, P., Bony, C., Tropel, P., Apparailly, F., Sany, J., Noel, D., and Jorgensen, C. (2003). Immuno- suppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 102, 3837-3844.
34. Espejel, S., Roll, G. R., McLaughlin, K. J., Lee, A. Y., Zhang, J. Y., Laird, D. J., Okita, K., Yamanaka, S., and Willen- bring, H. (2010). Induced pluripo- tent stem cell-derived hepatocytes have the functional and proliferative capabilities needed for liver regen- eration in mice. J. Clin. Invest. 120, 3120-3126.
35. Fausto, N. (2004). Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 39, 1477-1487.
36. Fausto, N., and Campbell, J. S. (2003). The role of hepatocytes and oval cells in liver regeneration and repopula- tion. Mech. Dev. 120, 117-130.
37. Feng, B., and Chen, L. (2009). Review of mesenchymal stem cells and tumors: executioner or coconspira- tor? Cancer Biother. Radiopharm. 24, 717-721.
38. Fox, I. J., Chowdhury, J. R., Kaufman, S. S., Goertzen, T. C., Chowdhury, N. R., Warkentin, P. I., Dorko, K., Sauter, B.V., and Strom, S. C. (1998). Treatment of the Crigler-Najjar syn- drome type I with hepatocyte trans- plantation. N. Engl. J. Med. 338, 1422-1426.
39. Fox, I. J., and Roy-Chowdhury, J. (2004a). Hepatocyte transplanta- tion. Am. J. Transplant. 4(Suppl. 6), 7-13.
40. Fox, I. J., and Roy-Chowdhury, J. (2004b). Hepatocyte transplanta- tion. J. Hepatol. 40, 878-886.
41. Galie, M., Konstantinidou, G., Peroni, D., Scambi, I., Marchini, C., Lisi, V., Krampera, M., Magnani, P., Merigo, F., Montani, M., Boschi, F., Mar- zola, P., Orrù, R., Farace, P., Sbar- bati, A., and Amici, A. (2008). Mes- enchymal stem cells share molecular signature with mesenchymal tumor cells and favor early tumor growth in syngeneic mice. Oncogene 27, 2542- 2551.
42. Ghodsizadeh, A., Taei, A., Totonchi, M., Seifinejad,A.,Gourabi,H.,Pournasr, B., Aghdami, N., Malekzadeh, R., Almadani, N., Salekdeh, G. H., and Baharvand, H. (2010). Generation of liver disease-specific induced pluripotent stem cells along with efficient differentiation to functional hepatocyte-like cells. Stem Cell Rev. 6, 622-632.
43. Gill, R. Q., and Sterling, R. K. (2001). Acute liver failure. J. Clin. Gastroen- terol. 33, 191-198.
44. Gouw, A. S. H., Clouston, A. D., and Theise, N. D. (2011). Ductular reac- tions in human liver: diversity at the interface. Hepatology 54,1853-1863
45. Grompe, M. (2003). The role of bone marrow stem cells in liver regenera- tion. Semin. Liver Dis. 23, 363-372
46. Groth, A., Ottinger, S., Kleist, C., Mohr, E., Golriz, M., Schultze, D., Bruns, H.,Mehrabi,A.,Schemmer,P.,Büch- ler, M. W., and Herr, I. (2012). Evaluation of porcine mesenchymal stem cells for therapeutic use in human liver cancer. Int. J. Oncol. 40, 391-401.
47. Gupta, S., Rajvanshi, P., Sokhi, R. P., Vaidya, S., Irani, A. N., and Gorla, G. R. (1999). Position-specific gene expression in the liver lobule is directed by the microenvironment and not by the previous cell differ- entiation state. J. Biol. Chem. 274, 2157-2165.
48. Hanna, J. H., Saha, K., and Jaenisch, R. (2010). Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell 143,508-525
49. Hematti, P. (2008). Role of mes- enchymal stromal cells in solid organ transplantation. Transplant. Rev. (Orlando) 22, 262-273.
50. Hong,S. H.,Gang,E. J.,Jeong,J.A.,Ahn, C., Hwang, S. H., Yang, I. H., Park, H. K., Han, H., and Kim, H. (2005). In vitro differentiation of human umbilical cord blood-derived mes- enchymal stem cells into hepatocyte- like cells. Biochem. Biophys. Res. Commun. 330, 1153-1161.
51. Horb, M. E., Shen, C.-N., Tosh, D., and Slack, J. M. W. (2003). Experimental conversion of liver to pancreas. Curr. Biol. 13, 105-115.
52. Hughes,R. D.,Mitry,R. R.,and Dhawan, A. (2012). Current status of hepa- tocyte transplantation. Transplanta- tion 93, 342-347.
53. Huss, R., Heil, M., Moosmann, S., Ziegelhoeffer, T., Sagebiel, S., Seliger, C., Kinston, S., and Gottgens, B. (2004). Improved arteriogenesis with simultaneous skeletal muscle repair in ischemic tissue by SCL+ multipotent adult progenitor cell clonesfrom peripheralblood. J.Vasc. Res. 41, 422-431.
54. Ishikawa, F., Drake, C. J., Yang, S., Flem- ing, P., Minamiguchi, H., Visconti, R. P., Crosby, C. V., Argraves, W. S., Harada, M., Key, L. L. Jr., Livingston,A. G., Wingard, J. R., and Ogawa, M. (2003). Transplanted human cord blood cells give rise to hepatocytes in engrafted mice. Ann. N. Y. Acad. Sci. 996, 174-185.
55. Ishikawa, H., Nakao, K., Matsumoto, K., Nishimura, D., Ichikawa, T., Hamasaki,K.,and Eguchi,K. (2004). Bone marrow engraftment in a rodent model of chemical carcino- genesis but no role in the histogene- sis of hepatocellular carcinoma. Gut 53, 884-889.
56. Jang, Y. Y., Collector, M. I., Baylin, S. B., Diehl, A. M., and Sharkis, S. J. (2004). Hematopoietic stem cells convert into liver cells within days without fusion. Nat. Cell. Biol. 6, 532-539.
57. Jiang, X. X., Zhang, Y., Liu, B., Zhang, S. X., Wu, Y., Yu, X. D., and Mao, N. (2005). Human mesenchy- mal stem cells inhibit differenti- ation and function of monocyte- derived dendritic cells. Blood 105, 4120-4126.
58. Jiang, Y., Jahagirdar, B. N., Reinhardt, R. L., Schwartz, R. E., Keene, C. D., Ortiz-Gonzalez, X. R., Reyes, M., Lenvik, T., Lund, T., Blackstad, M., Du, J., Aldrich, S., Lisberg, A., Low, W. C., Largaespada, D. A., and Ver- faillie, C. M. (2002). Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41-49.
59. Kharaziha, P., Hellström, P. M., Noori- nayer, B., Farzaneh, F., Agha- jani, K., Jafari, F., Telkabadi, M., Atashi, A., Honardoost, M., Zali, M. R., and Soleimani, M. (2009). Improvement of liver function in liver cirrhosis patients after autolo- gous mesenchymal stem cell injec- tion: a phase I-II clinical trial. Eur. J. Gastroenterol. Hepatol. 21, 1199-1205.
60. Kinnaird, T., Stabile, E., Burnett, M. S., Lee,C. W.,Barr,S.,Fuchs,S.,Epstein, S. E. (2004). Marrow-derived stro- mal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ. Res. 94, 678-685.
61. Klyushnenkova, E., Mosca, J. D., Zer- netkina, V., Majumdar, M. K., Beggs, K. J., Simonetti, D. W., Deans, R. J., and McIntosh, K. R. (2005). T cell responses to allogeneic human mesenchymal stem cells: immuno- genicity, tolerance, and suppression. J. Biomed. Sci. 12, 47-57.
62. Kode, J. A., Mukherjee, S., Joglekar, M. V., and Hardikar, A. A. (2009). Mes- enchymal stem cells: immunobiol- ogy and role in immunomodulation and tissue regeneration. Cytotherapy 11, 377-391.
63. Koenig, S., Aurich, H., Schneider, C., Krause, P., Haftendorn, R., Becker, H., and Christ, B. (2007). Zonal expression of hepatocytic marker enzymes during liver repopulation. Histochem. Cell Biol. 128, 105-114.
64. Kofman, A. V., Morgan, G., Kirschen- baum, A., Osbeck, J., Hussain, M., Swenson, S., and Theise, N. D. (2005). Dose- and time-dependent oval cell reaction in acetaminophen- induced murine liver injury. Hepa- tology 41, 1252-1261.
65. Koniaris, L. G., McKillop, I. H., Schwartz, S. I., and Zimmers, T. A. (2003). Liver regeneration. J. Am. Coll. Surg. 197, 634-659.
66. Krampera, M., Cosmi, L., Angeli, R., Pasini, A., Liotta, F., Andreini, A., Santarlasci, V., Mazzinghi, B., Pizzolo, G., Vinante, F., Romag- nani, P., Maggi, E., Romagnani, S., and Annunziato, F. (2006). Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchy- mal stem cells. Stem Cells 24, 386-398.
67. Krampera, M., Sartoris, S., Liotta, F., Pasini, A., Angeli, R., Cosmi, L., Andreini, A., Mosna, F., Bonetti, B., Rebellato, E., Testi, M. G., Frosali, F., Pizzolo, G., Tridente, G., Maggi, E., Romagnani, S., and Annunziato, F. (2007). Immune regulation by mes- enchymal stem cells derived from adult spleen and thymus. Stem Cells Dev. 16, 797-810.
68. Kubota, K., Soeda, J., Misawa, R., Mihara, M., Miwa, S., Ise, H., Taka- hashi, M., and Miyagawa, S. (2008). Bone marrow-derived cells fuse with hepatic oval cells but are not involved in hepatic tumorigenesis in the choline-deficient ethionine- supplemented diet rat model. Car- cinogenesis 29, 448-454.
69. Kusano, M., and Mito, M. (1982). Observations on the fine structure of long-survived isolated hepatocytes inoculated into rat spleen. Gastroen- terology 82, 616-628.
70. Lagasse, E., Connors, H., Al-Dhalimy, M., Reitsma, M., Dohse, M., Osborne, L., Wang, X., Finegold, M., Weissman, I. L., and Grompe, M. (2000). Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat. Med. 6, 1229-1234.
71. Lange, C., Bassler, P., Lioznov, M. V., Bruns, H., Kluth, D., Zander, A. R., and Fiegel, H. C. (2005). Hepato- cytic gene expression in cultured rat mesenchymal stem cells. Transplant. Proc. 37, 276-279.
72. Le Blanc, K., and Ringden, O. (2005). Immunobiology of human mes- enchymal stem cells and future use in hematopoietic stem cell transplanta- tion. Biol. Blood Marrow Transplant. 11, 321-334.
73. Le Blanc, K., Tammik, C., Rosendahl, K., Zetterberg, E., and Ringdén, O. (2003). HLA expression and immunologic properties of differ- entiated and undifferentiated mes- enchymal stem cells. Exp. Hematol. 31, 890-896.
74. Lee, K. D., Kuo, T. K., Whang-Peng, J., Chung, Y. F., Lin, C. T., Chou, S. H., Chen, J. R., Chen, Y. P., and Lee, O. K. (2004a). In vitro hepatic differen- tiation of human mesenchymal stem cells. Hepatology 40, 1275-1284.
75. Lee, S.-W., Wang, X., Chowdhury, N. R., and Chowdhury, J. R. (2004b). Hepatocyte transplantation: state of the art and strategies for overcom- ing existing hurdles. Ann. Hepatol. 3, 48-53.
76. Li, J., Zhang, L., Xin, J., Jiang, L., Li, J., Zhang, T., Jin, L., Li, J., Zhou, P., Hao, S., Cao, H., and Li, L. (2012). Imme- diate intraportal transplantation of human bone marrow mesenchy- mal stem cells prevents death from fulminant hepatic failure in pigs. Hepatology. doi: 10.1002/hep.25722. [Epub ahead of print].
77. Lysy, P. A., Campard, D., Smets, F., Malaise, J., Mourad, M., Najimi, M., and Sokal, E. M. (2008). Per- sistence of a chimerical phenotype after hepatocyte differentiation of human bone marrow mesenchymal stem cells. Cell Prolif. 41, 36-58.
78. Mao, F., Xu, W. R., Qian, H., Zhu, W., Yan, Y. M., Shao, Q. X., and HX, X. (2010). Immunosuppressive effects of mesenchymal stem cells in collagen-induced mouse arthritis. Inflamm. Res. 59, 219-225.
79. Martínez-Climent, J. A., Andreu, E. J., and Prosper, F. (2006). Somatic stem cells and the origin of cancer. Clin. Transl. Oncol. 8, 647-663.
80. Meisel, R., Zibert, A., Laryea, M., Gobel, U., Daubener, W., and Dil- loo, D. (2004). Human bone mar- row stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3- dioxygenase-mediated tryptophan degradation. Blood 103, 4619-4621.
81. Michalopoulos, G. K. (2007). Liver regeneration. J. Cell. Physiol. 213, 286-300.
82. Michalopoulos, G. K. (2010). Liver regeneration after partial hepatec- tomy: critical analysis of mechanistic dilemmas. Am. J. Pathol. 176, 2-13
83. Michalopoulos, G. K., Barua, L., and Bowen, W. C. (2005). Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury. Hepatology 41, 535-544.
84. Mishra, P. J., Mishra, P. J., Glod, J. W., and Banerjee, D. (2009). Mesenchy- mal stem cells: flip side of the coin. Cancer Res. 69, 1255-1258.
85. Munn, D. H., Zhou, M., Attwood, J. T., Bondarev, I., Conway, S. J., Mar- shall, B., Brown, C., and Mellor, A. L. (1998). Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191-1193.
86. Muraca, M. (2011). Evolving concepts in cell therapy of liver disease and current clinical perspectives. Dig. Liver. Dis. 43, 180-187.
87. Muraca, M., Gerunda, G., Neri, D.,Vilei, M. T., Granato, A., Feltracco, P., Meroni, M., Giron, G., and Burlina, A. B. (2002). Hepatocyte transplan- tation as a treatment for glycogen storage disease type 1a. Lancet 359, 317-318.
88. Najimi, M., Khuu, D. N., Lysy, P. A., Jazouli, N., Abarca, J., Sempoux, C., and Sokal, E. M. (2007). Adult- derived human liver mesenchymal- like cells as a potential progenitor reservoir of hepatocytes? Cell Trans- plant. 16, 717-728.
89. Nasef, A., Mathieu, N., Chapel, A., Frick, J., François, S., Mazurier, C., Boutarfa, A., Bouchet, S., Gorin, N. C., Thierry, D., and Fouillard, L. (2007). Immunosuppressive effects of mesenchymal stem cells: involve- ment of HLA-G. Transplantation 84, 231-237.
90. Nauta, A. J., and Fibbe, W. E. (2007). Immunomodulatory properties of mesenchymal stromal cells. Blood 110, 3499-3506.
91. Nauta, A. J., Kruisselbrink, A. B., Lurvink, E., Willemze, R., and Fibbe, W. E. (2006). Mesenchymal stem cells inhibit generation and func- tion of both CD34+-derived and monocyte-derived dendritic cells. J. Immunol. 177, 2080-2087.
92. Nejak-Bowen, K. N., and Monga, S. P. S. (2011). Beta-catenin signaling, liver regeneration and hepatocellu- lar cancer: Sorting the good from the bad. Semin. Cancer Biol. 21, 44-58.
93. Newman, R. E., Yoo, D., LeRoux, M. A., and Danilkovitch-Miagkova, A. (2009). Treatment of inflammatory diseases with mesenchymal stem cells. Inflamm. Allergy Drug Targets 8, 110-123.
94. Newsome, P. N., Johannessen, I., Boyle, S., Dalakas, E., McAulay, K. A., Samuel, K., Rae, F., Forrester, L., Turner, M. L., Hayes, P. C., Har- rison, D. J., Bickmore, W. A., and Plevris, J. N. (2003). Human cord blood-derived cells can differentiate into hepatocytes in the mouse liver with no evidence of cellular fusion. Gastroenterology 124, 1891-1900.
95. Noel, D., Djouad, F., Bouffi, C., Mru- gala, D., and Jorgensen, C. (2007). Multipotent mesenchymal stromal cells and immune tolerance. Leuk. Lymphoma 48, 1283-1289.
96. Oertel, M., and Shafritz, D. A. (2008). Stem cells, cell transplantation and liver repopulation. Biochim. Biophys. Acta 1782, 61-74.
97. Okita, K., and Yamanaka, S. (2011). Induced pluripotent stem cells: opportunities and challenges. Philos. Trans. R. Soc. Lond. B Biol. Sci. 366, 2198-2207.
98. Ostapowicz, G., and Lee, W. M. (2000). Acute hepatic failure: a western per- spective. J. Gastroenterol. Hepatol. 15, 480-488.
99. Oyagi, S., Hirose, M., Kojima, M., Okuyama, M., Kawase, M., Naka- mura, T., Ohgushi, H., and Yagi, K. (2006). Therapeutic effect of trans- planting HGF-treated bone mar- row mesenchymal cells into CCl4- injured rats. J. Hepatol. 44, 742-748
100. O'Grady,J. G. (2005).Acute liver failure. Postgrad. Med. J. 81, 148-154.
101. Pan, Q., Fouraschen, S. M. G., Kaya, F. S. F. A., Verstegen, M. M., Pesca- tori, M., Stubbs,A. P., van IJcken,W., van der Sloot, A., Smits, R., Kwekke- boom, J., Metselaar, H. J., Kazemier, G.,de Jonge,J.,Tilanus,H.W.,Wage- maker, G., Janssen, H. L., and van der Laan, L. J. (2011). Mobiliza- tion of hepatic mesenchymal stem cells from human liver grafts. Liver Transpl. 17, 596-609.
102. Parekkadan, B., Van Poll, D., Suganuma, K., Carter, E. A., Berthiaume, F., Tilles, A. W., and Yarmush, M. L. (2007). Mesenchymal stem cell- derived molecules reverse fulminant hepatic failure. PLoS ONE. 2, e941. doi:10.1371/journal.pone.0000941
103. Pereira,R. F.,Halford,K. W.,O'Hara,M. D., Leeper, D. B., Sokolov, B. P., Pol- lard,M. D.,Bagasra,O.,and Prockop, D. J. (1995). Cultured adherent cells from marrow can serve as long- lasting precursor cells for bone, car- tilage, and lung in irradiated mice. Proc. Natl. Acad. Sci. U.S.A. 92, 4857-4861.
104. Petersen, B. E., Bowen, W. C., Patrene, K. D., Mars, W. M., Sullivan, A. K., Murase, N., Boggs, S. S., Green- berger, J. S., and Goff, J. P. (1999). Bone marrow as a potential source of hepatic oval cells. Science 284, 1168-1170.
105. Pittenger, M. F., Mackay, A. M., Beck, S. C.,Jaiswal,R. K.,Douglas,R.,Mosca, J. D., Moorman, M. A., Simonetti, D. W., Craig, S., and Marshak, D. R. (1999). Multilineage potential of adult human mesenchymal stem cells. Science 284, 143-147.
106. Polyak, K., and Hahn, W. C. (2006). Roots and stems: stem cells in cancer. Nat. Med. 12, 296-300.
107. Puppi, J., Strom, S. C., Hughes, R. D., Bansal, S., Castell, J. V., Dagher, I., Ellis, E. C., Nowak, G., Ericzon, B. G., Fox, I. J., Gómez-Lechón, M. J., Guha, C., Gupta, S., Mitry, R. R., Ohashi, K., Ott, M., Reid, L. M., Roy- Chowdhury, J., Sokal, E., Weber, A., and Dhawan, A. (2011). Improving the techniques for human hepato- cyte transplantation: report from a consensus meeting in London. Cell Transplant. 21, 1-10.
108. Rahman, T., and Hodgson, H. (2001). Clinical management of acute hepatic failure. Intensive Care Med. 27, 467-476.
109. Rajvanshi, P., Fabrega, A., Bhargava, K. K., Kerr, A., Pollak, R., Blan- chard, J., Palestro, C. J., and Gupta, S. (1999). Rapid clearance of transplanted hepatocytes from pulmonary capillaries in rats indi- cates a wide safety margin of liver repopulation and the potential of using surrogate albumin particles for safety analysis. J. Hepatol. 30, 299-310.
110. Ramasamy, R., Fazekasova, H., Lam, E. W., Soeiro, I., Lombardi, G., and Dazzi, F. (2007). Mesenchymal stem cells inhibit dendritic cell differen- tiation and function by preventing entry into the cell cycle. Transplan- tation 83, 71-76.
111. Renner, P., Eggenhofer, E., Rose- nauer, A., Popp, F. C., Stein- mann, J. F., Slowik, P., Geissler, E. K., Piso, P., Schlitt, H. J., and Dahlke, M. H. (2009). Mesenchy- mal stem cells require a suffi- cient, ongoing immune response to exert their immunosuppres- sive function. Transplant. Proc. 41, 2607-2611.
112. Riehle, K. J., Dan, Y. Y., Campbell, J. S., and Fausto, N. (2011). New con- cepts in liver regeneration. J. Gas- troenterol. Hepatol. 26, 203-212.
113. Roskams, T., Katoonizadeh, A., and Komuta,M. (2010). Hepatic progen- itor cells: an update. Clin. Liver. Dis. 14, 705-718.
114. Roskams, T. A., Theise, N. D., Balabaud, C.,Bhagat,G.,Bhathal,P. S.,Bioulac- Sage, P., Brunt, E. M., Crawford, J. M., Crosby, H. A., Desmet, V., Fine- gold, M. J., Geller, S. A., Gouw, A. S., Hytiroglou, P., Knisely, A. S., Kojiro, M., Lefkowitch, J. H., Nakanuma, Y., Olynyk, J. K., Park, Y. N., Portmann, B., Saxena, R., Scheuer, P. J., Strain,A. J., Thung, S. N.,Wanless, I. R., and West, A. B. (2004). Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reac- tions in human livers. Hepatology 39, 1739-1745.
115. Rountree, C. B., Mishra, L., and Willen- bring, H. (2012). Stem cells in liver diseases and cancer: recent advances on the path to new therapies. Hepa- tology 55, 298-306.
116. Ryan, J. M., Barry, F., Murphy, J. M., and Mahon, B. P. (2007). Interferon-gamma does not break, but promotes the immunosuppres- sive capacity of adult human mes- enchymal stem cells. Clin. Exp. Immunol. 149, 353-363.
117. Santoni-Rugiu, E., Jelnes, P., Thorgeirs- son, S. S., and Bisgaard, H. C. (2005). Progenitor cells in liver regeneration: molecular responses controlling their activa- tion and expansion. APMIS 113, 876-902.
118. Sato, Y., Araki, H., Kato, J., Naka- mura, K., Kawano, Y., Kobune, M., Sato, T., Miyanishi, K., Takayama, T., Takahashi, M., Takimoto, R., Iyama, S., Matsunaga, T., Ohtani, S., Mat- suura, A., Hamada, H., and Niitsu,Y. (2005). Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepa- tocytes without fusion. Blood 106, 756-763.
119. Schneider, A., Attaran, M., Gratz, K. F., Bleck, J. S., Winkler, M., Manns, M. P., and Ott, M. (2003). Intraportal infusion of 99mtechnetium-macro- aggregrated albumin particles and hepatocytes in rabbits: assessment of shunting and portal hemody- namic changes. Transplantation 75, 296-302.
120. Schwartz, R. E., Reyes, M., Koodie, L., Jiang, Y., Blackstad, M., Lund, T., Lenvik, T., Johnson, S., Hu, W. S., and Verfaillie, C. M. (2002). Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte- like cells. J. Clin. Invest. 109, 1291-1302.
121. Sell, S. (2001). Heterogeneity and plas- ticity of hepatocyte lineage cells. Hepatology 33, 738-750.
122. Seo, M. J., Suh, S. Y., Bae, Y. C., and Jung, J. S. (2005). Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo. Biochem. Biophys. Res. Commun. 328, 258-264.
123. Sgodda, M., Aurich, H., Kleist, S., Aurich, I., Konig, S., Dollinger, M. M., Fleig, W. E., and Christ, B. (2007). Hepatocyte differentiation of mesenchymal stem cells from rat peritoneal adipose tissue in vitro and in vivo. Exp. Cell. Res. 313, 2875-2886.
124. Shafritz, D. A., and Oertel, M. (2011). Model systems and experimental conditions that lead to effective repopulation of the liver by trans- planted cells. Int. J. Biochem. Cell. Biol. 43, 198-213.
125. Shi, X. L., Gu, J. Y., Han, B., Xu, H. Y., Fang, L., and Ding, Y. T. (2010). Magnetically labeled mes- enchymal stem cells after autologous transplantation into acutely injured liver. World J. Gastroenterol. 16, 3674-3679.
126. Siegel, G., Schäfer, R., and Dazzi, F. (2009). The immunosuppressive properties of mesenchymal stem cells. Transplantation 87, S45-S49.
127. Sotiropoulou, P. A., Perez, S. A., Gritza- pis, A. D., Baxevanis, C. N., and Papamichail,M. (2006). Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 24, 74-85.
128. Spaggiari, G. M., Capobianco, A., Bec- chetti, S., Mingari, M. C., and Moretta, L. (2006). Mesenchymal stem cell-natural killer cell interac- tions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2- induced NK-cell proliferation. Blood 107, 1484-1490.
129. Spee, B., Carpino, G., Schotanus, B. A., Katoonizadeh, A., Borght, S. V., Gaudio, E., and Roskams, T. (2010). Characterisation of the liver progen- itor cell niche in liver diseases:poten- tial involvement of wnt and notch signalling. Gut 59, 247-257.
130. Stagg, J., and Galipeau, J. (2007). Immune plasticity of bone marrow- derived mesenchymal stromal cells. Handb. Exp. Pharmacol. 180, 45-66
131. Steiner, J. W., Perz, Z. M., and Taich- man, L. B. (1966). Cell popu- lation dynamics in the liver: a review of quantitative morpho- logical techniques applied to the study of physiological and patho- logical growth. Exp. Mol. Pathol. 5, 146-181.
132. Studeny, M., Marini, F. C., Dembin- ski, J. L., Zompetta, C., Cabreira- Hansen, M., Bekele, B. N., Cham- plin, R. E., and Andreeff, M. (2004). Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anti- cancer agents. J. Natl. Cancer Inst. 96, 1593-1603.
133. Stutchfield, B. M., Forbes, S. J., and Wig- more, S. J. (2010). Prospects for stem cell transplantation in the treatment of hepatic disease. Liver Transpl. 16, 827-836.
134. Takahashi, K., and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined fac- tors. Cell 126, 663-676.
135. Takayama, K., Inamura, M., Kawa- bata, K., Katayama, K., Higuchi, M., Tashiro, K., Nonaka, A., Sakurai, F., Hayakawa, T., Furue, M. K., and Mizuguchi, H. (2012). Efficient gen- eration of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4[alpha] transduction. Mol. Ther. 20, 127-137.
136. Taléns-Visconti, R., Bonora, A., Jover, R., Mirabet,V., Carbonell, F., Castell, J. V., and Gómez-Lechón, M. J. (2006). Hepatogenic differentiation of human mesenchymal stem cells from adipose tissue in comparison with bone marrow mesenchymal stem cells. World J. Gastroenterol. 12, 5834-5845.
137. Theise, N. D., Badve, S., Saxena, R., Henegariu, O., Sell, S., Crawford, J. M.,and Krause,D. S. (2000). Deriva- tion of hepatocytes from bone mar- row cells in mice after radiation- induced myeloablation. Hepatology 31, 235-240.
138. Tsai,P.-C.,Fu, T.-W., Chen,Y.-M. A., Ko, T.-L.,Chen,T.-H.,Shih,Y.-H.,Hung, S.-C., and Fu, Y. S. (2009). The ther- apeutic potential of human umbil- ical mesenchymal stem cells from Wharton's jelly in the treatment of rat liver fibrosis. Liver Transpl. 15, 484-495.
139. Turner, R., Lozoya, O., Wang, Y., Car- dinale, V., Gaudio, E., Alpini, G., Mendel, G.,Wauthier, E., Barbier, C., Alvaro, D., and Reid, L. M. (2011). Human hepatic stem cell and matu- rational liver lineage biology. Hepa- tology 53, 1035-1045.
140. Van Den Heuvel, M. C., Slooff, M. J. H., Visser, L., Muller, M., De Jong, K. P., Poppema, S., and Gouw, A. S. H. (2001). Expression of anti-OV6 antibody and anti-N-CAM antibody along the biliary line of normal and diseased human livers. Hepatology 33, 1387-1393.
141. Van Poll, D., Parekkadan, B., Cho, C. H., Berthiaume, F., Nahmias, Y., Tilles, A. W., and Yarmush, M. L. (2008). Mesenchymal stem cell- derived molecules directly modulate hepatocellular death and regenera- tion in vitro and in vivo. Hepatology 47, 1634-1643.
142. Vassilopoulos, G. P., Wang, R., and Russell, D. W. (2003). Transplanted bonemarrowregeneratesliver bycell fusion. Nature 422, 901-904.
143. Wang, P. P., Wang, J. H., Yan, Z. P., Hu, M. Y., Lau, G. K., Fan, S.T., and Luk, J. M. (2004). Expres- sion of hepatocyte-like phenotypes in bone marrow stromal cells after HGF induction. Biochem. Biophys. Res. Commun. 320, 712-716.
144. Wang, X., Ge, S., McNamara, G., Hao, Q.-L., Crooks, G. M., and Nolta, J. A. (2003a). Albumin-expressing hepatocyte-like cells develop in the livers of immune-deficient mice that received transplants of highly purified human hematopoi- etic stem cells. Blood 101, 4201-4208.
145. Wang, X., Willenbring, H., Akkari, Y., Torimaru,Y.,Foster,M.,Al-Dhalimy, M., Lagasse, E., Finegold, M., Olson, S., and Grompe, M. (2003b). Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422, 897-901.
146. Weber,A.,Groyer-Picard,M.-T.,Franco, D., and Dagher, I. (2009). Hepato- cyte transplantation in animal mod- els. Liver Transpl. 15, 7-14.
147. Wu, X.-Z., and Yu, X.-H. (2007). Bone marrow cells: the source of hepato- cellular carcinoma? Med. Hypotheses 69, 36-42.
148. Wu, X. Z. (2008). Origin of cancer stem cells: the role of self-renewal and dif- ferentiation. Ann. Surg. Oncol. 15, 407-414.
149. Yagi, H., Tafaleng, E., Nagaya, M., Hansel, M. C., Strom, S. C., Fox, I. J., and Soto-Gutierrez, A. (2009). Embryonic and induced pluripotent stem cells as a model for liver dis- ease. Crit. Rev. Biomed. Eng. 37, 377-398.
150. Yanez, R., Lamana, M. L., Garcia- Castro, J., Colmenero, I., Ramirez, M., Bueren, J. A. (2006). Adi- pose tissue-derived mesenchymal stem cells have in vivo immuno- suppressive properties applicable for the control of the graft- versus-host disease. Stem Cells 24, 2582-2591.
151. Zagoura, D. S., Roubelakis, M. G., Bitsika, V., Trohatou, O., Pappa, K. I., Kapelouzou, A., Antsaklis, A., and Anagnou, N. P. (2012). Therapeutic potential of a dis- tinct population of human amni- otic fluid mesenchymal stem cells and their secreted molecules in mice with acute hepatic failure. Gut 61, 894-906.
152. 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, G. K., and Wang, F. S. (2012). Human umbilical cord mesenchy- mal stem cells improve liver function and ascites in decompensated liver cirrhosis patients. J. Gastroenterol. Hepatol. 27, 112-120.
153. Zheng, J. F., and Liang, L. J. (2008). Transplanted bone marrow stromal cells are not cellular origin of hepa- tocellular carcinomas in a mouse model of carcinogenesis. World J. Gastroenterol. 14, 3015-3020.
154. Zheng, Z. H., Li, X. Y., Ding, J., Jia, J. F., and Zhu, P. (2008). Allogeneic mes- enchymal stem cell and mesenchy- mal stem cell-differentiated chon- drocyte suppress the responses of type II collagen-reactive T cells in rheumatoid arthritis. Rheumatology 47, 22-30.
155. Zhu, W., Xu, W., Jiang, R., Qian, H., Chen, M., Hu, J., Cao, W., Han, C., and Chen, Y. (2006). Mesenchymal stem cells derived from bone mar- row favor tumor cell growth in vivo. Exp. Mol. Pathol. 80, 267-274.
156. Zischek, C., Niess, H., Ischenko, I., Conrad, C., Huss, R., Jauch, K. W., Nelson, P. J., and Bruns, C. (2009). Targeting tumor stroma using engineered mesenchymal stem cells reduces the growth of pancre- atic carcinoma. Ann. Surg. Oncol. 250, 747-753.