Skip to main content

Advertisement

SpringerLink
Log in

Hepatic stellate cells: fibrogenic, regenerative or both? Heterogeneity and context are key

  • Review Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Since their original identification, our understanding of the role of hepatic stellate cells in both health and disease continues to grow. Numerous studies have delineated the role of stellate cell activation in contributing to the pool of myofibroblasts responsible for liver fibrosis, and these have resulted in the development of a number of anti-fibrotic strategies targeting this cell. However, their potential role in liver regeneration, both initiation and termination, is also emerging and needs to be contemplated when considering targeted therapy. Perhaps what is most striking is the increasing recognition that this is not just one cell, but rather, a heterogenous population made up of a number of different subsets of cells, each with differentiated and specific functions. The tools are emerging for this dissection and are greatly needed to truly develop targeted therapies that will inhibit fibrosis while promoting liver regeneration and repair.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Geerts A. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis 2001;21:311–335

  2. Wells RG, Schwabe RF. Origin and function of myofibroblasts in the liver. Semin Liver Dis 2015;35:e1

  3. Asahina K, Tsai SY, Li P, Ishii M, Maxson RE, Jr., Sucov HM, et al. Mesenchymal origin of hepatic stellate cells, submesothelial cells, and perivascular mesenchymal cells during mouse liver development. Hepatology 2009;49:998–1011

  4. Puche JE, Saiman Y, Friedman SL. Hepatic stellate cells and liver fibrosis. Compr Physiol 2013;3:1473–1492

  5. Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 2013;4:2823

  6. Yin C, Evason KJ, Asahina K, Stainier DY. Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Invest 2013;123:1902–1910

  7. Schirmacher P, Geerts A, Pietrangelo A, Dienes HP, Rogler CE. 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

  8. Shen K, Chang W, Gao X, Wang H, Niu W, Song L, et al. Depletion of activated hepatic stellate cell correlates with severe liver damage and abnormal liver regeneration in acetaminophen-induced liver injury. Acta Biochim Biophys Sin (Shanghai) 2011;43:307–315

  9. Nejak-Bowen KN, Orr AV, Bowen WC, Jr., Michalopoulos GK. Gliotoxin-induced changes in rat liver regeneration after partial hepatectomy. Liver Int 2013;33:1044–1055

  10. Puche JE, Lee YA, Jiao J, Aloman C, Fiel MI, Munoz U, et al. A novel murine model to deplete hepatic stellate cells uncovers their role in amplifying liver damage in mice. Hepatology 2013;57:339–350

  11. Kalinichenko VV, Bhattacharyya D, Zhou Y, Gusarova GA, Kim W, Shin B, et al. Foxf1 +/− mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury. Hepatology 2003;37:107–117

  12. Michalopoulos GK. Liver regeneration. J Cell Physiol 2007;213:286–300

  13. Issa R, Zhou X, Trim N, Millward-Sadler H, Krane S, Benyon C, et al. Mutation in collagen-1 that confers resistance to the action of collagenase results in failure of recovery from CCl4-induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration. Faseb J 2003;17:47–49

  14. Zindy F, Lamas E, Schmidt S, Kirn A, Brechot C. Expression of insulin-like growth factor II (IGF-II) and IGF-II, IGF-I and insulin receptors mRNAs in isolated non-parenchymal rat liver cells. J Hepatol 1992;14:30–34

  15. Mullhaupt B, Feren A, Fodor E, Jones A. Liver expression of epidermal growth factor RNA. Rapid increases in immediate-early phase of liver regeneration. J Biol Chem 1994;269:19667–19670

  16. Ramadori G, Neubauer K, Odenthal M, Nakamura T, Knittel T, Schwogler S, et al. The gene of hepatocyte growth factor is expressed in fat-storing cells of rat liver and is downregulated during cell growth and by transforming growth factor-beta. Biochem Biophys Res Commun 1992;183:739–742

  17. Ebrahimkhani MR, Oakley F, Murphy LB, Mann J, Moles A, Perugorria MJ, et al. Stimulating healthy tissue regeneration by targeting the 5-HT(2)B receptor in chronic liver disease. Nat Med 2011;17:1668–1673

  18. Mogler C, Wieland M, Konig C, Hu J, Runge A, Korn C, et al. Hepatic stellate cell-expressed endosialin balances fibrogenesis and hepatocyte proliferation during liver damage. EMBO Mol Med 2015;7:332–338

  19. Marsden ER, Hu Z, Fujio K, Nakatsukasa H, Thorgeirsson SS, Evarts RP. Expression of acidic fibroblast growth factor in regenerating liver and during hepatic differentiation. Lab Invest 1992;67:427–433

  20. Evarts RP, Nakatsukasa H, Marsden ER, Hu Z, Thorgeirsson SS. Expression of transforming growth factor-alpha in regenerating liver and during hepatic differentiation. Mol Carcinog 1992;5:25–31

  21. Lowes KN, Croager EJ, Olynyk JK, Abraham LJ, Yeoh GC. Oval cell-mediated liver regeneration: Role of cytokines and growth factors. J Gastroenterol Hepatol 2003;18:4–12

  22. Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, et al. TWEAK induces liver progenitor cell proliferation. J Clin Invest 2005;115:2330–2340

  23. Omenetti A, Choi S, Michelotti G, Diehl AM. Hedgehog signaling in the liver. J Hepatol 2011;54:366–373

  24. Kaur S, Anita K. Angiogenesis in liver regeneration and fibrosis: “a double-edged sword”. Hepatol Int 2013;7:959–968

  25. Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M, et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 1995;376:70–74

  26. Schrage A, Wechsung K, Neumann K, Schumann M, Schulzke JD, Engelhardt B, et al. Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines. Hepatology 2008;48:1262–1272

  27. Lehwald N, Duhme C, Wildner M, Kuhn S, Furst G, Forbes SJ, et al. HGF and SDF-1-mediated mobilization of CD133+ BMSC for hepatic regeneration following extensive liver resection. Liver Int 2014;34:89–101

  28. Saiman Y, Sugiyama T, Simchoni N, Spirli C, Bansal MB. Biliary epithelial cells are not the predominant source of hepatic CXCL12. Am J Pathol 2015;185:1859–1866

  29. Wang L, Wang X, Wang L, Chiu JD, van de Ven G, Gaarde WA, et al. Hepatic vascular endothelial growth factor regulates recruitment of rat liver sinusoidal endothelial cell progenitor cells. Gastroenterology 2012;143:1555–1563

  30. Kordes C, Sawitza I, Gotze S, Herebian D, Haussinger D. Hepatic stellate cells contribute to progenitor cells and liver regeneration. J Clin Invest 2014;124:5503–5515

  31. 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;26:2104–2113

  32. Lua I, James D, Wang J, Wang KS, Asahina K. Mesodermal mesenchymal cells give rise to myofibroblasts, but not epithelial cells, in mouse liver injury. Hepatology 2014;60:311–322

  33. Song G, Pacher M, Balakrishnan A, Yuan Q, Tsay HC, Yang D, et al. Direct reprogramming of hepatic myofibroblasts into hepatocytes in vivo attenuates liver fibrosis. Cell Stem Cell 2016;18:797–808

  34. Ochoa B, Syn WK, Delgado I, Karaca GF, Jung Y, Wang J, et al. Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice. Hepatology 2010;51:1712–1723

  35. Swiderska-Syn M, Syn WK, Xie G, Kruger L, Machado MV, Karaca G, et al. Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy. Gut 2014;63:1333–1344

Download references

Author information

Authors and Affiliations

  1. Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Box 1123, New York, NY, 10029, USA

    Meena B. Bansal

Authors
  1. Meena B. Bansal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meena B. Bansal.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bansal, M.B. Hepatic stellate cells: fibrogenic, regenerative or both? Heterogeneity and context are key. Hepatol Int 10, 902–908 (2016). https://doi.org/10.1007/s12072-016-9758-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-016-9758-x

Keywords

Search

Navigation