Top

Published in:

01-03-2012 | Original Article—Liver, Pancreas, and Biliary Tract

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

Authors: Takuya Iwamoto, Shuji Terai, Yuko Mizunaga, Naoki Yamamoto, Kaoru Omori, Koichi Uchida, Takahiro Yamasaki, Yasuhiko Fujii, Hiroshi Nishina, Isao Sakaida

Published in: Journal of Gastroenterology | Issue 3/2012

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.

Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, et al. Liver from bone marrow in humans. Hepatology. 2000;32:11–6.PubMedCrossRef

Alison MR, Poulsom R, Jeffery R, Dhillon AP, Quaglia A, Jacob J, et al. Hepatocytes from non-hepatic adult stem cells. Nature. 2000;406:257.PubMedCrossRef

Okamoto R, Yajima T, Yamazaki M, Kanai T, Mukai M, Okamoto S, et al. Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract. Nat Med. 2002;8:1011–7.PubMedCrossRef

Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet. 2002;360:427–35.PubMedCrossRef

Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet. 2003;361:45–6.PubMedCrossRef

Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC, et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature. 2004;428:668–73.PubMedCrossRef

Terai S, Sakaida I, Yamamoto N, Omori K, Watanabe T, Ohata S, et al. An in vivo model for monitoring trans-differentiation of bone marrow cells into functional hepatocytes. J Biochem (Tokyo). 2003;134:551–8.CrossRef

Sakaida I, Terai S, Yamamoto N, Aoyama K, Ishikawa T, Nishina H, et al. Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology. 2004;40:1304–11.PubMedCrossRef

Terai S, Yamaoto N, Omori K, Sakaida I, Okita K. A new cell therapy using bone marrow cells to repair damaged liver. J Gastroenterol. 2002;37:162–3.PubMed

10.

Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, et al. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells. 2006;24:2292–8.PubMedCrossRef

11.

Saito T, Okumoto K, Haga H, Nishise Y, Ishii R, Sato C, et al. Potential therapeutic application of intravenous autologous bone marrow infusion in patients with alcoholic liver cirrhosis. Stem Cells Dev. 2011;20(9):1503–10.

12.

Kim JK, Park YN, Kim JS, Park MS, Paik YH, Seok JY, et al. Autologous bone marrow infusion activates the progenitor cell compartment in patients with advanced liver cirrhosis. Cell Transplant. 2010. doi:10.3727/096368910X506863.

13.

Spigos DG, Jonasson O, Mozes M, Capek V. Partial splenic embolization in the treatment of hypersplenism. AJR Am J Roentgenol. 1979;132:777–82.PubMed

14.

Oh JW, Ahn SM, Kim KS, Choi JS, Lee WJ, Kim BR. The role of splenectomy in patients with hepatocellular carcinoma and secondary hypersplenism. Yonsei Med J. 2003;44:1053–8.PubMed

15.

Terai S, Sakaida I, Nishina H, Okita K. Lesson from the GFP/CCl4 model–translational research project: the development of cell therapy using autologous bone marrow cells in patients with liver cirrhosis. J Hepatobiliary Pancreat Surg. 2005;12:203–7.PubMedCrossRef

16.

Guo D, Fu T, Nelson JA, Superina RA, Soriano HE. Liver repopulation after cell transplantation in mice treated with retrorsine and carbon tetrachloride. Transplantation. 2002;73:1818–24.PubMedCrossRef

17.

Ohata S, Nawa M, Kasama T, Yamasaki T, Sawanobori K, Hata S, et al. Hematopoiesis-dependent expression of CD44 in murine hepatic progenitor cells. Biochem Biophys Res Commun. 2009;379(4):817–23.PubMedCrossRef

18.

Lee TS, Park KK, Kim KH, Chu YA, Jeon JP, Hwang M. Protective effect of bioactive ceramics on liver injury: regulation of pro-inflammatory cytokine expression. J Mater Sci Mater Med. 2009;20:295–9.PubMedCrossRef

19.

Christensen E, Schlichting P, Fauerholdt L, Gluud C, Andersen PK, Juhl E, et al. Prognostic value of Child-Turcotte criteria in medically treated cirrhosis. Hepatology. 1984;4:430–5.PubMedCrossRef

20.

Giannini E, Caglieris S, Ceppa P, Risso D, Lantieri PB, Testa R, et al. Serum pro-collagen III peptide levels are related to lobular necrosis in untreated patients with chronic hepatitis C. Eur J Gastroenterol Hepatol. 2001;13:137–41.PubMedCrossRef

21.

Tsubouchi H. Hepatocyte growth factor for liver disease. Hepatology. 1999;30:333–4.PubMedCrossRef

22.

Masuhara M, Yasunaga M, Tanigawa K, Tamura F, Yamashita S, Sakaida I, et al. Expression of hepatocyte growth factor, transforming growth factor alpha, and transforming growth factor beta 1 messenger RNA in various human liver diseases and correlation with hepatocyte proliferation. Hepatology. 1996;24:323–9.PubMed

23.

Pontremoli S, Arrigo L. Effects of splenectomy on regeneration of the liver after partial hepatectomy. Boll Soc Ital Biol Sper. 1950;26:355–7.PubMed

24.

Schanz U, Gmur J. Rapid and automated processing of bone marrow grafts without Ficoll density gradient for transplantation of cryopreserved autologous or ABO-incompatible allogeneic bone marrow. Bone Marrow Transplant. 1992;10:507–13.PubMed

25.

Marubashi S, Dono K, Miyamoto A, Takeda Y, Nagano H, Umeshita K, et al. Impact of graft size on postoperative thrombocytopenia in living donor liver transplant. Arch Surg. 2007;142:1054–8.PubMedCrossRef

26.

Thomas ED, Storb R. Technique for human marrow grafting. Blood. 1970;36:507–15.PubMed

27.

Masetti M, Siniscalchi A, De Pietri L, Braglia V, Benedetto F, Di Cautero N, et al. Living donor liver transplantation with left liver graft. Am J Transplant. 2004;4:1713–6.PubMedCrossRef

28.

Hellerbrand C, Stefanovic B, Giordano F, Burchardt ER, Brenner DA. The role of TGF beta1 in initiating hepaticstellate cell activation in vivo. J Hepatol. 1999;30:77–87.PubMedCrossRef

29.

Akahoshi T, Hashizume M, Tanoue K, Shimabukuro R, Gotoh N, Tomikawa M, et al. Role of the spleen in liver fibrosis in rats may be mediated by transforming growth factor beta-1. J Gastroenterol Hepatol. 2002;17:59–65.PubMedCrossRef

30.

Murata K, Shiraki K, Sugimoto K, Takase K, Nakano T, Furusaka A, et al. Splenectomy enhances liver regeneration through tumor necrosis factor (TNF)-alpha following dimethylnitrosamine-induced cirrhotic rat model. Hepatogastroenterology. 2001;48:1022–7.PubMed

31.

Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, et al. Platelet-derived serotonin mediates liver regeneration. Science. 2006;312(5770):104–7.PubMedCrossRef

32.

Yamamoto N, Terai S, Ohata S, Watanabe T, Omori K, Shinoda K, et al. A subpopulation of bone marrow cells depleted by a novel antibody, anti-Liv8, is useful for cell therapy to repair damaged liver. Biochem Biophys Res Commun. 2004;313:1110–8.PubMedCrossRef

33.

Dalakas E, Newsome PN, Harrison DJ, Plevris JN. Hematopoietic stem cell trafficking in liver injury. Faseb J. 2005;19:1225–31.PubMedCrossRef

34.

Houlihan DD, Newsome PN. Critical review of clinical trials of bone marrow stem cells in liver disease. Gastroenterology. 2008;135:438–50.PubMedCrossRef

Title: Splenectomy enhances the anti-fibrotic effect of bone marrow cell infusion and improves liver function in cirrhotic mice and patients
Authors: Takuya Iwamoto
Shuji Terai
Yuko Mizunaga
Naoki Yamamoto
Kaoru Omori
Koichi Uchida
Takahiro Yamasaki
Yasuhiko Fujii
Hiroshi Nishina
Isao Sakaida
Publication date: 01-03-2012
Publisher: Springer Japan
Published in: Journal of Gastroenterology / Issue 3/2012
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-011-0486-7

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 3/2012

Rikkunshito improves symptoms in PPI-refractory GERD patients: a prospective, randomized, multicenter trial in Japan

Inflammation and fibrogenesis in steatohepatitis

Reducing Peg-IFN doses causes later virologic response or no response in HCV genotype 1 patients treated with Peg-IFN alfa-2b plus ribavirin

Shall we use endoscopic submucosal dissection for every gastric neoplasia?

Usefulness of differentiating metabolic syndrome into visceral fat type and subcutaneous fat type using ultrasonography in Japanese males

A large-scale nationwide multicenter prospective observational study of triple therapy using rabeprazole, amoxicillin, and clarithromycin for Helicobacter pylori eradication in Japan

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials