Hepatology International

, Volume 8, Supplement 2, pp 514–525 | Cite as

Growth factors enhance liver regeneration in acute-on-chronic liver failure

  • Chandan Kumar Kedarisetty
  • Lovkesh Anand
  • Arshi Khanam
  • Anupam Kumar
  • Archana Rastogi
  • Rakhi Maiwall
  • Shiv Kumar SarinEmail author
Supplement Issue: ALPD


Acute-on-chronic liver failure is a distinct syndrome characterized by a rapid progression of liver disease culminating in organ failure and death. The only definitive treatment is liver transplantation. However, there is a possible element of reversibility and hepatic regeneration if the acute insult can be tided over. Exogenously administered growth factors may stimulate hepatocytes, hepatic progenitor cells and bone marrow-derived cells to supplement hepatic regeneration. The proposed review is intended to provide an in-depth analysis of the individual components of hepatic and bone marrow niches and highlight the growing role of various growth factors in liver regeneration in health and in liver failure.


Liver failure Liver regeneration Growth factors 


Compliance with ethical requirements and Conflict of interest





  1. 1.
    Sen S, William R, Jalan R. The pathophysiological basis of acute-on-chronic liver failure. Liver 2002;22(Suppl 2):5–13PubMedGoogle Scholar
  2. 2.
    Sarin SK, Kumar A, Almeida J, Chawla YC, Fan ST, Garg H, et al. Acute-on-chronic liver failure (ACLF): consensus recommendations of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int 2009;3:269–282PubMedPubMedCentralGoogle Scholar
  3. 3.
    Kjaergard LL, Liu J, Als-Nielsen B, Gluud C. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: a systematic review. JAMA 2003;289:217–222PubMedGoogle Scholar
  4. 4.
    Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426–1437PubMedGoogle Scholar
  5. 5.
    Wlodzimirow KA, Eslami S, Abu-Hanna A, Nieuwoudt M, Chamuleau RA. A systematic review on prognostic indicators of acute on chronic liver failure and their predictive value for mortality. Liver Int 2013;33(1):40–52PubMedGoogle Scholar
  6. 6.
    Garg H, Kumar A, Garg V, Sharma P, Sharma BC, Sarin SK. Clinical profile and predictors of mortality in patients of acute-on-chronic liver failure. Dig Liver Dis 2012;44(2):166–171PubMedGoogle Scholar
  7. 7.
    Malhi H, Gores GJ. Cellular and molecular mechanisms of liver injury. Gastroenterology 2008;134:1641–1654PubMedPubMedCentralGoogle Scholar
  8. 8.
    Ambrosino G, Naso A, Feltracco P, Carraro P, Basso SM, Varotto S, et al. Cytokines and liver failure: modification of TNF-a and IL–6 in patients with acute on chronic liver decompensation treated with molecular adsorbent recycling system (MARS). Acta Biomed 2003;74(Suppl 2):7–9PubMedGoogle Scholar
  9. 9.
    Roskams T. Relationships among stellate cell activation, progenitor cells and hepatic regeneration. Clin Liver Dis 2008;12:853–860PubMedGoogle Scholar
  10. 10.
    Bird TG, Lorenzini S, Forbes SJ. Activation of stem cells in hepatic diseases. Cell Tissue Res 2008;331(1):283–300PubMedPubMedCentralGoogle Scholar
  11. 11.
    Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology 2006;43:S45–S53PubMedGoogle Scholar
  12. 12.
    Falkowski O, An HJ, Ianus IA, Chiriboga L, Yee H, West AB, et al. Regeneration of hepatocyte “buds” in cirrhosis from intra-biliary stem cells. J Hepatol 2003;39:357–364PubMedGoogle Scholar
  13. 13.
    Wiemann SU, Satyanarayana A, Tsahuridu M, Tillmann HL, Zender L, Klempnauer J, et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J 2002;16:935–942PubMedGoogle Scholar
  14. 14.
    Marshall A, Rushbrook S, Davies SE, Morris LS, Scott IS, Vowler SL, et al. Relation between hepatocyte G1 arrest, impaired hepatic regeneration, and fibrosis in chronic hepatitis C virus infection. Gastroenterology 2005;128:33–42PubMedGoogle Scholar
  15. 15.
    Libbrecht L, Desmet V, Van Damme B, Roskams T. Deep intralobular extension of human hepatic “progenitor cells” correlates with parenchymal inflammation in chronic viral hepatitis: can “progenitor cells” migrate? J Pathol 2000;192:373–378PubMedGoogle Scholar
  16. 16.
    Lowes KN, Brennan BA, Yeoh GC, Olynyk JK. Oval cell numbers in human chronic liver diseases are directly related to disease severity. Am J Pathol 1999;154:537–541PubMedPubMedCentralGoogle Scholar
  17. 17.
    Roskams TA, Libbrecht L, Desmet VJ. Progenitor cells in diseased human liver. Semin Liver Dis 2003;23(4):385–396PubMedGoogle Scholar
  18. 18.
    Yang L, Jung Y, Omenetti A, Witek RP, Choi S, Vandongen HM, et al. Fate-mapping evidence that hepatic stellate cells are epithelial progenitors in adult mouse livers. Stem Cells 2008;26:2104–2143PubMedPubMedCentralGoogle Scholar
  19. 19.
    Kuwahara R, Kofman AV, Landis CS, Swenson ES, Barendswaard E, et al. The hepatic stem cell niche: identification by label-retaining cell assay. Hepatology 2008;47(6):1810–1812Google Scholar
  20. 20.
    Sawitza I, Kordes C, Reister S. H¨aussinger D. The niche of stellate cells within rat liver. Hepatology 2009;50(5):1617–1624PubMedGoogle Scholar
  21. 21.
    Moore KA, Lemischka I. Stem cells and their niches. Science 2006;311:1880–1885PubMedGoogle Scholar
  22. 22.
    Zhang L, Theise N, Chua M, Reid LM. The stem cell niche of human livers: symmetry between development and regeneration. Hepatology 2008;48(5):1598–1607PubMedGoogle Scholar
  23. 23.
    Cardinale V, Wang Y, Carpino G, Cui GB, Gatto M, Rossi M, et al. Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes and pancreatic issues. Hepatology 2011;54(6):2159–2172PubMedGoogle Scholar
  24. 24.
    Carpino G, Cardinale V, Onori P, Franchitto A, Berloco PB, Rossi M, et al. Biliary tree stem/progenitor cells in glands of extrahepatic and intrahepatic bile ducts: an anatomical in situ study yielding evidence of maturational lineages. J Anat 2012;220(2):186–199PubMedPubMedCentralGoogle Scholar
  25. 25.
    Spee B, Carpino G, Schotanus BA, Katoonizadeh A, Vander Borght S, Gaudio E, et al. Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signaling. Gut 2010;59:247–257PubMedGoogle Scholar
  26. 26.
    Rastogi A, Bihari C, Maiwall R, Ahuja A, Sharma MK, Kumar A, et al. Hepatic stellate cells are involved in the pathogenesis of acute-on-chronic liver failure (ACLF). Virchows Arch 2012;461(4):393–398PubMedGoogle Scholar
  27. 27.
    Knight B, Yeoh GC. TNF/LT alpha double knockout mice display abnormal inflammatory and regenerative responses to acute and chronic liver injury. Cell Tissue Res 2005;319:61–70PubMedGoogle Scholar
  28. 28.
    Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, et al. TWEAK induces liver progenitor cell proliferation. J Clin Investig 2005;115:2330–2340PubMedPubMedCentralGoogle Scholar
  29. 29.
    Weng HL, Feng DC, Radaeva S, Kong XN, Wang L, Liu Y, et al. IFN- gamma inhibits hepatic progenitor cell proliferation in HBV infected patients and in 3,5-diethoxycarbonyl-1,4- dihydrocollidine diet fed mice. J Hepatol 2013;59(4):738–745PubMedGoogle Scholar
  30. 30.
    Sun R, Gao B. Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-gamma). Gastroenterology 2004;127(5):1525–1539PubMedGoogle Scholar
  31. 31.
    Akhurst B, Matthews V, Husk K, Smyth MJ, Abraham LJ, Yeoh GC. Differential lymphotoxin-beta and interferon gamma signaling during mouse liver regeneration induced by chronic and acute injury. Hepatology 2005;41:327–335PubMedGoogle Scholar
  32. 32.
    Sanchez A, Factor VM, Schroeder IS, Nagy P, Thorgeirsson SS. Activation of NF-kappa B and STAT3 in rat oval cells during 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration. Hepatology 2004;39:376–385PubMedGoogle Scholar
  33. 33.
    Subrata LS, Lowes KN, Olynyk JK, Yeoh GC, Quail EA, Abraham LJ. Hepatic expression of the tumor necrosis factor family member lymphotoxin-beta is regulated by interleukin (IL)-6 and IL-1beta: transcriptional control mechanisms in oval cells and hepatoma cell lines. Liver Int 2005;25:633–646PubMedGoogle Scholar
  34. 34.
    Omori N, Evarts RP, Omori M, Hu Z, Marsden ER, Thorgeirsson SS. Expression of leukemia inhibitory factor and its receptor during liver regeneration in the adult rat. Lab Investig 1996;75(1):15–24PubMedGoogle Scholar
  35. 35.
    Znoyko I, Sohara N, Spicer SS, Trojanowska M, Reuben A. Expression of oncostatin M and its receptors in normal and cirrhotic human liver. J Hepatol 2005;43(5):893–900PubMedGoogle Scholar
  36. 36.
    Kamiya A, Kinoshita T, Ito Y, Matsui T, Morikawa Y, Senba E, et al. Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer. EMBO J 1999;18(8):2127–2136PubMedPubMedCentralGoogle Scholar
  37. 37.
    Heng BC, Yu H, Yin Y, Lim SG, Cao T. Factors influencing stem cell differentiation into the hepatic lineage in vitro. J Gastroenterol Hepatol 2005;20(7):975–987PubMedGoogle Scholar
  38. 38.
    Hamou C, Callaghan MJ, Thangarajah H, Chang E, Chang EI, et al. Mesenchymal stem cells can participate in ischemic neovascularization. Plast Reconstr Surg 2009;123(2 Suppl):45S–55SPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kucia MJ, Wysoczynski M, Wu W, Zuba-Surma EK, Ratajczak J, Ratajczak MZ. Evidence that very small embryonic-like stem cells are mobilized into peripheral blood. Stem Cells 2008;26(8):2083–2092PubMedGoogle Scholar
  40. 40.
    Tepper OM, Capla JM, Galiano RD, Ceradini DJ, Callaghan MJ, et al. Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells. Blood 2005;105(3):1068–1077PubMedGoogle Scholar
  41. 41.
    Chen Y, Xiang LX, Shao JZ, Pan RL, Wang YX, Dong XJ, et al. Recruitment of endogenous bone marrow mesenchymal stem cells towards injured liver. J Cell Mol Med 2010;14(6B):1494–1508PubMedGoogle Scholar
  42. 42.
    Si Y, Tsou CL, Croft K, Charo IF. CCR2 mediates hematopoietic stem and progenitor cell trafficking to sites of inflammation in mice. J Clin Investig 2010;120(4):1192–1203PubMedPubMedCentralGoogle Scholar
  43. 43.
    Massa M, Rosti V, Ferrario M, Campanelli R, Ramajoli I, Rosso R, et al. Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction. Blood 2005;105(1):199–206PubMedGoogle Scholar
  44. 44.
    Paczkowska E, Kucia M, Koziarska D, Halasa M, Safranow K, Masuik M, et al. Clinical evidence that very small embryonic-like stem cells are mobilized into peripheral blood in patients after stroke. Stroke 2009;40(4):1237–1244PubMedGoogle Scholar
  45. 45.
    Gehling UM, Willems M, Schlagner K, Benndorf RA, Dandri M, Petersen J, et al. Mobilization of hematopoietic progenitor cells in patients with liver cirrhosis. World J Gastroenterol 2010;16(2):217–224PubMedPubMedCentralGoogle Scholar
  46. 46.
    Drukala J, Paczkowska E, Kucia M, Mlynska E, Krajewski A, Machalinski M, et al. Stem cells, including a population of very small embryonic-like stem cells, mobilized into peripheral blood in patients after skin burn injury. Stem Cell Rev 2012;8(1):184–194PubMedGoogle Scholar
  47. 47.
    Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, et al. Bone marrow as a potential source of hepatic oval cells. Science 1999;284:1168–1170PubMedGoogle Scholar
  48. 48.
    Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2000;6:1229–1234PubMedGoogle Scholar
  49. 49.
    Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, et al. Liver from bone marrow in humans. Hepatology 2000;32:11–16PubMedGoogle Scholar
  50. 50.
    Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, AlDhalimy M, et al. Cell fusion is the principal source of bone marrow-derived hepatocytes. Nature 2003;422:897–901PubMedGoogle Scholar
  51. 51.
    Medvinsky A, Smith A. Stem cells: fusion brings down barriers. Nature 2003;422:823–825PubMedGoogle Scholar
  52. 52.
    Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002;297:2256–2259PubMedGoogle Scholar
  53. 53.
    Theise ND, Krause DS, Sharkis S. Comment on “little evidence for developmental plasticity of adult hematopoietic stem cells”. Science 2003;299:1317PubMedGoogle Scholar
  54. 54.
    Yoon CH, Hur J, Park KW, Kim JH, Lee CS, Oh IY, et al. Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases. Circulation 2005;112(11):1618–1627PubMedGoogle Scholar
  55. 55.
    Challen GA, Boles N, Lin KK, Goodell MA. Mouse hematopoietic stem cell identification and analysis. Cytometry A 2009;75(1):14–24PubMedPubMedCentralGoogle Scholar
  56. 56.
    Timmermans F, Van Hauwermeiren F, De Smedt M, Raedt R, Plasschaert F, De Buyzere M, et al. Endothelial outgrowth cells are not derived from CD133+ cells or CD45+ hematopoietic precursors. Arterioscler Thromb Vasc Biol 2007;27(7):1572–1579PubMedGoogle Scholar
  57. 57.
    Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F, et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 2007;109(5):1801–1809PubMedPubMedCentralGoogle Scholar
  58. 58.
    Timmermans F, Plum J, Yoder MC, Ingram DA, Vandekerckhove B, Case J. Endothelial progenitor cells: identity defined? J Cell Mol Med 2009;13(1):87–102PubMedGoogle Scholar
  59. 59.
    Bailey AS, Willenbring H, Jiang S, Anderson DA, Schroeder DA, Wong MH, et al. Myeloid lineage progenitors give rise to vascular endothelium. Proc Natl Acad Sci USA 2006;103(35):13156–13161PubMedPubMedCentralGoogle Scholar
  60. 60.
    Masuda H, Alev C, Akimaru H, Ito R, Shizuno T, Kobori M, et al. Methodological development of a clonogenic assay to determine endothelial progenitor cell potential. Circ Res 2011;109(1):20–37PubMedGoogle Scholar
  61. 61.
    Sandri M, Beck EB, Adams V, Geilen S, Lenk L, Hollriegel R, et al. Maximal exercise, limb ischemia, and endothelial progenitor cells. Eur J Cardiovasc Prev Rehabil 2011;18(1):55–64PubMedGoogle Scholar
  62. 62.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284(5411):143–147PubMedGoogle Scholar
  63. 63.
    Sachetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 2007;131:324–336Google Scholar
  64. 64.
    Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol 2008;180(4):2581–2587PubMedGoogle Scholar
  65. 65.
    Bae KS, Park JB, Kim HS, Kim DS, Park DJ, Kang SJ. Neuron-like differentiation of bone marrow-derived mesenchymal stem cells. Yonsei Med J 2011;52(3):401–412PubMedPubMedCentralGoogle Scholar
  66. 66.
    Nguyen BK, Maltais S, Perrault LP, Tanguay JF, Tardif JC, Stevens LM, et al. Improved function and myocardial repair of infarcted heart by intracoronary injection of mesenchymal stem cell-derived growth factors. J Cardiovasc Transl Res 2010;3(5):547–558PubMedGoogle Scholar
  67. 67.
    Katsha AM, Ohkouchi S, Xin H, Kanehira M, Sun R, Nukiwa T, et al. Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model. Mol Ther 2011;19(1):196–203PubMedPubMedCentralGoogle Scholar
  68. 68.
    Xu X, Xu Z, Xu Y, Cui G. Selective down-regulation of extracellular matrix gene expression by bone marrow derived stem cell transplantation into infarcted myocardium. Circ J 2005;69(10):1275–1283PubMedGoogle Scholar
  69. 69.
    Xu X, Xu Z, Xu Y, Cui G. Effects of mesenchymal stem cell transplantation on extracellular matrix after myocardial infarction in rats. Coron Artery Dis 2005;16(4):245–255PubMedGoogle Scholar
  70. 70.
    Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K, et al. Interleukin 1 receptor antagonist mediates the anti-inflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci USA 2007;104(26):11002–11007PubMedPubMedCentralGoogle Scholar
  71. 71.
    Dayan V, Yannarelli G, Billia F, Filomeno P, Wang XH, Davies JE, et al. Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction. Basic Res Cardiol 2011;106(6):1299–1310PubMedGoogle Scholar
  72. 72.
    Peng L, Xie DY, Lin BL, Liu J, Zhu HP, Xie C, et al. Autologous bone marrow mesenchymal stem cell transplantation in liver failure caused by hepatitis B: short term and long term outcomes. Hepatology 2011;54(3):820–828PubMedGoogle Scholar
  73. 73.
    Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, 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):725–731PubMedPubMedCentralGoogle Scholar
  74. 74.
    Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigembaum GS, Margititch IS, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res 2010;107(7):913–922PubMedPubMedCentralGoogle Scholar
  75. 75.
    Discher DE, Mooney DJ, Zandstra PW. Growth factors, matrices, and forces combine and control stem cells. Science 2009;324(5935):1673–1677PubMedPubMedCentralGoogle Scholar
  76. 76.
    Youn SW, Lee SW, Lee J, Jeong HK, Suh JW, Yoon CH, et al. COMP-Ang1 stimulates HIF-1α-mediated SDF-1 overexpression and recovers ischemic injury through BM-derived progenitor cell recruitment. Blood 2011;117(16):4376–4386PubMedGoogle Scholar
  77. 77.
    Brandao D, Costa C, Canedo A, Vaz G, Pignatelli D. Endogenous vascular endothelial growth factor and angiopoietin-2 expression in critical limb ischemia. Int Angiol 2011;30(1):25–34PubMedGoogle Scholar
  78. 78.
    Massberg S, Konrad I, Schurzinger K, Lorenz M, Schneider S, Zohlnhoefer D, et al. Platelets secrete stromal cell-derived factor 1α and recruit bone marrow-derived progenitor cells to arterial thrombi in vivo. J Exp Med 2006;203(5):1221–1233PubMedPubMedCentralGoogle Scholar
  79. 79.
    Hattori K, Dias S, Heissig B, Hackett NR, Lyden D, Tateno M, et al. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med 2001;193(9):1005–1014PubMedPubMedCentralGoogle Scholar
  80. 80.
    Pitchford SC, Furze RC, Jones CP, Wengner AM, Rankin SM. Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell 2009;4(1):62–72PubMedGoogle Scholar
  81. 81.
    Hopkins SP, Bulgrin JP, Sims RL, Bowman B, Donovan DL, Schmidt SP. Controlled delivery of vascular endothelial growth factor promotes neovascularization and maintains limb function in a rabbit model of ischemia. J Vasc Surg 1998;27(5):886–894PubMedGoogle Scholar
  82. 82.
    Pitchford SC, Furze RC, Jones CP, Wengner AM, Rankin SM. Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell 2009;4(1):62–72PubMedGoogle Scholar
  83. 83.
    Broxmeyer HE, Hangoc G, Cooper S, Campbell T, Ito S, Mantel C. AMD3100 and CD26 modulate mobilization, engraftment, and survival of hematopoietic stem and progenitor cells mediated by the SDF-1/CXCL12-CXCR4 axis. Ann N Y Acad Sci 2007;1106:1–19PubMedGoogle Scholar
  84. 84.
    Levesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Investig 2003;111(2):187–196PubMedPubMedCentralGoogle Scholar
  85. 85.
    Liu F, Pan X, Chen G, Jiang D, Cong X, Fei R, et al. Hematopoietic stem cells mobilized by granulocyte colony-stimulating factor partly contribute to liver graft regeneration after partial orthotopic liver transplantation. Liver Transplant 2006;12(7):1129–1137Google Scholar
  86. 86.
    Takamiya M, Okigaki M, Jin D, Takai S, Nozawa Y, Adachi Y, et al. Granulocyte colony-stimulating factor-mobilized circulating c-Kit+/Flk-1+ progenitor cells regenerate endothelium and inhibit neointimal hyperplasia after vascular injury. Arterioscler Thromb Vasc Biol 2006;26(4):751–757PubMedGoogle Scholar
  87. 87.
    Li X, Xu B. HMG-CoA reductase inhibitor regulates endothelial progenitor function through the phosphatidylinositol 3′-kinase/AKT signal transduction pathway. Appl Biochem Biotechnol 2009;157(3):545–553PubMedGoogle Scholar
  88. 88.
    Urao N, Okigaki M, Yamada H, Aadachi Y, Matsuno K, Matsui A, et al. Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia. Circ Res 2006;98(11):1405–1413PubMedGoogle Scholar
  89. 89.
    Gensch C, Clever YP, Werner C, Hanhoun M, Bohm M, Laufs U. The PPAR-γ agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells. Atherosclerosis 2007;192(1):67–74PubMedGoogle Scholar
  90. 90.
    Oh SH, Miyazaki M, Kouchi H, Inoue Y, Sakaguchi M, Tsuji T, et al. Hepatocyte growth factor induces differentiation of adult rat bone marrow cells into a hepatocyte lineage in vitro. Biochem Biophys Res Commun 2000;279(2):500–504PubMedGoogle Scholar
  91. 91.
    Cui YL, Meng MB, Tang H, Zheng MH, Wang YB, Han HX, et al. Recombinant human hepatocyte growth factor for liver failure. Contemp Clin Trials 2008;29(5):696–704PubMedGoogle Scholar
  92. 92.
    Gandhi CR. Augmenter of liver regeneration. Fibrogenes Tissue Repair 2012;5:10Google Scholar
  93. 93.
    De Silvestro G, Vicarioto M, Donadel C, Menegazzo M, Marson P, Corsini A. Mobilization of peripheral blood hematopoietic stem cells following liver resection surgery. Hepatogastroenterology 2004;51(57):805–810PubMedGoogle Scholar
  94. 94.
    Lorenzini S, Isidori A, Catani L, Gramenzi A, Talarico S, Bonifazi F, et al. Stem cell mobilization and collection in patients with liver cirrhosis. Aliment Pharmacol Ther 2008;27(10):932–939PubMedGoogle Scholar
  95. 95.
    Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature 2003;422:901–904PubMedGoogle Scholar
  96. 96.
    Gianni AM, Siena S, Bregni M, Tarella C, Stern AC, Pileri A, et al. Granulocyte-macrophage colony-stimulating factor to harvest circulating haemopoietic stem cells for autotransplantation. Lancet 1989;2:580–585PubMedGoogle Scholar
  97. 97.
    Gaia S, Smedile A, Omede P, Olivero A, Sanavio F, Balzola F. Feasibility and safety of G-CSF administration to induce bone marrow derived cells mobilization in patients with end stage liver disease. J Hepatol 2006;45:13–19PubMedGoogle Scholar
  98. 98.
    Spahr L, Lambert JF, Brandt LR, Chalandon Y, Frossard JL, Giostra E, et al. Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial. Hepatology 2008;48(1):221–229PubMedGoogle Scholar
  99. 99.
    Garg V, Garg H, Khan A, Trehanpati N, Kumar A, Sharma BC, et al. Granulocyte-colony stimulating factor (G- CSF) therapy mobilizes CD34 cells and improves survival in patients with acute on chronic liver failure. Gastroenterology 2012;142(3):505–512PubMedGoogle Scholar
  100. 100.
    Duan XZ, Liu FF, Tong JJ, Yang HZ, Chen J, Liu XY, 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;19:1104–1110PubMedPubMedCentralGoogle Scholar
  101. 101.
    Murat O. Arcasoy. Non erythroid effects of erythropoietin. Haematologica 2010;95(11):1803–1804PubMedPubMedCentralGoogle Scholar
  102. 102.
    Schmeding M, Boas-KnoopS LippertS, Ruehl S, Somasundaram R, Dagdelen T, et al. Erythropoietin promotes hepatic regeneration after extended liver resection in rats. J Gastroenterol Hepatol 2008;23(7):1125–1131PubMedGoogle Scholar
  103. 103.
    Greif F, Ben Ari Z, Taya R, Pappo O, Kurtzwald E, Cheparko Y. Dual effect of EPO on liver protection and regeneration after subtotal hepatectomy in rats. Liver Transplant 2010;16(5):631–638Google Scholar
  104. 104.
    Ben Ari Z, Zilbermints V, Pappo O, Avlas O, Sharon E, Grief F, et al. Erythropoetin increases survival and attenuates fulminant hepatic failure induced by D- galactosamine/lipopolysaccharide in mice. Transplantation 2011;92(1):18–24PubMedGoogle Scholar
  105. 105.
    Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig MC, Steinman RM. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8 + T cell tolerance. J Exp Med 2002;196:1627–1638PubMedPubMedCentralGoogle Scholar
  106. 106.
    Zhang Z, Zou ZS, Fu JL, Cai L, Jin L, Liu YJ, et al. Severe dendritic cell perturbation is actively involved in the pathogenesis of acute-on-chronic hepatitis B liver failure. J Hepatol 2008;49:396–406PubMedGoogle Scholar
  107. 107.
    Zhao J, Zhang JY, Yu HW, He YL, Zhao JJ, Li J, et al. Improved survival ratios correlate with myeloid dendritic cell restoration in acute-on-chronic liver failure patients receiving methyl prednisolone therapy. Cell Mol Immunol 2012;9(5):417–422PubMedPubMedCentralGoogle Scholar
  108. 108.
    Sumpter TL, Abe M, Tokita D, Thomson AW. Dendritic cells, the liver and transplantation. Hepatology 2007;46:2021–2031PubMedGoogle Scholar
  109. 109.
    Castellaneta A, Di Leo A, Amoruso A, Francavilla R, Margiotta M, Barone M, et al. Functional modification of CD11c liver dendritic cells during liver regeneration after hepatectomy in mice. Hepatology 2006;43(4):807–816PubMedGoogle Scholar
  110. 110.
    Khanam A, Trehanpati N, Garg V, Kumar C, Garg H, Sarin SK. Altered Frequencies of Dendritic cells and IFN-γ secreting T cells with Granulocyte colony stimulating factor (G-CSF) therapy in acute-on-chronic liver failure. Liver Int. 2014. doi:  10.1111/liv.12415
  111. 111.
    Liu T, Wang Y, Wen C, Zhang S, Zhang C. Stem cells or macrophages: which contribute to bone marrow cell therapy for liver cirrhosis? Hepatology 2011;54(3):1103PubMedGoogle Scholar
  112. 112.
    Thomas AJ, Pope C, Wojtacha D, Robson A, Gordon Walker TT, Hartland S, et al. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology 2011;53:2003–2015PubMedGoogle Scholar
  113. 113.
    Viebahn CS, Benseler V, Holz LE, Elsegood CL, Vo M, Bertolino P, et al. Invading macrophages play a major role in the liver progenitor cell response to chronic liver injury. J Hepatol 2010;53(3):500–507PubMedGoogle Scholar
  114. 114.
    Wang J, Zhou X, Cui L, Yan L, Liang J, Cheng X, et al. The significance of CD14+ monocytes in peripheral blood stem cells for the treatment of rat liver cirrhosis. Cytotherapy 2010;12(8):1022–1034PubMedGoogle Scholar
  115. 115.
    Wasmuth HE, Kunz D, Yagmur E, Timmer-Strangho¨ner A, Vidacek D, Siewert E, et al. Patients with acute on chronic liver failure display ‘sepsis like’ immune paralysis. J Hepatol 2005;42:195–201PubMedGoogle Scholar
  116. 116.
    Katoonizadeh A, Laleman W, Versylpe C, Wilmer A, Maleux G, Roskams T, et al. Early features of acute-on-chronic alcoholic liver failure: a prospective cohort study. Gut 2010;59:1561–1569PubMedGoogle Scholar
  117. 117.
    Mookerjee RP, Stadlbauer V, Lidder S, Wright GA, Hodges SJ, Davies NA, et al. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 2007;46(3):831–840PubMedGoogle Scholar
  118. 118.
    Jalan R, Gines P, Olson JC, Mookerjee RP, Moreau R, Garcia-Tsao G, et al. Acute-on-chronic liver failure review. J Hepatol 2012;57(6):1336–1348PubMedGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2014

Authors and Affiliations

  • Chandan Kumar Kedarisetty
    • 1
  • Lovkesh Anand
    • 1
  • Arshi Khanam
    • 2
  • Anupam Kumar
    • 2
  • Archana Rastogi
    • 3
  • Rakhi Maiwall
    • 1
  • Shiv Kumar Sarin
    • 1
    Email author
  1. 1.Department of HepatologyInstitute of Liver and Biliary SciencesNew DelhiIndia
  2. 2.Department of ResearchInstitute of Liver and Biliary SciencesNew DelhiIndia
  3. 3.Department of PathologyInstitute of Liver and Biliary SciencesNew DelhiIndia

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