Peripheral vein infusion of autologous mesenchymal stem cells in Egyptian HCV-positive patients with end-stage liver disease

Hosny Salama, Abdel-Rahman N Zekri, Eman Medhat, Shereen A Al Alim, Ola S Ahmed, Abeer A Bahnassy, Mai M Lotfy, Rasha Ahmed, Sherief Musa, Hosny Salama, Abdel-Rahman N Zekri, Eman Medhat, Shereen A Al Alim, Ola S Ahmed, Abeer A Bahnassy, Mai M Lotfy, Rasha Ahmed, Sherief Musa

Abstract

Introduction: We have assessed the utility of autologous mesenchymal stem cell (MSC) peripheral vein infusion as a possible therapeutic modality for patients with end-stage liver diseases.

Methods: Forty patients with post-hepatitis C virus (HCV) end-stage liver disease were randomized into two groups: Group 1 (GI): 20 patients who received granulocyte colony-stimulating factor (G-CSF) for 5 days followed by autologous MSCs peripheral-vein infusion and group 2 (GII): 20 patients who received regular liver-supportive treatment only (control group).

Results: In MSC-infused patients (GI), 54% showed near normalization of liver enzymes and improvement in liver synthetic function. Significant changes were reported in albumin (P = 0.000), bilirubin (P = 0.002), increased international normalized ratio (INR) (P = 0.017), prothrombin concentration (P = 0.029) and alanine transaminase (ALT) levels (P = 0.029), with stabilization of clinical and biochemical status in 13% of cases. None of the patients in GII showed any significant improvement. Hepatic fibrosis was assessed in GI by detection of procollagen IIIC peptide level (PIIICP) and procollagen III N peptide level (PIIINP). The pretreatment values of s-PIIICP and s-PIIINP were 9.4 ± 4.2 and 440 ± 189, respectively, with a decrease to 8.1 ± 2.6 and 388 ± 102, respectively, 3 months after MSC therapy. However, the difference was statistically nonsignificant (P = 0.7). A significant correlation coefficient was reported after 3 months between the s-PIIINP and prothrombin concentration (P = -0.5) and between s-PIIICP and ascites (P = 0.550).

Conclusions: First, autologous MSC infusion into a peripheral vein is as effective as the previously reported intrahepatic infusion. Second, MSCs have a supportive role in the treatment of end-stage liver disease, with satisfactory tolerability and beneficial effects on liver synthetic functions and hepatic fibrosis. Third, IV infusion of MSCs after G-CSF mobilization improves s-albumin within the first 2 weeks and prothrombin concentration and alanine Taransaminase after 1 month. According to the data from this current study and those previously reported by our group, we recommend further studies on patients' infusion with pure CD133 and CD34 followed by IV infusion of in vitro-differentiated MSCs within 1 week and another infusion after 3 months.

Trial registration: ClinicalTrials.gov NCT01729221. Registered 17 November 2012.

Figures

Figure 1
Figure 1
Work flow chart.
Figure 2
Figure 2
Child-Pugh scores in the study population (A) and control group (B).
Figure 3
Figure 3
Scattered plot distribution of PIIINP concentration in treated group before transplant, after 1 month, after 3 months, and after 6 months.
Figure 4
Figure 4
Correlation coefficient between PIIINP and prothrombin concentration.
Figure 5
Figure 5
Scattered plot distribution of PIIICP concentration in the treated group before transplant, 1 month, 3 months and 6 months.
Figure 6
Figure 6
Correlation coefficient between PIIICP and ascites.
Figure 7
Figure 7
Performance-score difference after 2 weeks, 1, 3, and 6 months in treated group.
Figure 8
Figure 8
This diagram illustrates our assumption of concomitant mode of action of both GCSF priming followed by MSC transplantation for regeneration of liver cells in end-stage liver disease.

References

    1. Zekri AR, Hassan ZK, Bahnassy AA, Sherif GM, ELdahshan D, Abouelhoda M, Ali A, Hafez MM. Molecular prognostic profile of Egyptian HCC cases infected with hepatitis C virus. Asian Pac J Cancer Prev. 2012;13:5433–5438.
    1. Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, Mavilio F. Muscle regeneration by bone marrow-derived myogenic progenitors. Science. 1998;279:1528–1530.
    1. Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci U S A. 1999;96:10711–10716.
    1. Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, Boggs SS, Greenberger JS, Goff JP. Bone marrow as a potential source of hepatic oval cells. Science. 1999;284:1168–1170.
    1. Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, Yokoyama Y, Uchida K, Yamasaki T, Fujii Y, Okita K, Sakaida I. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells. 2006;24:2292–2298.
    1. Ogawa S, Miyagawa S. Regenerative medicine for liver disease. Surg Today. 2009;39:1019–1025.
    1. Lee KD, Kuo TK, Whang-Peng J, Chung YF, Lin CT, Chou SH, Chen JR, Chen YP, Lee OK. In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology. 2004;40:1275–1284.
    1. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002;418:41–49.
    1. Salama H, Zekri AR, Bahnassy AA, Medhat E, Halim HA, Ahmed OS, Mohamed G, Al Alim SA, Sherif GM. Autologous CD34+ and CD133+ stem cells transplantation in patients with end stage liver disease. World J Gastroenterol. 2010;16:5297–5305.
    1. Salama H, Zekri AR, Zern M, Bahnassy A, Loutfy S, Shalaby S, Vigen C, Burke W, Mostafa M, Medhat E, Alfi O, Huttinger E. Autologous hematopoietic stem cell transplantation in 48 patients with end-stage chronic liver diseases. Cell Transplant. 2010;19:1475–1486.
    1. Miltenyi Biotec Company. [ ]
    1. Christensen E. Prognostic models including the Child-Pugh, MELD and Mayo risk scores: where are we and where should we go? J Hepatol. 2004;41:344–350.
    1. Piscaglia C, Shupe TD, Oh S, Gasbarrini A, Petersen BE. Granulocyte-colony stimulating factor promotes liver repair and induces oval cell migration and proliferation in rats. Gastroenterology. 2007;133:619–631.
    1. Pai M, Zacharoulis D, Milicevic MN, Helmy S, Jiao LR, Levicar N, Tait P, Scott M, Marley SB, Jestice K, Glibetic M, Bansi D, Khan SA, Kyriakou D, Rountas C, Thillainayagam A, Nicholls JP, Jensen S, Apperley JF, Gordon MY, Habib NA. Autologous infusion of expanded mobilized adult bone marrow-derived CD34+ cells into patients with alcoholic liver cirrhosis. Am J Gastroenterol. 2008;103:1952–1958.
    1. Liongue C, Wright C, Russell AP, Ward AC. Granulocyte colony-stimulating factor receptor: stimulating granulopoiesis and much more. Int J Biochem Cell Biol. 2009;41:2372–2375.
    1. Yan L, Xu S, Wang S, Wu B. G-CSF mobilized PBMCS contribute to the liver function of cirrhotic rats. EXCLI J. 2010;9:67–75.
    1. Langer DA, Das A, Semela D, Kang-Decker N, Hendrickson H, Bronk SF, Katusic ZS, Gores GJ, Shah VH. Nitric oxide promotes caspase-independent hepatic stellate cell apoptosis through the generation of reactive oxygen species. Hepatology. 2008;47:1983–1993.
    1. Jiang JX, Venugopal S, Serizawa N, Chen X, Scott F, Li Y, Adamson R, Devaraj S, Shah V, Gershwin ME, Friedman SL, Török NJ. Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in vivo. Gastroenterology. 2010;139:1375–1384.
    1. Myung SJ, Yoon JH, Kim BH, Lee JH, Jung EU, Lee HS. Heat shock protein 90 inhibitor induces apoptosis and attenuates activation of hepatic stellate cells. J Pharmacol Exp Ther. 2009;330:276–282.
    1. Hartland SN, Murphy F, Aucott RL, Abergel A, Zhou X, Waung J, Patel N, Bradshaw C, Collins J, Mann D, Benyon RC, Iredale JP. Active matrix metalloproteinase-2 promotes apoptosis of hepatic stellate cells via the cleavage of cellular N-cadherin. Liver Int. 2009;29:966–978.
    1. Ciruna BG, Schwartz L, Harpal K, Yamaguchi T, Rossant J. Chimeric analysis of fibroblast growth factor receptor-1 (Fgfr1) function: a role for FGFR1 in morphogenetic movement through the primitive streak. Development. 1997;124:2829–2841.
    1. Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E, Birchmeier C. Scatter factor/hepatocyte growth factor is essential for liver development. Nature. 1995;373:699–702.
    1. Bladt F, Riethmatcher D, Isenmann S, Aguzzi A, Birchmeier C. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature. 1995;376:768–771.
    1. Furge KA, Zhang YW, Vande Woude GF. Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Oncogene. 2000;19:5582–5589.
    1. Son BR, Marquez-Curtis LA, Kucia M, Wysoczynski M, Turner AR, Ratajczak J, Ratajczak MZ, Janowska-Wieczorek A. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells. 2006;24:1254–1264.
    1. Potian JA, Aviv H, Ponzio NM, Harrison JS, Rameshwar P. Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens. J Immunol. 2003;171:3426–3434.
    1. Dong XJ, Zhang H, Pan RL, Xiang LX, Shao JZ. Identification of cytokines involved in hepatic differentiation of mBM-MSCs under liver-injury conditions. World J Gastroenterol. 2010;16:3267–3278.
    1. Gordon MY, Levicar N, Pai M, Bachellier P, Dimarakis I, Al-Allaf F, M’Hamdi H, Thalji T, Welsh JP, Marley SB, Davies J, Dazzi F, Marelli-Berg F, Tait P, Playford R, Jiao L, Jensen S, Nicholls JP, Ayav A, Nohandani M, Farzaneh F, Gaken J, Dodge R, Alison M, Apperley JF, Lechler R, Habib NA. Characterization and clinical application of human CD34+ stem/progenitor cell populations mobilized into the blood by granulocyte colony-stimulating factor. Stem Cells. 2006;24:1822–1830.
    1. Lyra AC, Soares MB, da Silva LF, Fortes MF, Silva AG, Mota AC, Oliveira SA, Braga EL, de Carvalho WA, Genser B, dos Santos RR, Lyra LG. Feasibility and safety of autologous bone marrow mononuclear cell transplantation in patients with advanced chronic liver disease. World J Gastroenterol. 2007;13:1067–1073.
    1. Moriya K, Yoshikawa M, Ouji Y, Saito K, Nishiofuku M, Matsuda R, Ishizaka S, Fukui H. Embryonic stem cells reduce liver fibrosis in CCl4-treated mice. Int J Exp Pathol. 2008;89:401–409.
    1. Mohamadnejad M, Alimoghaddam K, Mohyeddin-Bonab M, Bagheri M, Bashtar M, Ghanaati H, Baharvand H, Ghavamzadeh A, Malekzadeh R. Phase 1 trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis. Arch Iranian Med. 2007;10:459–466.

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