Advertisement

Cell and Tissue Research

, Volume 343, Issue 2, pp 371–378 | Cite as

Enhanced expression of fibroblast growth factor 2 in bone marrow cells and its potential role in the differentiation of hepatic epithelial stem-like cells into the hepatocyte lineage

  • Hiroaki Haga
  • Takafumi SaitoEmail author
  • Kazuo Okumoto
  • Satoshi Ugajin
  • Chikako Sato
  • Rika Ishii
  • Yuko Nishise
  • Junitsu Ito
  • Hisayoshi Watanabe
  • Koji Saito
  • Hitoshi Togashi
  • Sumio Kawata
Regular Article

Abstract

The transplantation of bone marrow cells (BMCs) has been applied in liver regenerative cell therapy. However, details of the interaction between the transplanted BMCs and hepatic stem cells have not been elucidated. The aim of the present study was to investigate the interaction of BMCs with hepatic stem-like cells (HSLCs) and to determine the BMC factor that steers HSLC differentiation into the hepatocyte lineage. Both BMCs and HSLCs were obtained from an adult Sprague-Dawley rat, and a co-culture system was established. Cell proliferation was analyzed by a proliferation assay, and the differentiation of HSLCs into the hepatocyte lineage was evaluated by the detection of cellular mRNA for liver-specific proteins. DNA microarray analysis was applied to BMCs co-cultured with HSLCs to determine the genes upregulated by their interaction. The proliferation of HSLCs co-cultured with BMCs was significantly higher than that of HSLCs cultured alone, and the expression of mRNAs for both albumin and tryptophan-2,3-dioxygenase was detectable in the co-cultured HSLCs. DNA microarray analysis showed the upregulated expression of fibroblast growth factor 2 (FGF2) mRNA in BMCs co-cultured with HSLCs, and the expression of mRNAs for both albumin and tyrosine aminotransferase became detectable in HSLCs cultured with FGF2. Thus, BMCs stimulate both the proliferation of HSLCs and their differentiation into the hepatocyte lineage. FGF2 is one of the factors that is produced by the interacting BMCs and that stimulates this differentiation.

Keywords

Bone marrow Hepatic stem cell Interaction FGF2 Differentiation Rat (Sprague-Dawley) 

Notes

Acknowledgments

The authors thank Dr. T. Sugiyama (Akita University School of Medicine, Japan) fot the gift of HSLC.

Conflicts of interest

We have no conflicts of interest to declare.

References

  1. Alison MR, Poulsom R, Jeffery R, Dhillon AP, Quaglia A, Jacob J, Novelli M, Prentice G, Williamson J, Wright NA (2000) Hepatocytes from non-hepatic adult stem cells. Nature 406:257CrossRefPubMedGoogle Scholar
  2. Bisgaard HC, Nagy P, Ton PT, Hu Z, Thorgeirsson SS (1994) Modulation of keratin 14 and alpha-fetoprotein expression during hepatic oval cell proliferation and liver regeneration. J Cell Physiol 159:475–484CrossRefPubMedGoogle Scholar
  3. Fu X, Shen Z, Guo Z, Zhang M, Sheng Z (2002) Healing of chronic cutaneous wounds by topical treatment with basic fibroblast growth factor. Chin Med J 115:331–335PubMedGoogle Scholar
  4. Goodman SB, Song Y, Yoo JY, Fox N, Trindade MC, Kajiyama G, Ma T, Regula D, Brown J, Smith RL (2003) Local infusion of FGF-2 enhances bone ingrowth in rabbit chambers in the presence of polyethylene particles. J Biomed Mater Res 65:454–461CrossRefGoogle Scholar
  5. Grisham JW, Thorgeirsson SS (1997) Liver stem cells. In: Potten CS (ed) Stem cells. Academic Press, San Diego, pp 233–282CrossRefGoogle Scholar
  6. Grisham JW, Coleman WB, Smith GJ (1993) Isolation, culture, and transplantation of rat hepatocytic precursor (stem-like) cells. Proc Soc Exp Biol Med 204:270–279PubMedGoogle Scholar
  7. Hattori E, Shu HJ, Saito T, Okumoto K, Haga H, Yokozawa J, Ito JI, Watanabe H, Saito K, Togashi H, Kawata S (2010) Expression of the RNA-binding protein Musashi1 in adult liver stem-like cells. Hepatol Res 40:432–437CrossRefPubMedGoogle Scholar
  8. Hioki O, Minemura M, Shimizu Y, Kasii Y, Nishimori H, Takahara T, Higuchi K, Yoshitake Y, Nishikawa K, Watanabe A (1996) Expression and localization of basic fibroblast growth factor (bFGF) in the repair process of rat liver injury. J Hepatol 24:217–224CrossRefPubMedGoogle Scholar
  9. Hoffmann B, Paul D (1990) Basic fibroblast growth factor and transforming growth factor-alpha are hepatotrophic mitogens in vitro. J Cell Physiol 142:149–154CrossRefPubMedGoogle Scholar
  10. Hu Z, Evarts RP, Fujio K, Marsden ER, Thorgeirsson SS (1993) Expression of hepatocyte growth factor and c-met genes during hepatic differentiation and liver development in the rat. Am J Pathol 42:1823–1830Google Scholar
  11. Ishikawa T, Terai S, Urata Y, Marumoto Y, Aoyama K, Murata T, Mizunaga Y, Yamamoto N, Nishina H, Shinoda K, Sakaida I (2007) Administration of fibroblast growth factor 2 in combination with bone marrow transplantation synergistically improves carbon-tetrachloride-induced liver fibrosis in mice. Cell Tissue Res 327:463–470CrossRefPubMedGoogle Scholar
  12. Jung J, Zheng M, Goldfarb M, Zaret KS (1999) Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science 284:1998–2003CrossRefPubMedGoogle Scholar
  13. Laham RJ, Post M, Rezaee M, Donnell-Fink L, Wykrzykowska JJ, Lee SU, Baim DS, Sellke FW (2005) Transendocardial and transepicardial intramyocardial fibroblast growth factor-2 administration: myocardial and tissue distribution. Drug Metab Dispos 33:1101–1107CrossRefPubMedGoogle Scholar
  14. Lederman RJ, Mendelsohn FO, Anderson RD, Saucedo JF, Tenaglia AN, Hermiller JB, Hillegass WB, Rocha-Singh K, Moon TE, Whitehouse MJ, Annex BH, Investigators TRAFFIC (2002) Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 359:2053–2058CrossRefPubMedGoogle Scholar
  15. Lemaigre F, Zaret KS (2004) Liver development update: new embryo models, cell lineage control, and morphogenesis. Curr Opin Genet Dev 14:582–590CrossRefPubMedGoogle Scholar
  16. Miura K, Nagai H, Ueno Y, Goto T, Mikami K, Nakane K, Yoneyama K, Watanabe D, Terada K, Sugiyama T, Imai K, Senoo H, Watanabe S (2003) Epimorphin is involved in differentiation of rat hepatic stem-like cells through cell-cell contact. Biochem Biophys Res Commun 311:415–423CrossRefPubMedGoogle Scholar
  17. Nagai H, Terada K, Watanabe G, Ueno Y, Aiba N, Shibuya T, Kawagoe M, Kameda T, Sato M, Senoo H, Sugiyama T (2002) Differentiation of liver epithelial (stem-like) cells into hepatocytes induced by coculture with hepatic stellate cells. Biochem Biophys Res Commun 293:1420–1425CrossRefPubMedGoogle Scholar
  18. Okumoto K, Saito T, Hattori E, Ito JI, Suzuki A, Misawa K, Ishii R, Karasawa T, Haga H, Sanjo M, Takeda T, Sugahara K, Saito K, Togashi H, Kawata S (2005a) Differentiation of rat bone marrow cells cultured on artificial basement membrane containing extracellular matrix into a liver cell lineage. J Hepatol 43:110–116CrossRefPubMedGoogle Scholar
  19. Okumoto K, Saito T, Hattori E, Ito JI, Suzuki A, Misawa K, Sanjyo M, Takeda T, Sugahara K, Saito K, Togashi H, Kawata S (2005b) Expression of Notch signaling markers in bone marrow cells that differentiate into a liver cell lineage in a rat transplanted model. Hepatol Res 31:7–12CrossRefPubMedGoogle Scholar
  20. Okumoto K, Saito T, Haga H, Hattori E, Ishii R, Karasawa T, Suzuki A, Misawa K, Sanjo M, Ito JI, Sugahara K, Saito K, Togashi H, Kawata S (2006) Characteristics of rat bone marrow cells differentiated into a liver cell lineage and dynamics of the transplanted cells in the injured liver. J Gastroenterol 41:62–69CrossRefPubMedGoogle Scholar
  21. Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, Boggs SS, Greenberger JS, Goff JP (1999) Bone marrow as a potential source of hepatic oval cells. Science 284:1168–1170CrossRefPubMedGoogle Scholar
  22. Saji Y, Tamura S, Yoshida Y, Kiso S, Iizuka AS, Matsumoto H, Kawasaki T, Kamada Y, Matsuzawa Y, Shinomura Y (2004) 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 41:545–450CrossRefPubMedGoogle Scholar
  23. 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 40:1304–1311CrossRefPubMedGoogle Scholar
  24. Shiota G, Kunisada T, Oyama K, Udagawa A, Nomi T, Tanaka K, Tsutsumi A, Isono M, Nakamura T, Hamada H, Sakatani T, Sell S, Sato K, Ito H, Kawasaki H (2000) In vivo transfer of hepatocyte growth factor gene accelerates proliferation of hepatic oval cells in a 2-acetylaminofluorene/partial hepatectomy model in rats. FEBS Lett 470:325–330CrossRefPubMedGoogle Scholar
  25. Terai S, Sakaida I, Yamamoto N, Omori K, Watanabe T, Ohata S, Katada T, Miyamoto K, Shinoda K, Nishina H, Okita K (2003) An in vivo model for monitoring trans-differentiation of bone marrow cells into functional hepatocytes. J Biochem 134:551–558CrossRefPubMedGoogle Scholar
  26. Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, Yokoyama Y, Uchida K, Yamasaki T, Fujii Y, Okita K, Sakaida I (2006) Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells 24:2292–2298CrossRefPubMedGoogle Scholar
  27. Theise ND, Badve S, Saxena R, Henegariu O, Sell S, Crawford JM, Krause DS (2000a) Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology 31:235–240CrossRefPubMedGoogle Scholar
  28. Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, Henegariu O, Krause (2000b) Liver from bone marrow in humans. Hepatology 32:11–16CrossRefPubMedGoogle Scholar
  29. Zhao R, Duncan SA (2005) Embryonic development of the liver. Hepatology 41:956–967CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Hiroaki Haga
    • 1
  • Takafumi Saito
    • 1
    Email author
  • Kazuo Okumoto
    • 1
  • Satoshi Ugajin
    • 1
  • Chikako Sato
    • 1
  • Rika Ishii
    • 1
  • Yuko Nishise
    • 1
  • Junitsu Ito
    • 1
  • Hisayoshi Watanabe
    • 1
  • Koji Saito
    • 1
  • Hitoshi Togashi
    • 2
  • Sumio Kawata
    • 1
  1. 1.Department of GastroenterologyYamagata University School of MedicineYamagataJapan
  2. 2.Health Administrative CenterYamagata UniversityYamagataJapan

Personalised recommendations