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Fibroblast growth factor 2 facilitates the differentiation of transplanted bone marrow cells into hepatocytes

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Abstract

We have developed an in vivo mouse model, the green fluorescent protein (GFP)/carbon tetrachloride (CCl4) model, and have previously reported that transplanted GFP-positive bone marrow cells (BMCs) differentiate into hepatocytes via hepatoblast intermediates. Here, we have investigated the growth factors that are closely related to the differentiation of transplanted BMCs into hepatocytes, and the way that a specific growth factor affects the differentiation process in the GFP/CCl4 model. We performed immunohistochemical analysis to identify an important growth factor in our model, viz., fibroblast growth factor (FGF). In liver samples, the expression of FGF1 and FGF2 and of FGF receptors (FGFRs; FGFR1, FGFR2) was significantly elevated with time after bone marrow transplantation (BMT) compared with other factors, and co-expression of GFP and FGFs or FGFRs could be detected. We then analyzed the effect and molecular mechanism of FGF signaling on the enhancement of BMC differentiation into hepatocytes by immunohistochemistry, immunoblotting, and microarray analysis. Treatment with recombinant FGF (rFGF), especially rFGF2, elevated the repopulation rate of GFP-positive cells in the liver and significantly increased the expression of both Liv2 (hepatoblast marker) and albumin (hepatocyte marker). Administration of rFGF2 at BMT also raised serum albumin levels and improved the survival rate. Transplantation of BMCs with rFGF2 specifically activated tumor necrosis factor-alpha (TNF-α) signaling. Thus, FGF2 facilitates the differentiation of transplanted BMCs into albumin-producing hepatocytes via Liv2-positive hepatoblast intermediates through the activation of TNF-α signaling. Administration of FGF2 in combination with BMT improves the liver function and prognosis of mice with CCl4-induced liver damage.

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Abbreviations

BMC:

bone marrow cell

BMT:

bone marrow transplantation

GFP:

green fluorescent protein

CCl4 :

carbon tetrachloride

SOM:

self-organizing map

FGF:

fibroblast growth factor

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

FGFR:

fibroblast growth factor receptor

HGF:

hepatocyte growth factor

VEGF:

vascular endothelial growth factor

VEGFR:

vascular endothelial growth factor receptor

PDGF:

platelet-derived growth factor

PDGFR:

platelet-derived growth factor receptor

TGFβ:

transforming growth factor β

TGFβR:

transforming growth factor β receptor

rFGF:

recombinant fibroblast growth factor

TNF-α:

tumor necrosis factor-α

TNFIP3:

tumor necrosis factor-α induced protein 3

NF-κB:

nuclear factor-κB

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Acknowledgements

We thank Dr. Masaru Okabe (Genome Research Center, Osaka University) for the gift of GFP transgenic mice and Mr. Jun Oba for valuable technical support.

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Authors and Affiliations

  1. Department of Molecular Science & Applied Medicine (Gastroenterology & Hepatology), Yamaguchi University School of Medicine, Minami Kogushi 1-1-1, Ube, 755-8505, Yamaguchi, Japan

    Tsuyoshi Ishikawa, Shuji Terai, Yohei Urata, Yoshio Marumoto, Koji Aoyama, Isao Sakaida & Kiwamu Okita

  2. Science Research Center, Yamaguchi University, Minami Kogushi 1-1-1, Ube, 755-8505, Yamaguchi, Japan

    Tomoaki Murata

  3. Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan

    Hiroshi Nishina

  4. Department of Neuroanatomy & Neuroscience, Yamaguchi University School of Medicine, Minami Kogushi 1-1-1, Ube, 755-8505, Yamaguchi, Japan

    Koh Shinoda

  5. Department of Computer Science and Systems Engineering, Faculty of Engineering, Yamaguchi University, Tokiwadai 2-16-1, Ube, 755-8611, Yamaguchi, Japan

    Shunji Uchimura & Yoshihiko Hamamoto

Authors
  1. Tsuyoshi Ishikawa
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  2. Shuji Terai
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  3. Yohei Urata
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  4. Yoshio Marumoto
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  5. Koji Aoyama
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  6. Isao Sakaida
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  7. Tomoaki Murata
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  8. Hiroshi Nishina
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  9. Koh Shinoda
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  10. Shunji Uchimura
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  11. Yoshihiko Hamamoto
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  12. Kiwamu Okita
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Corresponding author

Correspondence to Shuji Terai.

Additional information

This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (nos. 13470121, 13770262, 15790348, 16390211, and 16590597) and for translational research from the Ministry of Health, Labor and Welfare (H-trans-5).

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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 323, 221–231 (2006). https://doi.org/10.1007/s00441-005-0077-0

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