Use of Stem Cells to Block the Activation of Hepatic Stellate Cells in Diseased Liver

  • Syamantak Majumder
  • Palanivel Gajalakshmi
  • Suvro Chatterjee


Liver is an important organ in vertebrates and performs major functions such as digestion, drug detoxification, and protein synthesis. Chronic liver fibrosis is a major threat to human life. The etiology of liver fibrosis includes chronic hepatitis infection, alcohol abuse, and nonalcoholic steatohepatitis. The pathophysiology of liver fibrosis shows that there is accumulation of extracellular matrix (ECM) proteins including collagen, proteoglycan, and adhesive glycoproteins. Activated hepatic stellate cells (HSCs) are the major collagen-producing cells in the liver. The present in vitro study demonstrates that bipotential murine oval liver (BMOL) stem cells secrete soluble factors, which are capable of inducing apoptosis in activated HSCs and inhibit the formation of collagen. Further, the study can be extended to identify the soluble factors capable of attenuating activated HSCs and opens a new research direction to control liver fibrosis.


Conditioned Medium Liver Fibrosis Hepatic Stellate Cell Normal Medium Fibrotic Liver 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was financially supported by grants from the Department of Biotechnology (DBT), Government of India (BT/SBIRI/779/34-B15/2011), and University Grants Commission (UGC), Government of India, under Faculty Recharge Program to SC. This work was partially supported by the Department of Science and Technology (DST), Government of India (SR/WOS-A/LS-14/2011(G) to PG).


  1. 1.
    Maton A, Hopkins J, McLaughlin CW, Johnson S, Warner MQ, LaHart D, Wright JD (1993) Human biology and health. Prentice Hall, Englewood CliffsGoogle Scholar
  2. 2.
    Pond SM, Tozer TN (1984) First-pass elimination. Basic concepts and clinical consequences. Clin Pharmacokinet 9(1):1–25PubMedCrossRefGoogle Scholar
  3. 3.
    Saxena R, Theise ND, Crawford JM (1999) Microanatomy of the human liver-exploring the hidden interfaces. Hepatology 30:1339–1346PubMedCrossRefGoogle Scholar
  4. 4.
    Friedman SL (2004) Mechanisms of disease: mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol 1(2):98–105PubMedCrossRefGoogle Scholar
  5. 5.
    Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115(2):209–218PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Forbes JS (2008) Stem cell therapy for chronic liver disease choosing the right tools for the job Commentaries. Gut 57:153–155PubMedCrossRefGoogle Scholar
  7. 7.
    Espanol-Suner R et al (2012) Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Gastroenterology 143(6):1564–1575PubMedCrossRefGoogle Scholar
  8. 8.
    Troeger JS, Mederacke I, Gwak GY, Dapito DH, Mu X, Hsu CC, Pradere JP, Friedman RA, Schwabe RF (2012) Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 143(4):1073–1083PubMedCrossRefGoogle Scholar
  9. 9.
    Tomita K et al (2004) Piogliazone prevents alcohol-induced fatty liver in rats through upregulation of c-Met. Gastroenterology 126:873–885PubMedCrossRefGoogle Scholar
  10. 10.
    Yokohama S, Yoneda M, Haneda M, Okamoto S, Okada M, Aso K, Hasegawa T, Tokusashi Y, Miyokawa N, Nakamura K (2004) Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 40:1222–1225PubMedCrossRefGoogle Scholar
  11. 11.
    Thyagarajan SP, Jayaram S, Gopalakrishnan V, Hari R, Jeyakumar P, Sripathi MS (2002) Herbal medicines for liver diseases in India. J Gastroenterol Hepatol 17(Suppl 3):S370–S376PubMedCrossRefGoogle Scholar
  12. 12.
    Girish C, Pradhan SC (2012) Indian herbal medicines in the treatment of liver diseases: problems and promises. Fundam Clin Pharmacol 26(2):180–189PubMedCrossRefGoogle Scholar
  13. 13.
    Wang BE (2000) Treatment of chronic liver diseases with traditional Chinese medicine. J Gastroenterol Hepatol 15(Suppl):E67–E70PubMedCrossRefGoogle Scholar
  14. 14.
    Geerts A (2001) History, heterogeneity, developmental biology and functions of quiescent HSC. Semin Liver Dis 21:311–335PubMedCrossRefGoogle Scholar
  15. 15.
    Friedman SL (2000) Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 275:2247–2250PubMedCrossRefGoogle Scholar
  16. 16.
    Gressner AM, Lotfi S, Gressner G, Haltner E, Kropf J (1993) Synergism between hepatocytes and Kupffer cells in the activation of fat storing cells (perisinusoidal lipocytes). J Hepatol 19:117–132PubMedCrossRefGoogle Scholar
  17. 17.
    Gressner AM (1995) Cytokines and cellular crosstalk involved in the activation of fat-storing cells. J Hepatol 22:28–36PubMedCrossRefGoogle Scholar
  18. 18.
    Svegliati-Baroni G, Saccomanno S, van Goor H, Jansen P, Benedetti A, Moshage H (2001) Involvement of reactive oxygen species and NO radicals in activation and proliferation of rat HSC. Liver 21:1–12PubMedCrossRefGoogle Scholar
  19. 19.
    Lee KS, Buck M, Houglum K, Chojkier M (1995) Activation of HSC by TGF-α and collagen type I is mediated by oxidative stress through c-myb expression. J Clin Invest 96:2461–2468PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Pinzani M, Gesualdo L, Sabbah GM, Abboud HE (1989) Effects of platelet-derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat storing cells. J Clin Invest 84:1786–1793PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Forbes SJ et al (2004) A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 126:955–963PubMedCrossRefGoogle Scholar
  22. 22.
    Mannaerts I, Eysackers N, Onyema OO, Van Beneden K, Valente S, Mai A, Odenthal M, van Grunsven LA (2013) Class II HDAC inhibition hampers hepatic stellate cell activation by induction of microRNA-29. PLoS One 8(1):e55786PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Christ B, Pelz S (2013) Implication of hepatic stem cells in functional liver repopulation. Cytometry A 83(1):90–102PubMedCrossRefGoogle Scholar
  24. 24.
    Roskams T, De Vos R, Van Eyken P, Myazaki H, Van Damme B, Desmet V (1998) Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man. J Hepatol 29(3):455–463PubMedCrossRefGoogle Scholar
  25. 25.
    Kisseleva T, Gigante E, Brenner DA (2010) Recent advances in liver stem cell therapy. Curr Opin Gastroenterol 26(4):395–402PubMedCrossRefGoogle Scholar
  26. 26.
    Grisham JW, Hartroft WS (1961) Morphologic identification by electron microscopy of “oval” cells in experimental hepatic degeneration. Lab Invest 10:317–332PubMedGoogle Scholar
  27. 27.
    Tirnitz-Parker JE, Tonkin JN, Knight B, Olynyk JK, Yeoh GC (2007) Isolation, culture and immortalisation of hepatic oval cells from adult mice fed a choline-deficient, ethionine-supplemented diet. Int J Biochem Cell Biol 39:2226–2239PubMedCrossRefGoogle Scholar
  28. 28.
    Nagy P, Kiss A, Schnur J, Thorgeirsson SS (1998) Dexamethasone inhibits the proliferation of hepatocytes and oval cells but not bile duct cells in rat liver. Hepatology 28:423–429PubMedCrossRefGoogle Scholar
  29. 29.
    Bisgaard HC, Muller S, Nagy P, Rasmussen LJ, Thorgeirsson SS (1999) Modulation of the gene network connected to interferon-gamma in liver regeneration from oval cells. Am J Pathol 155:1075–1085PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Crosby HA, Hubscher SG, Joplin RE, Kelly DA, Strain AJ (1998) Immunolocalization of OV-6, a putative progenitor cell marker in human fetal and diseased pediatric liver. Hepatology 28(4):980–985PubMedCrossRefGoogle Scholar
  31. 31.
    Suzuki A, Sekiya S, Onishi M, Oshima N, Kiyonari H, Nakauchi H, Taniguchi H (2008) Flow cytometric isolation and clonal identification of self-renewing bipotent hepatic progenitor cells in adult mouse liver. Hepatology 48(6):1964–1978PubMedCrossRefGoogle Scholar
  32. 32.
    Lowes KN, Croager EJ, Olynyk JK, Abraham LJ, Yeoh GC (2003) Oval cell-mediated liver regeneration: role of cytokines and growth factors. J Gastroenterol Hepatol 18:4–12PubMedCrossRefGoogle Scholar
  33. 33.
    de Oliveira SA, de Freitas Souza BS, Sá Barreto EP, Kaneto CM, Neto HA, Azevedo CM, Guimarães ET, de Freitas LA, Ribeiro-Dos-Santos R, Soares MB (2012) Reduction of galectin-3 expression and liver fibrosis after cell therapy in a mouse model of cirrhosis. Cytotherapy 14(3):339–349PubMedCrossRefGoogle Scholar
  34. 34.
    Manuelpillai U, Tchongue J, Lourensz D, Vaghjiani V, Samuel CS, Liu A, Williams ED, Sievert W (2010) Transplantation of human amnion epithelial cells reduces hepatic fibrosis in immunocompetent CCl4-treated mice. Cell Transplant 19(9):1157–1168PubMedCrossRefGoogle Scholar
  35. 35.
    Lam SP, Luk JM, Man K, Ng KT, Cheung CK, Rose-John S, Lo CM (2010) Activation of interleukin-6-induced glycoprotein 130/signal transducer and activator of transcription 3 pathway in mesenchymal stem cells enhances hepatic differentiation, proliferation, and liver regeneration. Liver Transpl 16(10):1195–1206PubMedCrossRefGoogle Scholar
  36. 36.
    Gur C, Doron S, Kfir-Erenfeld S, Horwitz E, Abu-Tair L, Safadi R, Mandelboim O (2012) NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis. Gut 61(6):885–893PubMedCrossRefGoogle Scholar
  37. 37.
    Majumder S, Siamwala JH, Srinivasan S, Sinha S, Sridhara SR, Soundararajan G, Seerapu HR, Chatterjee S (2011) Simulated microgravity promoted differentiation of bipotential murine oval liver stem cells by modulating BMP4/Notch1 signaling. J Cell Biochem 112(7):1898–1908PubMedCrossRefGoogle Scholar
  38. 38.
    Srinivas G, Anto RJ, Srinivas P, Vidhyalakshmi S, Senan VP, Karunagaran D (2003) Emodin induces apoptosis of human cervical cancer cells through poly (ADP-ribose) polymerase cleavage and activation of caspase-9. Eur J Pharmacol 473:117–125PubMedCrossRefGoogle Scholar
  39. 39.
    Moriya K, Yoshikawa M, Ouji Y, Saito K, Nishiofuku M, Matsuda R, Ishizaka S, Fukui H (2008) Embryonic stem cells reduce liver fibrosis in CCl4-treated mice. Int J Exp Pathol 89:401–409PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Sakaida I, Terai S, Yamamoto N, Aoyama K, Ishikawa T, Nishina H, Okita K (2004) Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology 40:1304–1311PubMedCrossRefGoogle Scholar
  41. 41.
    Zhao DC, Lei JX, Chen R, Yu WH, Zhang XM, Li SN, Xiang P (2005) Bone marrow derived mesenchymal stem cells protect against experimental liver fibrosis in rats. World J Gastroenterol 11:3431–3440PubMedGoogle Scholar
  42. 42.
    Oyagi S, Hirose M, Kojima M, Okuyama M, Kawase M, Nakamura T, Ohgushi H, Yagi K (2006) Therapeutic effect of transplanting HGF-treated bone marrow mesenchymal cells into CCl4-injured rats. J Hepatol 44:742–748PubMedCrossRefGoogle Scholar
  43. 43.
    Zheng JF, Liang LJ, Wu CX, Chen JS, Zhang ZS (2006) Transplantation of fetal liver epithelial progenitor cells ameliorates experimental liver fibrosis in mice. World J Gastroenterol 12:7292–7298PubMedCentralPubMedGoogle Scholar
  44. 44.
    Vessey CJ, Hall PM (2001) Hepatic stem cells: a review. Pathology 33:130–141PubMedGoogle Scholar
  45. 45.
    Sell S (2001) Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology 33:738–750PubMedCrossRefGoogle Scholar
  46. 46.
    Lowes KN, Brennan BA, Yeoh GC, Olynyk JK (1999) Ovel cell numbers in human chronic liver disease are directly related to disease severity. Am J Pathol 154:537–541PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Mann J, Oakely F, Akiboye F, Elsharkawy A, Thorne AW, Mann DA (2007) Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implication for wound healing and fibrogenesis. Cell Death Differ 14:275–285PubMedCrossRefGoogle Scholar
  48. 48.
    Paizis G et al (2002) Up-regulation of components of the renin-angiotensin system in the bile duct ligated rat liver. Gastroenterology 123:1667–1676PubMedCrossRefGoogle Scholar
  49. 49.
    Bataller R et al (2003) Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II. Gastroenterology 125:117–125PubMedCrossRefGoogle Scholar
  50. 50.
    Spee B, Carpino G, Schotanus BA, Katoonizadeh A, Vander Borght S, Gaudio E, Roskams T (2010) Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling. Gut 59(2):247–257PubMedCrossRefGoogle Scholar
  51. 51.
    Español-Suñer R, Carpentier R, Van Hul N, Legry V, Achouri Y, Cordi S, Jacquemin P, Lemaigre F, Leclercq IA (2012) Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Gastroenterology 143(6):1564–1575PubMedCrossRefGoogle Scholar
  52. 52.
    Parekkadan B, van Poll D, Megeed Z, Kobayashi N, Tilles AW, Berthiaume F, Yarmush ML (2007) Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells. Biochem Biophys Res Commun 363(2):247–252PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer India 2014

Authors and Affiliations

  • Syamantak Majumder
    • 1
  • Palanivel Gajalakshmi
    • 2
  • Suvro Chatterjee
    • 3
    • 4
  1. 1.Aab Cardiovascular Research Institute, School of Medicine and DentistryUniversity of RochesterRochesterUSA
  2. 2.Life Sciences Division, Vascular Biology Lab, AU-KBC Research CentreAnna UniversityChennaiIndia
  3. 3.Department of Biotechnology, Vascular Biology Lab, AU-KBC Research CentreAnna UniversityChennaiIndia
  4. 4.Centre for BiotechnologyAnna UniversityChennaiIndia

Personalised recommendations