Bone marrow stem cells and the liver: Are they relevant?
Mélanie A Eckersley-Maslin,
Fiona J Warner,
Candice A Grzelak, Geoffrey W McCaughan,
Nicholas A Shackel,
Mélanie A Eckersley-Maslin
Liver Cell Biology, Centenary Institute,
Search for more papers by this authorFiona J Warner
Liver Cell Biology, Centenary Institute,
Sydney Medical School, the University of Sydney, Sydney, and
Search for more papers by this authorGeoffrey W McCaughan
Liver Cell Biology, Centenary Institute,
Sydney Medical School, the University of Sydney, Sydney, and
A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
Search for more papers by this authorCorresponding Author
Nicholas A Shackel
Liver Cell Biology, Centenary Institute,
Sydney Medical School, the University of Sydney, Sydney, and
A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
Dr Nicholas Shackel, Liver Cell Biology, Centenary Institute, Locked Bag No. 6, Newtown, NSW 2042, Australia. Email: [email protected]Search for more papers by this authorMélanie A Eckersley-Maslin,
Fiona J Warner,
Candice A Grzelak, Geoffrey W McCaughan,
Nicholas A Shackel,
Mélanie A Eckersley-Maslin
Liver Cell Biology, Centenary Institute,
Search for more papers by this authorFiona J Warner
Liver Cell Biology, Centenary Institute,
Sydney Medical School, the University of Sydney, Sydney, and
Search for more papers by this authorGeoffrey W McCaughan
Liver Cell Biology, Centenary Institute,
Sydney Medical School, the University of Sydney, Sydney, and
A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
Search for more papers by this authorCorresponding Author
Nicholas A Shackel
Liver Cell Biology, Centenary Institute,
Sydney Medical School, the University of Sydney, Sydney, and
A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
Dr Nicholas Shackel, Liver Cell Biology, Centenary Institute, Locked Bag No. 6, Newtown, NSW 2042, Australia. Email: [email protected]Search for more papers by this authorAbstract
The contribution of bone marrow stem cell responses to liver homeostasis, injury and malignancy is discussed in this review. Pluripotent stem cells or their more committed progenitor progeny are essential to tissue development, regeneration and repair and are widely implicated in the pathogenesis of malignancy. Stem cell responses to injury are the focus of intense research efforts in the hope of future therapeutic manipulation. Stem cells occur within tissues, such as the liver, or arise from extrahepatic sites, in particular, the bone marrow. As the largest reservoir of stem cells in the adult, the bone marrow has been implicated in the stem cell response associated with liver injury. However, in liver injury, the relative contribution of bone marrow stem cells compared to intrahepatic progenitor responses is poorly characterized. Intrahepatic progenitor responses have been recently reviewed elsewhere. In this review, we have summarized liver-specific extrahepatic stem cell responses originating from the bone marrow. The physiological relevance of bone marrow stem cell responses to adult liver homeostasis, injury and malignancy is discussed with emphasis on mechanisms of bone marrow stem cell recruitment to sites of liver injury and its contribution to intrahepatic malignancy.
References
- 1 Shackel N, Rockey D. In pursuit of the ‘Holy Grail’—stem cells, hepatic injury, fibrogenesis and repair. Hepatology 2005; 41: 16–18.
- 2 Vieyra DS, Jackson KA, Goodell MA. Plasticity and tissue regenerative potential of bone marrow-derived cells. Stem Cell Rev. 2005; 1: 65–9.
- 3 Filip S, English D, Mokry J. Issues in stem cell plasticity. J. Cell. Mol. Med. 2004; 8: 572–7.
- 4 Kallis K, Alison M, Forbes SJ. Bone marrow stem cells and liver disease. Gut 2007; 56: 716–24.
- 5 Stocker E, Heine WD. Regeneration of liver parenchyma under normal and pathological conditions. Beitr. Pathol. 1971; 144: 400–8.
- 6 Bird TG, Lorenzini S, Forbes SJ. Activation of stem cells in hepatic diseases. Cell Tissue Res. 2008; 331: 283–300.
- 7 Paku S, Schnur J, Nagy P, Thorgeirsson SS. Origin and structural evolution of the early proliferating oval cells in rat liver. Am. J. Pathol. 2001; 158: 1313–23.
- 8 Theise ND, Saxena R, Portmann BC et al. The canals of Hering and hepatic stem cells in humans. Hepatology 1999; 30: 1425–33.
- 9 Dan YY, Yeoh GC. Liver stem cells: a scientific and clinical perspective. J. Gastroenterol. Hepatol. 2008; 23: 687–98.
- 10 Chen Y, Dong X-J, Zhang G-R, Shao J-Z, Xiang L-X. In vitro differentiation of mouse bone marrow stromal stem cells into hepatocytes induced by conditional culture medium of hepatocytes. J. Cell. Biochem. 2007; 31: 223–31.
- 11 Saji Y, Tamura S, Yoshida Y et al. Basic fibroblast growth factor promotes the trans-differentiation of mouse bone marrow cells into hepatic lineage cells via multiple liver-enriched transcription factors. J. Hepatol. 2004; 41: 545–50.
- 12 Schwartz RE, Reyes M, Koodie L et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J. Clin. Invest. 2002; 109: 1291–302.
- 13 Lagasse E, Connors H, Al-Dhalimy M et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat. Med. 2000; 6: 1229–34.
- 14 Theise ND, Badve S, Saxena R et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology 2000; 31: 235–40.
- 15 Jeffery R, Poulsom R, Alison MR. Sources of adult hepatic stem cells: haematopoietic. Methods Mol. Biol. 2009; 481: 141–54.
- 16 Skalka M. Anaemia and liver damage in x-irradiated animals. Nature 1958; 182: 1603–4.
- 17 Ng IO, Chan KL, Shek WH et al. High frequency of chimerism in transplanted livers. Hepatology 2003; 38: 989–98.
- 18 Weissman IL. Stem cells: units of development, units of regeneration, and units in evolution. Cell 2000; 100: 157–68.
- 19 Coulombel L. Identification of hematopoietic stem/progenitor cells: strength and drawbacks of functional assays. Oncogene 2004; 23: 7210–22.
- 20 Lazennec G, Jorgensen C. Concise review: adult multipotent stromal cells and cancer: risk or benefit? Stem Cells 2008; 26: 1387–94.
- 21 Jang YY, Collector MI, Baylin SB, Diehl AM, Sharkis SJ. Hematopoietic stem cells convert into liver cells within days without fusion. Nat. Cell Biol. 2004; 6: 532–9.
- 22 Krause DS, Theise ND, Collector MI et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001; 105: 369–77.
- 23 Valfre di Bonzo L, Ferrero I, Cravanzola C et al. Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine: engraftment and hepatocyte differentiation versus profibrogenic potential. Gut 2007; 57: 223–31.
- 24 Zhao D, Lei J, Chen R et al. Bone marrow-derived mesenchymal stem cells protect against experimental liver fibrosis in rats. World J. Gastroenterol. 2005; 11: 3431–40.
- 25 Kucia M, Ratajczak J, Reca R, Janowska-Wieczorek A, Ratajczak MZ. Tissue-specific muscle, neural and liver stem/progenitor cells reside in the bone marrow, respond to an SDF-1 gradient and are mobilised into peripheral blood during stress and tissue injury. Blood Cells Mol. Dis. 2004; 32: 52–7.
- 26 Kucia M, Reca R, Campbell FR et al. A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4+ stem cells identified in adult bone marrow. Leukemia 2006; 20: 857–69.
- 27 Ratajczak MZ, Kucia M, Reca R, Majka M, Janowska-Wieczorek A, Ratajczak J. Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells ‘hide out’ in the bone marrow. Leukemia 2004; 18: 29–40.
- 28 Togel F, Isaaz J, Hu Z, Weiss K, Westernfelder C. Renal SDF-1 signals mobilization and homing of CXCR4-positive cells to the kidney after ischemic injury. Kidney Int. 2005; 67: 1722–84.
- 29 Swenson ES, Kuwahara R, Krause DS, Theise ND. Physiological variations of stem cell factor and stromal-derived factor-1 in murine models of liver injury and regeneration. Liver Int. 2008; 28: 308–18.
- 30 Hatch HM, Zheng D, Jorgensen ML, Petersen BE. SDF-1alpha/ CXCR4: a mechanism for hepatic oval cell activation and bone marrow stem cell recruitment to the injured liver of rats. Cloning Stem Cells 2002; 4: 339–51.
- 31 Kollet O, Shivtiel S, Chen YQ et al. HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver. J. Clin. Invest. 2003; 112: 160.
- 32 Son BR, Marquez-Curtis LA, Kucia M et al. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells 2006; 24: 1254–64.
- 33 Asano Y, Iimuro Y, Son G, Hirano T, Fujimoto J. Hepatocyte growth factor promotes remodeling of murine liver fibrosis, accelerating recruitment of bone marrow-derived cells into the liver. Hepatol. Res. 2007; 37: 1080–94.
- 34 Xu J, Deng X, Demetriou AA, Farkas DL, Hui T, Wang C. Factors released from cholestatic rat livers possibly involved in inducing bone marrow hepatic stem cell priming. Stem Cells Dev. 2008; 17: 143–55.
- 35 Shackel NA, Rockey DC. Stem cells and liver disease: promise laced with confusion and intrigue. Gastroenterology 2004; 127: 346–8.
- 36 Orkin SH, Zon LI. Hematopoiesis and stem cells: plasticity versus developmental heterogeneity. Nat. Immunol. 2002; 3: 323–8.
- 37 Theise ND, Nimmakayalu M, Gardner R et al. Liver from bone marrow in humans. Hepatology 2000; 32: 11–16.
- 38 Wynn TA. Cellular and molecular mechanisms of fibrosis. J. Pathol. 2008; 214: 199–210.
- 39 Ikegami T, Zhang Y, Matsuzaki Y. Liver fibrosis: possible involvement of EMT. Cells Tissues Organs 2007; 185: 213–21.
- 40 Zeisberg M, Yang C, Martino M et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J. Biol. Chem. 2007; 282: 23337–47.
- 41 Terada N, Hamazaki T, Oka M et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002; 416: 542–5.
- 42 Ying QL, Nichols J, Evans EP, Smith AG. Changing potency by spontaneous fusion. Nature 2002; 416: 545–8.
- 43 Wurmser AE, Nakashima K, Summers RG et al. Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature 2004; 430: 350–6.
- 44 Harris RG, Herzog EL, Bruscia EM, Grove JE, Van Arnam JS, Krause DS. Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 2004; 305: 90–3.
- 45 Zhao Y, Yin X, Qin H et al. Two supporting factors greatly improve the efficiency of human iPSC generation. Cell Stem Cell 2008; 3: 475–9.
- 46 Maherali N, Hochedlinger K. Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell 2008; 3: 595–605.
- 47 Welstead GG, Schorderet P, Boyer LA. The reprogramming language of pluripotency. Curr. Opin. Genet. Dev. 2008; 18: 123–9.
- 48 Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 2006; 20: 1487–95.
- 49 Aliotta JM, Sanchez-Guijo FM, Dooner GJ et al. Alteration of marrow cell gene expression, protein production, and engraftment into lung by lung-derived microvesicles: a novel mechanism for phenotype modulation. Stem Cells 2007; 25: 2245–56.
- 50 Brulport M, Schormann W, Bauer A et al. Fate of extrahepatic human stem and precursor cells after transplantation into mouse livers. Hepatology 2007; 46: 861–70.
- 51 Terrace JD, Currie IS, Hay DC et al. Progenitor cell characterization and location in the developing human liver. Stem Cells Dev. 2007; 16: 771–8.
- 52 Turner WS, Schmelzer E, McClelland R, Wauthier E, Chen W, Reid LM. Human hepatoblast phenotype maintained by hyaluronan hydrogels. J. Biomed. Mater. Res. 2007; 82: 156–68.
- 53 Detrich HW 3rd, Kieran MW, Chan FY et al. Intraembryonic hematopoietic cell migration during vertebrate development. Proc. Natl. Acad. Sci. USA 1995; 92: 10713–17.
- 54 Almeida-Porada G, Porada CD, Chamberlain J, Torabi A, Zanjani ED. Formation of human hepatocytes by human hematopoietic stem cells in sheep. Blood 2004; 104: 2582–90.
- 55 Kienstra KA, Jackson KA, Hirschi KK. Injury mechanism dictates contribution of bone marrow-derived cells to murine hepatic vascular regeneration. Pediatr. Res. 2008; 63: 131–6.
- 56 Jensen CH, Jauho EI, Santoni-Rugiu E et al. Transit-amplifying ductular (oval) cells and their hepatocytic progeny are characterized by a novel and distinctive expression of delta-like protein/ preadipocyte factor 1/fetal antigen 1. Am. J. Pathol. 2004; 164: 1347–59.
- 57 Fausto N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 2004; 39: 1477–87.
- 58 Rountree CB, Barsky L, Ge S, Zhu J, Senadheera S, Crooks GM. A CD133-expressing murine liver oval cell population with bilineage potential. Stem Cells 2007; 25: 2419–29.
- 59 Shmelkov SV, St Clair R, Lyden D, Rafii S. AC133/CD133/ Prominin-1. Int. J. Biochem. Cell Biol. 2005; 37: 715–19.
- 60 Schmelzer E, Zhang L, Bruce A et al. Human hepatic stem cells from fetal and postnatal donors. J. Exp. Med. 2007; 204: 1973–87.
- 61 Shackel NA, Warner FJ. Identification of resident hepatic stem cell populations. Hepatology 2007; 46: 2042–4.
- 62 Sigal SH, Brill S, Fiorino AS, Reid LM. The liver as a stem cell and lineage system. Am. J. Physiol. 1992; 263: G139–48.
- 63 Petersen BE, Bowen WC, Patrene KD et al. Bone marrow as a potential source of hepatic oval cells. Science 1999; 284: 1168–70.
- 64 Petersen BE, Grossbard B, Hatch H, Pi L, Deng J, Scott EW. Mouse A6-positive hepatic oval cells also express several hematopoietic stem cell markers. Hepatology 2003; 37: 632–40.
- 65 Yovchev MI, Grozdanov PN, Zhou H, Racherla H, Guha C, Dabeva MD. Identification of adult hepatic progenitor cells capable of repopulating injured rat liver. Hepatology 2008; 47: 636–47.
- 66 Khurana S, Mukhopadhyay A. Characterization of the potential subpopulation of bone marrow cells involved in the repair of injured liver tissue. Stem Cells 2007; 25: 1439–47.
- 67 Asawa S, Saito T, Satoh A et al. Participation of bone marrow cells in biliary fibrosis after bile duct ligation. J. Gastroenterol. Hepatol. 2007; 22: 2001–8.
- 68 Kubota K, Soeda J, Misawa R et al. 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. Carcinogenesis 2008; 29: 448–54.
- 69 Shackel NA, McCaughan GW, Warner FJ. Hepatocellular carcinoma development requires hepatic stem cells with altered transforming growth factor and interleukin-6 signaling. Hepatology 2008; 47: 2134–6.
- 70 Wu XZ, Chen D. Origin of hepatocellular carcinoma: role of stem cells. J. Gastroenterol. Hepatol. 2006; 21: 1093–8.
- 71 Houghton J, Stoicov C, Nomura S et al. Gastric cancer originating from bone marrow-derived cells. Science 2004; 306: 1568–71.
- 72 Marx J. Medicine. Bone marrow cells: the source of gastric cancer? Science 2004; 306: 1455–7.
- 73 Rizvi AZ, Swain JR, Davies PS et al. Bone marrow-derived cells fuse with normal and transformed intestinal stem cells. Proc. Natl. Acad. Sci. USA 2006; 103: 6321–5.
- 74 Liu C, Chen Z, Chen Z, Zhang T, Lu Y. Multiple tumor types may originate from bone marrow-derived cells. Neoplasia 2006; 8: 716–24.
- 75 Zheng JF, Liang LJ. Transplanted bone marrow stromal cells are not cellular origin of hepatocellular carcinomas in a mouse model of carcinogenesis. World J. Gastroenterol. 2008; 14: 3015–20.
- 76 Ishikawa H, Nakao K, Matsumoto K et al. Bone marrow engraftment in a rodent model of chemical carcinogenesis but no role in the histogenesis of hepatocellular carcinoma. Gut 2004; 53: 884–9.
- 77 Snape K, Izatt L, Ross P, Ellis D, Mann K, O'Grady J. Donor-transmitted malignancy confirmed by quantitative fluorescence polymerase chain reaction genotype analysis: a rare indication for liver retransplantation. Liver Transpl. 2008; 14: 155–8.
- 78 Ishimura M, Ohga S, Nagatoshi Y et al. Malignant hepatic tumor occurring 10 years after a histocompatible sibling donor bone marrow transplantation for severe aplastic anemia. Pediatr. Transplant. 2007; 11: 945–9.
- 79 Al-Joundi T, Gibson S, Brunt EM, Shakil O, Lee RS, Di Bisceglie AM. Delayed recurrence of hepatocellular carcinoma after liver transplantation: detection of origin by chromosomal analysis. Liver Transpl. 2000; 6: 374–5.
- 80 Flemming P, Tillmann HL, Barg-Hock H et al. Donor origin of de novo hepatocellular carcinoma in hepatic allografts. Transplantation 2003; 76: 1625–7.
- 81 Yang ZF, Ngai P, Ho DW et al. Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 2008; 47: 919–28.
- 82 Jeong WI, Jeong DH, Do SH et al. Expression of cytokeratins 8 and 18 on Mallory body and oval cell in rats during hepatic fibrosis. In Vivo 2005; 19: 769–75.
- 83 Petersen BE, Goff JP, Greenberger JS, Michalopoulos GK. Hepatic oval cells express the hematopoietic stem cell marker Thy-1 in the rat. Hepatology 1998; 27: 433–45.
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