The liver has the outstanding ability to regenerate itself and restore parenchymal tissue after injury. The most common cell source in liver growth/regeneration is replication of preexisting hepatocytes although liver progenitor cells have been postulated to participate in liver regeneration in cases of massive injury. Bone marrow derived hematopoietic stem cells (BM-HSC) have the formal capacity to act as a source for hepatic regeneration under special circumstances; however, the impact of this process in liver tissue maintenance and regeneration remains controversial. Whether BM-HSC are involved in liver regeneration or not would be of particular interest as the cells have been suggested to be an alternative donor source for the treatment of liver failure. Data from murine models of liver disease show that BM-HSC can repopulate liver tissue and restore liver function; however, data obtained from human liver transplantation show only little evidence for liver regeneration by this mechanism. The cell source for liver regeneration seems to depend on the nature of regeneration process and the extent of injury; however, the precise mechanisms still need to be resolved. Current data suggest, that in human orthotopic liver transplantation, liver regeneration by BM-HSC is a rather rare event and therefore not of clinical relevance. 1. Introduction Liver diseases are an important cause of morbidity and mortality in both Europe [1] and the USA [2], and the incidence for acute or chronic liver failure is rising due to hepatitis C infections, alcohol abuse, and hepatocellular carcinoma in cirrhosis [3]. Importantly, the liver represents the only vital organ (with exception of the brain) that cannot be replaced by a device because of the complexity of its functions. Orthotopic liver transplantation (OLT) is the treatment of choice for acute or chronic liver failure but is limited by general organ shortage, leading to increased mortality among patients on the waiting list. Although early graft loss as a consequence of primary nonfunction, hepatic artery thrombosis and acute rejection episodes is negligible due to constant improvement of surgical techniques, patient management, and immunosuppressive strategies, bacterial and fungal infections are a major problem being responsible for the majority of patient morbidity and graft loss in the first months after OLT. One-year survival rates for both the patient and graft survival are around 80% [4], with approximately 50% of all deaths happening within the first 6 months. The concept of liver cell transplantation by
References
[1]
M. Blachier, H. Leleu, M. Peck-Radosavljevic, D. C. Valla, and F. Roudot-Thoraval, “The burden of liver disease in Europe: a review of available epidemiological data,” Journal of Hepatology, vol. 58, no. 3, pp. 593–608, 2013.
[2]
S. K. Asrani, J. J. Larson, B. Yawn, T. M. Therneau, and W. R. Kim, “Underestimation of liver-related mortality in the United States,” Gastroenterology, vol. 145, no. 2, pp. 375–382, 2013.
[3]
M. Colombo, J. L. Raoul, R. Lencioni, et al., “Multidisciplinary strategies to improve treatment outcomes in hepatocellular carcinoma: a European perspective,” European Journal of Gastroenterology & Hepatology, vol. 25, no. 6, pp. 639–651, 2013.
[4]
R. Adam, V. Karam, V. Delvart, et al., “Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR),” Journal of Hepatology, vol. 57, no. 3, pp. 675–688, 2012.
[5]
A. Nussler, S. Konig, M. Ott, et al., “Present status and perspectives of cell-based therapies for liver diseases,” Journal of Hepatology, vol. 45, no. 1, pp. 144–159, 2006.
[6]
A. Dhawan, J. Puppi, R. D. Hughes, and R. R. Mitry, “Human hepatocyte transplantation: current experience and future challenges,” Nature Reviews Gastroenterology and Hepatology, vol. 7, no. 5, pp. 288–298, 2010.
[7]
B. E. Petersen, B. Grossbard, H. Hatch, L. Pi, J. Deng, and E. W. Scott, “Mouse A6-positive hepatic oval cells also express several hematopoietic stem cell markers,” Hepatology, vol. 37, no. 3, pp. 632–640, 2003.
[8]
H. M. Hatch, D. Zheng, M. L. Jorgensen, and B. E. Petersen, “SDF-1α/CXCR4: a mechanism for hepatic oval cell activation and bone marrow stem cell recruitment to the injured liver of rats,” Cloning and Stem Cells, vol. 4, no. 4, pp. 339–351, 2002.
[9]
B. E. Petersen, W. C. Bowen, K. D. Patrene et al., “Bone marrow as a potential source of hepatic oval cells,” Science, vol. 284, no. 5417, pp. 1168–1170, 1999.
[10]
E. Lagasse, H. Connors, M. Al-Dhalimy et al., “Purified hematopoietic stem cells can differentiate into hepatocytes in vivo,” Nature Medicine, vol. 6, no. 11, pp. 1229–1234, 2000.
[11]
A. J. Wagers, R. I. Sherwood, J. L. Christensen, and I. L. Weissman, “Little evidence for developmental plasticity of adult hematopoietic stem cells,” Science, vol. 297, no. 5590, pp. 2256–2259, 2002.
[12]
X. Wang, H. Willenbring, Y. Akkari et al., “Cell fusion is the principal source of bone-marrow-derived hepatocytes,” Nature, vol. 422, no. 6934, pp. 897–901, 2003.
[13]
G. Vassilopoulos, P.-R. Wang, and D. W. Russell, “Transplanted bone marrow regenerates liver by cell fusion,” Nature, vol. 422, no. 6934, pp. 901–904, 2003.
[14]
M. R. Alison, R. Poulsom, R. Jeffery et al., “Hepatocytes from non-hepatic adult stem cells,” Nature, vol. 406, no. 6793, p. 257, 2000.
[15]
N. D. Theise, M. Nimmakayalu, R. Gardner et al., “Liver from bone marrow in humans,” Hepatology, vol. 32, no. 1, pp. 11–16, 2000.
[16]
M. K？rbling, R. L. Katz, A. Khanna et al., “Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells,” The New England Journal of Medicine, vol. 346, no. 10, pp. 738–746, 2002.
[17]
F. Fogt, K. H. Beyser, C. Poremba, R. L. Zimmerman, U. Khettry, and J. Ruschoff, “Recipient-derived hepatocytes in liver transplants: a rare event in sex-mismatched transplants,” Hepatology, vol. 36, no. 1, pp. 173–176, 2002.
[18]
W. Kleeberger, T. Roth？mel, S. Gl？ckner, P. Flemming, U. Lehmann, and H. Kreipe, “High frequency of epithelial chimerism in liver transplants demonstrated by microdissection and STR-analysis,” Hepatology, vol. 35, no. 1, pp. 110–116, 2002.
[19]
T. Wu, K. Cieply, M. A. Nalesnik et al., “Minimal evidence of transdifferentiation from recipient bone marrow to parenchymal cells in regenerating and long-surviving human allografts,” American Journal of Transplantation, vol. 3, no. 9, pp. 1173–1181, 2003.
[20]
W. R. ten Hove, B. van Hoek, I. M. Bajema, J. Ringers, J. H. J. M. van Krieken, and E. L. Lagaaij, “Extensive chimerism in liver transplants: vascular endothelium, bile duct epithelium, and hepatocytes,” Liver Transplantation, vol. 9, no. 6, pp. 552–556, 2003.
[21]
I. O.-L. Ng, K.-L. Chan, W.-H. Shek et al., “High frequency of chimerism in transplanted livers,” Hepatology, vol. 38, no. 4, pp. 989–998, 2003.
[22]
R. Idilman, E. Erden, I. Kuzu et al., “Recipient-derived hepatocytes in sex-mismatched liver allografts after liver transplantation: early versus late transplant biopsies,” Transplantation, vol. 78, no. 11, pp. 1647–1652, 2004.
[23]
R. Idilman, E. Erden, I. Kuzu, S. Ersoz, and S. Karayalcin, “The fate of recipient-derived hepatocytes in sex-mismatched liver allograft following liver transplantation,” Clinical Transplantation, vol. 21, no. 2, pp. 202–206, 2007.
[24]
N. Pilat, S. Schoppmann, J. Stift, P. Mazal, T. Wekerle, and G. A. Berlakovich, “No evidence for recipient-derived hepatocytes in serial biopsies of sex-mismatched liver transplants,” Transplantation, vol. 94, no. 9, pp. 953–957, 2012.
[25]
W. Aini, A. Miyagawa-Hayashino, M. Ozeki et al., “Frequent hepatocyte chimerism in long-term human liver allografts independent of graft outcome,” Transplant Immunology, vol. 28, no. 2-3, pp. 2100–2135, 2013.
[26]
T. Okabayashi, A. M. Cameron, M. Hisada, R. A. Montgomery, G. M. Williams, and Z. Sun, “Mobilization of host stem cells enables long-term liver transplant acceptance in a strongly rejecting rat strain combination,” American Journal of Transplantation, vol. 11, no. 10, pp. 2046–2056, 2011.
[27]
N. Fausto, “Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells,” Hepatology, vol. 39, no. 6, pp. 1477–1487, 2004.
[28]
P. S. Randhawa, T. Starzl, H. C. Ramos, M. A. Nalesnik, and J. Demetris, “Allografts surviving for 26 to 29 years following living-related kidney transplantation: analysis by light microscopy, in situ hybridization for the Y chromosome, and anti-HLA antibodies,” American Journal of Kidney Diseases, vol. 24, no. 1, pp. 72–77, 1994.
[29]
S. H. Hong, E. J. Gang, J. A. Jeong et al., “In vitro differentiation of human umbilical cord blood-derived mesenchymal stem cells into hepatocyte-like cells,” Biochemical and Biophysical Research Communications, vol. 330, no. 4, pp. 1153–1161, 2005.
[30]
D. S. Krause, N. D. Theise, M. I. Collector et al., “Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell,” Cell, vol. 105, no. 3, pp. 369–377, 2001.
[31]
D. D. Houlihan and P. N. Newsome, “Critical review of clinical trials of bone marrow stem cells in liver disease,” Gastroenterology, vol. 135, no. 2, pp. 438–450, 2008.
[32]
B. Fang, M. Shi, L. Liao, S. Yang, Y. Liu, and R. C. Zhao, “Systemic infusion of FLK1+ mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice,” Transplantation, vol. 78, no. 1, pp. 83–88, 2004.
[33]
Q. Zhao, H. Ren, D. Zhu, and Z. Han, “Stem/progenitor cells in liver injury repair and regeneration,” Biology of the Cell, vol. 101, no. 10, pp. 557–571, 2009.
[34]
W. Zhao, J.-J. Li, D.-Y. Cao et al., “Intravenous injection of mesenchymal stem cells is effective in treating liver fibrosis,” World Journal of Gastroenterology, vol. 18, no. 10, pp. 1048–1058, 2012.
[35]
D. van Poll, B. Parekkadan, C. H. Cho et al., “Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo,” Hepatology, vol. 47, no. 5, pp. 1634–1643, 2008.
[36]
Y. Shi, G. Hu, J. Su et al., “Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair,” Cell Research, vol. 20, no. 5, pp. 510–518, 2010.
[37]
J. M. Ryan, F. P. Barry, J. M. Murphy, and B. P. Mahon, “Mesenchymal stem cells avoid allogeneic rejection,” Journal of Inflammation, vol. 2, article 8, 2005.
[38]
E. K. Moioli, P. A. Clark, M. Chen et al., “Synergistic actions of hematopoietic and mesenchymal stem/progenitor cells in vascularizing bioengineered tissues,” PLoS One, vol. 3, no. 12, Article ID e3922, 2008.
[39]
T. E. Ichim, F. Solano, F. Lara, et al., “Combination stem cell therapy for heart failure,” International Archives of Medicine, vol. 3, no. 1, article 5, 2010.
[40]
M. Kassem, “Mesenchymal stem cells: biological characteristics and potential clinical applications,” Cloning and Stem Cells, vol. 6, no. 4, pp. 369–374, 2004.
[41]
Y. Jiang, B. N. Jahagirdar, R. L. Reinhardt et al., “Pluripotency of mesenchymal stem cells derived from adult marrow,” Nature, vol. 418, no. 6893, pp. 41–49, 2002.
[42]
Q. Li, X. Zhou, Y. Shi, et al., “In vivo tracking and comparison of the therapeutic effects of MSCs and HSCs for liver injury,” PLoS One, vol. 8, no. 4, Article ID e62363, 2013.
[43]
B. Christ and M. M. Dollinger, “The generation of hepatocytes from mesenchymal stem cells and engraftment into the liver,” Current Opinion in Organ Transplantation, vol. 16, no. 1, pp. 69–75, 2011.
[44]
H. Aurich, M. Sgodda, P. Kaltwa？er et al., “Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo,” Gut, vol. 58, no. 4, pp. 570–581, 2009.
[45]
K.-D. Lee, T. K.-C. Kuo, J. Whang-Peng et al., “In vitro hepatic differentiation of human mesenchymal stem cells,” Hepatology, vol. 40, no. 6, pp. 1275–1284, 2004.
[46]
A. Banas, T. Teratani, Y. Yamamoto et al., “IFATS collection: in vivo therapeutic potential of human adipose tissue mesenchymal stem cells after transplantation into mice with liver injury,” Stem Cells, vol. 26, no. 10, pp. 2705–2712, 2008.
[47]
A. W. Duncan, C. Dorrell, and M. Grompe, “Stem cells and liver regeneration,” Gastroenterology, vol. 137, no. 2, pp. 466–481, 2009.
[48]
S. L. Friedman, “Liver fibrosis—from bench to bedside,” Journal of Hepatology, vol. 38, supplement 1, pp. S38–S53, 2003.
[49]
V. A. Dolgachev, M. R. Ullenbruch, N. W. Lukacs, and S. H. Phan, “Role of stem cell factor and bone marrow-derived fibroblasts in airway remodeling,” American Journal of Pathology, vol. 174, no. 2, pp. 390–400, 2009.
[50]
S. B. Haudek, Y. Xia, P. Huebener et al., “Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 48, pp. 18284–18289, 2006.
[51]
W. Nimphius, R. Moll, P. Olbert, A. Ramaswamy, and P. J. Barth, “CD34+ fibrocytes in chronic cystitis and noninvasive and invasive urothelial carcinomas of the urinary bladder,” Virchows Archiv, vol. 450, no. 2, pp. 179–185, 2007.
[52]
T. Kisseleva, H. Uchinami, N. Feirt et al., “Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis,” Journal of Hepatology, vol. 45, no. 3, pp. 429–438, 2006.
[53]
S. J. Forbes, F. P. Russo, V. Rey et al., “A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis,” Gastroenterology, vol. 126, no. 4, pp. 955–963, 2004.
[54]
B. D. Paredes, L. A. Faccioli, L. F. Quintanilha et al., “Bone marrow progenitor cells do not contribute to liver fibrogenic cells,” World Journal of Hepatology, vol. 4, no. 10, pp. 274–283, 2012.
[55]
I. Sakaida, S. Terai, N. Yamamoto et al., “Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice,” Hepatology, vol. 40, no. 6, pp. 1304–1311, 2004.
[56]
K.-A. Cho, G.-W. Lim, S.-Y. Joo et al., “Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice,” Liver International, vol. 31, no. 7, pp. 932–939, 2011.
[57]
S. Nunes de Carvalho, E. Helal-Neto, D. C. de Andrade et al., “Bone marrow mononuclear cell transplantation increases metalloproteinase-9 and 13 and decreases tissue inhibitors of metalloproteinase-1 and 2 expression in the liver of cholestatic rats,” Cells, Tissues, Organs, 2013.
[58]
T. Takami, S. Terai, and I. Sakaida, “Stem cell therapy in chronic liver disease,” Current Opinion in Gastroenterology, vol. 28, no. 3, pp. 203–208, 2012.
[59]
D. Schuppan and Y. O. Kim, “Evolving therapies for liver fibrosis,” The Journal of Clinical Investigation, vol. 123, no. 5, pp. 1887–1901, 2013.
[60]
G. Ferrari, G. Cusella-De Angelis, M. Coletta et al., “Muscle regeneration by bone marrow-derived myogenic progenitors,” Science, vol. 279, no. 5356, pp. 1528–1530, 1998.
[61]
N. D. Theise, S. Badve, R. Saxena et al., “Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation,” Hepatology, vol. 31, no. 1, pp. 235–240, 2000.
[62]
D. Orlic, J. Kajstura, S. Chimenti et al., “Bone marrow cells regenerate infarcted myocardium,” Nature, vol. 410, no. 6829, pp. 701–705, 2001.
[63]
E. Mezey, K. J. Chandross, G. Harta, R. A. Maki, and S. R. McKercher, “Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow,” Science, vol. 290, no. 5497, pp. 1779–1782, 2000.
[64]
Z. Zhang, J. Liu, Y. Liu, Z. Li, W. Q. Gao, and Z. He, “Generation, characterization and potential therapeutic applications of mature and functional hepatocytes from stem cells,” Journal of Cellular Physiology, vol. 228, no. 2, pp. 298–305, 2013.
