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Splenectomy enhances the anti-fibrotic effect of bone marrow cell infusion and improves liver function in cirrhotic mice and patients

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

In 2003, we initiated a clinical trial to examine autologous bone marrow cell infusion (ABMi) therapy for cirrhotic patients and reported the clinical effect of the therapy. To analyze how splenectomy may potentiate the effects of bone marrow cell infusion on cirrhosis, we performed a mouse study and a clinical trial on patients with cirrhosis.

Methods

In mice, we analyzed the effect of splenectomy on bone marrow cell infusion in four experimental groups (group A, splenectomy + bone marrow cell infusion + CCl4; group B, sham operation + bone marrow cell infusion + CCl4; group C, splenectomy + CCl4; group D, sham operation + CCl4). In clinical, we compared the effect of splenectomy on ABMi therapy.

Results

We observed significantly increased average serum albumin levels and higher expression of green fluorescent protein (GFP), matrix metalloproteinase 9 (MMP9), and proliferating cell nuclear antigen in the livers of group A. We observed MMP9/GFP double-positive cells in the cirrhotic livers. A significant decrease in the liver fibrosis areas was observed in group A. Splenectomy enhanced the repopulation of bone marrow cells into the cirrhotic liver and improved the liver microenvironment via expression of MMP9 secreted from repopulating GFP-positive cells. Next, we performed a clinical trial to compare the effect of splenectomy on the efficacy of ABMi therapy. Cirrhotic patients who underwent splenectomy before ABMi therapy tended to have a greater improvement in liver function.

Conclusion

ABMi therapy with splenectomy may be an effective therapeutic modality for cirrhosis.

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Abbreviations

ABMi :

Autologous bone marrow cell infusion

PBS:

Phosphate-buffered saline

Alb:

Albumin

PT-INR:

Prothrombin time international normalized ratio

P3P:

Pro-collagen-III peptide

HGF:

Hepatocyte growth factor

Plt:

Platelet count

CCl4 :

Carbon tetrachloride

GFP:

Green fluorescent protein

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Acknowledgments

This study was supported by Grants-in-Aid for scientific research from the Japan Society for the Promotion of Science, Ministry of Health, Labour and Welfare, and Japan Science and Technology agency. We also wish to thank Mrs. Shoko Watanabe for help for FACS analysis.

Conflict of interest

All authors declare that no competing interests exist.

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan

    Takuya Iwamoto, Shuji Terai, Yuko Mizunaga, Naoki Yamamoto, Kaoru Omori, Koichi Uchida, Takahiro Yamasaki & Isao Sakaida

  2. Center of Regenerative Medicine and Cell Therapy, Yamaguchi University Hospital, Minami Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan

    Yasuhiko Fujii

  3. Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo, 113-0034, Japan

    Hiroshi Nishina

Authors
  1. Takuya Iwamoto
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  2. Shuji Terai
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  3. Yuko Mizunaga
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  4. Naoki Yamamoto
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  5. Kaoru Omori
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  6. Koichi Uchida
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  7. Takahiro Yamasaki
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  8. Yasuhiko Fujii
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  9. Hiroshi Nishina
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  10. Isao Sakaida
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Corresponding author

Correspondence to Shuji Terai.

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Iwamoto, T., Terai, S., Mizunaga, Y. et al. Splenectomy enhances the anti-fibrotic effect of bone marrow cell infusion and improves liver function in cirrhotic mice and patients. J Gastroenterol 47, 300–312 (2012). https://doi.org/10.1007/s00535-011-0486-7

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  • DOI: https://doi.org/10.1007/s00535-011-0486-7

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