Hepatic stellate cells - regional stem cells of the liver or a component of microenvironment?

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access


For years, it is debated about the nature and localization of stem cell of the liver. In recent years, a particular interest is paid to hepatic stellate cells According to the conducted researches, these cells are actively involved in restoring of hepatocytes population by different liver damages and they have a number of properties specific to stem cells. It should be noted that hepatic stellate cells are able to maintain viability in culture and differentiate into hepatocyte direction under certain conditions in vitro. Interestingly, hepatic stellate cells may themselves create such conditions for progenitor cells in vivo, as well as in vitro This is achieved thanks to the hepatic stellate cells secretion of the extracellular matrix proteins, a complex of growth factors and establishment of direct intercellular contacts. Stellate cells, localized in perisinusoidal space, are also influenced by the surrounding hepatocytes and endothelial cells Thus, perisinusoidal space is a kind of dynamic system, in which hepatocytes and endothelial cells determine the “resting” state of stellate cells, and the latter, if necessary, can be activated and participate in restoration of the liver cell populations. Based on these data, the researchers suggest that the hepatic perisinusoidal space - a niche of hepatic stellate cells, regional stem cells of the liver

Full Text

Restricted Access

About the authors

A. K Shafigullina

Kazan (Volga region) Federal University

Email: sh.aygul@gmail.com

A. A Gumerova

Kazan (Volga region) Federal University

A. P Kiassov

Kazan (Volga region) Federal University


  1. Stewart S. Is There a Liver Stem Cell? Cancer research. 1990; 50: 3811-5.
  2. Alison M.R., Poulsom R., Wright N.A. An introduction to stem cells. J. Path. 2002; 197: 419-23.
  3. Zhang J., Niu C., Ye L. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 2003; 425: 836-41.
  4. Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 1978; 4: 7-25.
  5. Reya T., Duncan A.W., Ailles L. et al. A role for WNT signaling in self-reneval of haemotopoietic stem cell. Nature 2003; 423: 409-14.
  6. Spradling A., Drummond-Barbosa D., Kai T. Stem cells find their niche. Nature 2001; 414(6859): 98-104.
  7. Katayama Y., Battista M., Kao W. M. et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from the bone marrow. Cell. 2006; 124: 407-21.
  8. Mauro A. Satellite cell of skeletal muscle fibers. J. Biophys. Biochem Cytol 1961; 9: 493-5
  9. Oakberg E.F. Spermatogonial stem-cell renewal in the mouse. Anat. Rec. 1971; 169: 515-31.
  10. Fuchs E., Tumbar T., Guasch G. Socializing with the neighbors: stem cells and their niche Cell 2004; 116: 769-78
  11. Morrison S.J., Spradling A.C. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life Cell 2008; 132: 598-611.
  12. Stewart S. Heterogeneity and Plasticity of Hepatocyte Lineage Cells. Hepatology 2001; 33(3): 738-50.
  13. Sawitza I., Kordes C., Haussinger D. The niche of stellate cells within rat liver. Hepatology 2009; 50: 1617-24.
  14. Watt F. M., Hogan B. L. Out of Eden: stem cells and their niches. Science 2000; 287: 1427-30.
  15. Ara T., Tokoyoda K., Sugiyama T. et al. Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny. Immunity 2003; 19(2): 257-67.
  16. Aiuti A., Webb I.J., Bleul C. et al. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34 + progenitors to peripheral blood. J. Exp. Med. 1997; 185(1): 111-20.
  17. Bioulac-Sage P., Lafon M.E., Saric J. et al. Nerves and perisinusoidal cells in human liver. J. Hepatol. 1990; 10: 105-12.
  18. Ueno T. Intrinsic innervation of the human liver. J. Clin. Electorn. Microsc. 1988; 21: 481-91.
  19. Athary A., Hanecke K., Jungermann K. Prostaglandin F2a and D2 release from primary Ito cell cultures after stimulation with noradrenaline and ATP but not adenosine. Hepatology 1994; 20: 142-8.
  20. Friedman S.L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 2008; 88: 125-72.
  21. Гумерова А.А., Титова М.А., Киясов А.П. Экспрессия маркеров различных типов клеток печени на ранних этапах пренатального развития человека. Цитология 2007; 2: 133-41.
  22. Kiassov A.P., Van Eyken P., van Pelt J.F. et al. Desmin expressing nonhematopoietic liver cells during rat liver development: an immunohistochemical and morphometric study Differentiation 1995; 59(4): 253-8.
  23. Kordes C., Sawitza I., Haussinger D. Hepatic and pancreatic stellate cells in focus. Biol. Chem. 2009; 390(10): 1003-12.
  24. Гумерова А.А., Шафигуллина А.К., Трондин А.А. и др. Звёздчатые клетки печени стимулируют дифференцировку мезенхимальных стволовых клеток костного мозга крысы в гепатоциты in vitro. клеточная трансплантология и тканевая инженерия 2012; 6(4): 72-81
  25. Burt A.D., Robertson J.L., Heir J. et al. Desmin-containing stellate cells in rat liver; distribution in normal animals and response to experimental acute liver injury. J. Pathol. 1986; 150(1): 29-35.
  26. Tsutsumi M., Takada A., Takase S. Characterization of desminpositive rat liver sinusoidal cells. Hepatology 1987; 7(2): 277-84.
  27. Knittel T., Dinter C., Kobold D. et al. Expression and regulation of cell adhesion molecules by hepatic stellate cells (HSC) of rat liver: involvement of HSC in recruitment of inflammatory cells during hepatic tissue repair. Am. J. Pathol. 1999; 154(1): 153-67.
  28. Kordes C., Sawitza I., Müller-Marbach A. et al. CD133 + hepatic stellate cells are progenitor cells Biochem Biophys Res Commun. 2007; 352(2): 410-7.
  29. Baba S., Fujii H., Hirose T. et al. Commitment of bone marrow cells to hepatic stellate cells in mouse J Hepatol 2004; 40(2): 255-60
  30. Snykers S., Vanhaecke T., Papeleu P. et al. Sequential exposure to cytokines reflecting embryogenesis: the key for in vitro differentiation of adult bone marrow stem cells into functional hepatocyte-like cells. Toxicol. Sci. 2006; 94(2): 330-41.
  31. Colletti E.J., Airey J.A., Liu W. et al. Generation of tissue-specific cells from MSC does not require fusion or donor-to-host mitochondrial/ membrane transfer. Stem Cell Res. 2009; 2(2): 125-38.
  32. Kordes C., Sawitza I., Götze S. et al. Stellate cells are mesenchymal stem cells. Eur. J. Med. Res. 2014; 19(1): S6.
  33. Petersen B.E., Zajac V.F., Michalopoulos G.K. Hepatic oval cell activation in response to injury following chemically induced periportal or pericentral damage in rats. Hepatology 1998; 27(4): 1030-8.
  34. Киясов А.П., Гумерова А.А., Титова М.А. Мезенхимально-эпителиальная трансформация клеток Ито in vitro. Клеточные технологии в биологии и медицине 2006; 3: 150-4.
  35. Schirmacher P., Geerts A., Pietrangelo A. et al. Hepatocyte growth factor/hepatopoietin A is expressed in fat-storing cells from rat liver but not myofibroblast-like cells derived from fat-storing cells Hepatology 1992; 15: 5-11.
  36. Maher J.J. Cell-specific expression of hepatocyte growth factor in liver Upregulation in sinusoidal endothelial cells after carbon tetrachloride. J. Clin. Invest. 1993; 91(5): 2244-52.
  37. Weidner K.M., Arakaki N., Hartmann G. et al. Evidence for the identity of human scatter factor and human hepatocyte growth factor PNAS USA 1991; 88: 7001-5.
  38. Gohda E., Tsubouchi H., Nakayama H. et al. Purification and partial characterization of hepatocyte growth factor from plasma of a patient with fulminant hepatic failure. J. Clin. Invest. 1988; 81: 414-9.
  39. Birchmeier C., Gherardi E. Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol. 1998; 8: 404-10.
  40. Matsumoto K., Nakamura T. Emerging multipotent aspects of hepatocyte growth factor. J. Biochem. Tokyo. 1996; 119(4): 591-600.
  41. Zarnegar R., DeFrances M.C., Kost D.P. Expression of hepatocyte growth factor mRNA in regenerating rat liver after partial hepatectomy. Biochem. Biophys. Res. Commun. 1991; 177(1): 559-65
  42. Kollet O., Shivtiel S., Chen Y. Q. 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(2): 160-9.
  43. Bladt F., Riethmacher D., Isenmann S. et al. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature 1995; 376: 768-71.
  44. Nakamura T., Nishizawa T., Hagiya M. et al. Molecular cloning and expression of human hepatocyte growth factor. Nature 1989; 342(6248): 440-3
  45. Yoon J.H., Lee H.V., Lee J.S. et al. Development of a nontransformed human liver cell line with differentiated-hepatocyte and urea-synthetic functions: applicable for bioartificial liver. Int. J. Artif. Organs. 1999; 22(11): 769-77.
  46. Hamamoto R., Kamihira M., Iijima S. Growth and differentiation of cultured fetal hepatocytes isolated various developmental stages. Biosci. Biotechnol. Biochem. 1999; 63(2): 395-401.
  47. Oyagi S., Hirose M., Kojima M. et al. Therapeutic effect of transplanting HGF-treated bone marrow mesenchymal cells into CCl4-injured rats. J. Hepatol. 2006; 44(4): 742-8.
  48. Fujio K. Expression of stem cell factor and its receptor, c-kit, during liver regeneration from putative stem cells in adult rat. Lab. Invest. 1994; 70: 511-6.
  49. Mullhaupt B., Feren A., Fodor E. Liver expression of epidermal growth factor RNA. Rapid increases in immediate-early phase of liver regeneration. J. Biol. Chem. 1994; 269(31): 19667-70.
  50. Meyer D.H., Bachem M.G., Gressner A.M. Modulation of hepatic lipocyte proteoglycan synthesis and proliferation by Kupffer cellderived transforming growth factors type beta 1 and type alpha. Biochem. Biophys. Res. Commun. 1990; 171: 1122-9.
  51. Yoshino R., Miura K., Segawa D. et al. Epimorphin expression and stellate cell status in mouse liver injury. Hepatol. Res. 2006; 34: 238-49
  52. Asahina K., Sato H., Yamasaki C. et al. Pleiotrophin/heparinbinding growth-associated molecule as a mitogen of rat hepatocytes and its role in regeneration and development of liver. Am. J. Pathol. 2002; 160: 2191-205.
  53. Marsden E.R., Hu Z., Fujio K. et al. Expression of acidic fibroblast growth factor in regenerating liver and during hepatic differentiation. Lab. Invest. 1992; 67(4): 427-33.
  54. Pinzani M., Knauss T.C., Pierce G.F. et al. Mitogenic signals for platelet-derived growth factor isoforms in liver fat-storing cells. Am. J. Physiol. 1991; 260(3): C485-91.
  55. Corson L.B., Yamanaka Y., Lai K.M. et al. Spatial and temporal patterns of ERK signaling during mouse embryogenesis. Development 2003; 130(19): 4527-37.
  56. Yoon J.H., Lee H.V., Lee J.S. et al. Development of a nontransformed human liver cell line with differentiated-hepatocyte and urea-synthetic functions: applicable for bioartificial liver. Int. J. Artif. Organs. 1999; 22(11): 769-77.
  57. Flaumenhaft R., Abe M., Mignatti P. et al. Basic fibroblast growth factor-induced activation of latent transforming growth factor beta in endothelial cells: regulation of plasminogen activator activity. J. Cell Biol. 1992; 118(4): 901-9.
  58. Ishikawa T., Terai S., Urata Y. et al. Fibroblast growth factor 2 facilitates the differentiation of transplanted bone marrow cells into hepatocytes. Cell Tissue Res. 2006; 323(2): 221-31.
  59. Wright D.E., Bowman E.P., Wagers A.J. et al. Hematopoietic stem cells are uniquely selective in their migratory response to chemokines. J. Exp. Med. 2002; 195: 1145-54.
  60. Kubota H., Yao H.L., Reid L.M. Identification and characterization of vitamin A-storing cells in fetal liver: implications for functional importance of hepatic stellate cells in liver development and hematopoiesis. Stem Cells. 2007; 25(9): 2339-49.
  61. Lints T.J., Hartley L., Parsons L.M. et al. Mesoderm-specific expression of the divergent homeobox gene Hlx during murine embryogenesis. Dev. Dyn. 1996; 205: 457-70.
  62. Eckardt K.U. Erythropoietin production in liver and kidneys. Curr. Opin. Nephrol. Hypertens. 1996; 5(1): 28-34.
  63. Passino M.A., Adams R.A., Sikorski S.L. et al. Regulation of hepatic stellate cell differentiation by the neurotrophin receptor p75NTR. Science 2007; 315: 1853-6.
  64. Tocci A., Parolini I., Gabbianelli M. et al. Dual action of retinoic acid on human embryonic/fetal hematopoiesis: blockade of primitive progenitor proliferation and shift from multipotent/erythroid/monocytic to granulocytic differentiation program. Blood 1996; 88(8): 2878-88.
  65. Evarts R.P., Hu Z., Omori N. et al. Effect of vitamin A deficiency on the integrity of hepatocytes after partial hepatectomy. Am. J. Pathol. 1995; 147(3): 699-706.
  66. Nagai H., Terada K., Watanabe G. et al. Differentiation of liver epithelial (stem-like) cells into hepatocytes induced by coculture with hepatic stellate cells. Biochem. Biophys. Res. Commun. 2002; 293(5): 1420-5.
  67. Scadden D.T. The stem-cell niche as an entity of action. Nature 2006; 441(7097): 1075-9.
  68. Киясов А.П., Гумерова А.А., Билалов М.М. Экспрессия цитокератинов в пре- и постнатальном онтогенезе. Онтогенез 1997; 28(5): 389-93
  69. Vassy J., Rigaut J.P., Briane D. et al. Confocal microscopy immunofluorescence localization of desmin and other intermediate filament proteins in fetal rat livers. Hepatology 1993; 17(2): 293-300
  70. Hoppo T., Fujii H., Hirose T. et al. Thy1-positive mesenchymal cells promote the maturation of CD49f-positive hepatic progenitor cells in the mouse fetal liver. Hepatology 2004; 39: 1362-70.
  71. Friedman S.L. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008; 134(6): 1655-69.
  72. Sanchez A., Alvarez A.M., Pagan R. et al. Fibronectin regulates morphology, cell organization and gene expression of rat fetal hepatocytes in primary culture. J. Hepatol. 2000; 32: 242-50.
  73. Schwartz R.E., 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.

Copyright (c) 2015 Eco-Vector

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ПИ № ФС 77 - 85657 от 21.07.2023 от 11.03.2014.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies