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Open Access 01-12-2012 | Research article

Therapeutic potential of transplanted placental mesenchymal stem cells in treating Chinese miniature pigs with acute liver failure

Authors: Hongcui Cao, Jinfeng Yang, Jiong Yu, Qiaoling Pan, Jianzhou Li, Pengcheng Zhou, Yanyuan Li, Xiaoping Pan, Jun Li, Yingjie Wang, Lanjuan Li

Published in: BMC Medicine | Issue 1/2012

Abstract

Background

Stem cell-based therapy to treat liver diseases is a focus of current research worldwide. So far, most such studies depend on rodent hepatic failure models. The purpose of this study was to isolate mesenchymal stem cells from human placenta (hPMSCs) and determine their therapeutic potential for treating Chinese experimental miniature pigs with acute liver failure (ALF).

Methods

hPMSCs were isolated and analyzed for their purity and differentiation potential before being employed as the donor cells for transplantation. ALF models of Chinese experimental miniature pigs were established and divided into four groups: no cell transplantation; hPMSCs transplantation via the jugular vein; X-ray-treated hPMSCs transplantation via the portal vein; and hPMSCs transplantation via the portal vein. The restoration of biological functions of the livers receiving transplantation was assessed via a variety of approaches such as mortality rate determination, serum biochemical analysis, and histological, immunohistochemical, and genetic analysis.

Results

hPMSCs expressed high levels of CD29, CD73, CD13, and CD90, had adipogenic, osteogenic, and hepatic differentiation potential. They improved liver functions in vivo after transplantation into the D-galactosamine-injured pig livers as evidenced by the fact that ALT, AST, ALP, CHE, TBIL, and TBA concentrations returned to normal levels in recipient ALF pigs. Meanwhile, histological data revealed that transplantation of hPMSCs via the portal vein reduced liver inflammation, decreased hepatic denaturation and necrosis, and promoted liver regeneration. These ameliorations were not found in the other three groups. The result of 7-day survival rates suggested that hPMSCs transplantation via the portal vein was able to significantly prolong the survival of ALF pigs compared with the other three groups. Histochemistry and RT-PCR results confirmed the presence of transplanted human cells in recipient pig livers (Groups III, IV).

Conclusions

Our data revealed that hPMSCs could not only differentiate into hepatocyte-like cells in vitro and in vivo, but could also prolong the survival time of ALF pigs. Regarding the transplantation pathways, the left branch of the portal vein inside the liver was superior to the jugular vein pathway. Thus, hPMSCs transplantation through the portal vein by B-ultrasonography may represent a superior approach for treating liver diseases.

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Fiegel HC, Lange C, Kneser U, Lambrecht W, Zander AR, Rogiers X, Kluth D: Fetal and adult liver stem cells for liver regeneration and tissue engineering. J Cell Mol Med. 2006, 10: 577-587. 10.1111/j.1582-4934.2006.tb00422.x.CrossRefPubMed

Di Campli C, Nestola M, Piscaglia AC, Santoliquido A, Gasbarrini G, Pola P, Gasbarrini A: Cell-based therapy for liver diseases. Eur Rev Med Pharmacol Sci. 2003, 7: 41-44.PubMed

Stutchfield BM, Forbes SJ, Wigmore SJ: Prospects for stem cell transplantation in the treatment of hepatic disease. Liver Transpl. 2010, 16: 827-836. 10.1002/lt.22083.CrossRefPubMed

Enns GM, Millan MT: Cell-based therapies for metabolic liver disease. Mol Genet Metab. 2008, 95: 3-10. 10.1016/j.ymgme.2008.06.001.CrossRefPubMed

Lorenzo M, Angrisani L, Santoro A, Di Salvo E: [Hepatocyte transplantation. From experimentation to therapeutic attempts in man]. G Chir. 1994, 15: 59-63.PubMed

Puppi J, Dhawan A: Human hepatocyte transplantation overview. Methods Mol Biol. 2009, 481: 1-16.CrossRefPubMed

Gewartowska M, Olszewski WL: Hepatocyte transplantation-biology and application. Ann Transplant. 2007, 12: 27-36.PubMed

Satija NK, Gurudutta GU, Sharma S, Afrin F, Gupta P, Verma YK, Singh VK, Tripathi RP: Mesenchymal stem cells: molecular targets for tissue engineering. Stem Cells Dev. 2007, 16: 7-23. 10.1089/scd.2006.9998.CrossRefPubMed

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 (6893): 41-49. 10.1038/nature00870.CrossRefPubMed

10.

Young HE, Steele TA, Bray RA, Hudson J, Floyd JA, Hawkins K, Thomas K, Austin T, Edwards C, Cuzzourt J, Duenzl M, Lucas PA, Black AC: Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis derived from fetal, adult, and geriatric donors. Anat Rec. 2001, 264: 51-62. 10.1002/ar.1128.CrossRefPubMed

11.

Suchanek J, Visek B, Soukup T, El-Din Mohamed SK, Ivancakova R, Mokry J, Aboul-Ezz EH, Omran A: Stem cells from human exfoliated deciduous teeth--isolation, long term cultivation and phenotypical analysis. Acta Medica (Hradec Kralove). 2010, 53: 93-99.

12.

Jo YY, Lee HJ, Kook SY, Choung HW, Park JY, Chung JH, Choung YH, Kim ES, Yang HC, Choung PH: Isolation and characterization of postnatal stem cells from human dental tissues. Tissue Eng. 2007, 13: 767-773. 10.1089/ten.2006.0192.CrossRefPubMed

13.

Tsai MS, Lee JL, Chang YJ, Hwang SM: Isolation of human multipotent mesenchymal stem cells from second-trimester amniotic fluid using a novel two-stage culture protocol. Hum Reprod. 2004, 19: 1450-1456. 10.1093/humrep/deh279.CrossRefPubMed

14.

Shih DT, Lee DC, Chen SC, Tsai RY, Huang CT, Tsai CC, Shen EY, Chiu WT: Isolation and characterization of neurogenic mesenchymal stem cells in human scalp tissue. Stem Cells. 2005, 23: 1012-1020. 10.1634/stemcells.2004-0125.CrossRefPubMed

15.

Perng CK, Ku HH, Chiou SH, Chen IL, Tsai FT, Yang YP, Chang KY, Kao CL: Evaluation of wound healing effect on skin-defect nude mice by using human dermis-derived mesenchymal stem cells. Transplant Proc. 2006, 38: 3086-3087. 10.1016/j.transproceed.2006.08.146.CrossRefPubMed

16.

In 't Anker PS, Scherjon SA, Kleijburg-van der Keur C, de Groot-Swings GM, Claas FH, Fibbe WE, Kanhai HH: Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells. 2004, 22: 1338-1345. 10.1634/stemcells.2004-0058.CrossRefPubMed

17.

Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, Osaki M, Kawamata M, Kato T, Okochi H, Ochiya T: IFATS collection: in vivo therapeutic potential of human adipose tissue mesenchymal stem cells after transplantation into mice with liver injury. Stem Cells. 2008, 26: 2705-2712. 10.1634/stemcells.2008-0034.CrossRefPubMed

18.

Musina RA, Bekchanova ES, Belyavskii AV, Grinenko TS, Sukhikh GT: Umbilical cord blood mesenchymal stem cells. Bull Exp Biol Med. 2007, 143: 127-131. 10.1007/s10517-007-0032-z.CrossRefPubMed

19.

Bajek A, Olkowska J, Drewa T: [Mesenchymal stem cells as a therapeutic tool in tissue and organ regeneration]. Postepy Hig Med Dosw (Online). 2011, 65: 124-132.CrossRef

20.

Lysy PA, Campard D, Smets F, Najimi M, Sokal EM: Stem cells for liver tissue repair: current knowledge and perspectives. World J Gastroenterol. 2008, 14: 864-875. 10.3748/wjg.14.864.CrossRefPubMedPubMedCentral

21.

Cho KA, Ju SY, Cho SJ, Jung YJ, Woo SY, Seoh JY, Han HS, Ryu KH: Mesenchymal stem cells showed the highest potential for the regeneration of injured liver tissue compared with other subpopulations of the bone marrow. Cell Biol Int. 2009, 33: 772-777. 10.1016/j.cellbi.2009.04.023.CrossRefPubMed

22.

Sato Y, Araki H, Kato J, Nakamura K, Kawano Y, Kobune M, Sato T, Miyanishi K, Takayama T, Takahashi M, Takimoto R, Iyama S, Matsunaga T, Ohtani S, Matsuura A, Hamada H, Niitsu Y: Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. Blood. 2005, 106: 756-763. 10.1182/blood-2005-02-0572.CrossRefPubMed

23.

Jung KH, Shin HP, Lee S, Lim YJ, Hwang SH, Han H, Park HK, Chung JH, Yim SV: Effect of human umbilical cord blood-derived mesenchymal stem cells in a cirrhotic rat model. Liver Int. 2009, 29: 898-909. 10.1111/j.1478-3231.2009.02031.x.CrossRefPubMed

24.

Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, Osaki M, Kato T, Okochi H, Ochiya T: Rapid hepatic fate specification of adipose-derived stem cells and their therapeutic potential for liver failure. J Gastroenterol Hepatol. 2009, 24: 70-77. 10.1111/j.1440-1746.2008.05496.x.CrossRefPubMed

25.

Forraz N, McGuckin CP: The umbilical cord: a rich and ethical stem cell source to advance regenerative medicine. Cell Prolif. 2011, Suppl 1: 60-69.CrossRef

26.

Barlow S, Brooke G, Chatterjee K, Price G, Pelekanos R, Rossetti T, Doody M, Venter D, Pain S, Gilshenan K, Atkinson K: Comparison of human placenta- and bone marrow-derived multipotent mesenchymal stem cells. Stem Cells Dev. 2008, 17: 1095-1107. 10.1089/scd.2007.0154.CrossRefPubMed

27.

Parolini O, Alviano F, Bagnara GP, Bilic G, Buhring HJ, Evangelista M, Hennerbichler S, Liu B, Magatti M, Mao N, Miki T, Marongiu F, Nakajima H, Nikaido T, Portmann-Lanz CB, Sankar V, Soncini M, Stadler G, Surbek D, Takahashi TA, Redl H, Sakuragawa N, Wolbank S, Zeisberger S, Zisch A, Strom SC: Concise review: isolation and characterization of cells from human term placenta: outcome of the first international Workshop on Placenta Derived Stem Cells. Stem Cells. 2008, 26: 300-311. 10.1634/stemcells.2007-0594.CrossRefPubMed

28.

Wulf GG, Viereck V, Hemmerlein B, Haase D, Vehmeyer K, Pukrop T, Glass B, Emons G, Trumper L: Mesengenic progenitor cells derived from human placenta. Tissue Eng. 2004, 10: 1136-1147.CrossRefPubMed

29.

Semenov OV, Koestenbauer S, Riegel M, Zech N, Zimmermann R, Zisch AH, Malek A: Multipotent mesenchymal stem cells from human placenta: critical parameters for isolation and maintenance of stemness after isolation. Am J Obstet Gynecol. 2010, 202: 193.e191-193.e113.CrossRef

30.

Chien CC, Yen BL, Lee FK, Lai TH, Chen YC, Chan SH, Huang HI: In vitro differentiation of human placenta-derived multipotent cells into hepatocyte-like cells. Stem Cells. 2006, 24: 1759-1768. 10.1634/stemcells.2005-0521.CrossRefPubMed

31.

Lee MJ, Jung J, Na KH, Moon JS, Lee HJ, Kim JH, Kim GI, Kwon SW, Hwang SG, Kim GJ: Anti-fibrotic effect of chorionic plate-derived mesenchymal stem cells isolated from human placenta in a rat model of CCl(4)-injured liver: potential application to the treatment of hepatic diseases. J Cell Biochem. 2010, 111: 1453-1463. 10.1002/jcb.22873.CrossRefPubMed

32.

Li LJ, Du WB, Zhang YM, Li J, Pan XP, Chen JJ, Cao HC, Chen Y, Chen YM: Evaluation of a bioartificial liver based on a nonwoven fabric bioreactor with porcine hepatocytes in pigs. J Hepatol. 2006, 44: 317-324. 10.1016/j.jhep.2005.08.006.CrossRefPubMed

33.

Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, Keating A: Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy. 2005, 7: 393-395. 10.1080/14653240500319234.CrossRefPubMed

34.

Chang CJ, Yen ML, Chen YC, Chien CC, Huang HI, Bai CH, Yen BL: Placenta-derived multipotent cells exhibit immunosuppressive properties that are enhanced in the presence of interferon-gamma. Stem Cells. 2006, 24: 2466-2477. 10.1634/stemcells.2006-0071.CrossRefPubMed

35.

Bailo M, Soncini M, Vertua E, Signoroni PB, Sanzone S, Lombardi G, Arienti D, Calamani F, Zatti D, Paul P, Albertini A, Zorzi F, Cavagnini A, Candotti F, Wengler GS, Parolini O: Engraftment potential of human amnion and chorion cells derived from term placenta. Transplantation. 2004, 78: 1439-1448. 10.1097/01.TP.0000144606.84234.49.CrossRefPubMed

36.

Hay DC, Zhao D, Fletcher J, Hewitt ZA, McLean D, Urruticoechea-Uriguen A, Black JR, Elcombe C, Ross JA, Wolf R, Cui W: Efficient differentiation of hepatocytes from human embryonic stem cells exhibiting markers recapitulating liver development in vivo. Stem Cells. 2008, 26: 894-902. 10.1634/stemcells.2007-0718.CrossRefPubMed

37.

Zhang D, Jiang M, Miao D: Transplanted human amniotic membrane-derived mesenchymal stem cells ameliorate carbon tetrachloride-induced liver cirrhosis in mouse. PLoS One. 2011, 6: e16789-10.1371/journal.pone.0016789.CrossRefPubMedPubMedCentral

38.

Kanazawa H, Fujimoto Y, Teratani T, Iwasaki J, Kasahara N, Negishi K, Tsuruyama T, Uemoto S, Kobayashi E: Bone marrow-derived mesenchymal stem cells ameliorate hepatic ischemia reperfusion injury in a rat model. PLoS One. 2011, 6: e19195-10.1371/journal.pone.0019195.CrossRefPubMedPubMedCentral

39.

Rabani V, Shahsavani M, Gharavi M, Piryaei A, Azhdari Z, Baharvand H: Mesenchymal stem cell infusion therapy in a carbon tetrachloride-induced liver fibrosis model affects matrix metalloproteinase expression. Cell Biol Int. 2010, 34: 601-605. 10.1042/CBI20090386.CrossRefPubMed

40.

Sakaida I, Terai S, Yamamoto N, Aoyama K, Ishikawa T, Nishina H, Okita K: Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology. 2004, 40: 1304-1311. 10.1002/hep.20452.CrossRefPubMed

41.

Oyagi S, Hirose M, Kojima M, Okuyama M, Kawase M, Nakamura T, Ohgushi H, Yagi K: Therapeutic effect of transplanting HGF-treated bone marrow mesenchymal cells into CCl4-injured rats. J Hepatol. 2006, 44: 742-748. 10.1016/j.jhep.2005.10.026.CrossRefPubMed

42.

Ying QL, Nichols J, Evans EP, Smith AG: Changing potency by spontaneous fusion. Nature. 2002, 416: 545-548. 10.1038/nature729.CrossRefPubMed

43.

Piscaglia AC, Novi M, Campanale M, Gasbarrini A: Stem cell-based therapy in gastroenterology and hepatology. Minim Invasive Ther Allied Technol. 2008, 17: 100-118. 10.1080/13645700801969980.CrossRefPubMed

44.

Vassilopoulos G, Wang PR, Russell DW: Transplanted bone marrow regenerates liver by cell fusion. Nature. 2003, 422: 901-904. 10.1038/nature01539.CrossRefPubMed

45.

Misawa R, Ise H, Takahashi M, Morimoto H, Kobayashi E, Miyagawa S, Ikeda U: Development of liver regenerative therapy using glycoside-modified bone marrow cells. Biochem Biophys Res Commun. 2006, 342: 434-440. 10.1016/j.bbrc.2006.01.169.CrossRefPubMed

46.

Muraca M, Ferraresso C, Vilei MT, Granato A, Quarta M, Cozzi E, Rugge M, Pauwelyn KA, Caruso M, Avital I, Inderbitzin D, Demetriou AA, Forbes SJ, Realdi G: Liver repopulation with bone marrow derived cells improves the metabolic disorder in the Gunn rat. Gut. 2007, 56: 1725-1735. 10.1136/gut.2007.127969.CrossRefPubMedPubMedCentral

47.

Kuo TK, Hung SP, Chuang CH, Chen CT, Shih YR, Fang SC, Yang VW, Lee OK: Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology. 2008, 134: 2111-2121. 10.1053/j.gastro.2008.03.015. 2121.e1-3CrossRefPubMedPubMedCentral

48.

Ogawa S, Miyagawa S: Potentials of regenerative medicine for liver disease. Surg Today. 2009, 39: 1019-1025. 10.1007/s00595-009-4056-z.CrossRefPubMed

49.

Malhi H, Irani AN, Gagandeep S, Gupta S: Isolation of human progenitor liver epithelial cells with extensive replication capacity and differentiation into mature hepatocytes. J Cell Sci. 2002, 115: 2679-2688.PubMed

50.

Haynesworth SE, Baber MA, Caplan AI: Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha. J Cell Physiol. 1996, 166: 585-592. 10.1002/(SICI)1097-4652(199603)166:3<585::AID-JCP13>3.0.CO;2-6.CrossRefPubMed

51.

Caplan AI, Dennis JE: Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006, 98: 1076-1084. 10.1002/jcb.20886.CrossRefPubMed

52.

Gnecchi M, He H, Noiseux N, Liang OD, Zhang L, Morello F, Mu H, Melo LG, Pratt RE, Ingwall JS, Dzau VJ: Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. 2006, 20: 661-669. 10.1096/fj.05-5211com.CrossRefPubMed

53.

Le Blanc K: Mesenchymal stromal cells: Tissue repair and immune modulation. Cytotherapy. 2006, 8: 559-561. 10.1080/14653240601045399.CrossRefPubMed

54.

Xu G, Zhang L, Ren G, Yuan Z, Zhang Y, Zhao RC, Shi Y: Immunosuppressive properties of cloned bone marrow mesenchymal stem cells. Cell Res. 2007, 17: 240-248.PubMed

55.

Sheng H, Wang Y, Jin Y, Zhang Q, Zhang Y, Wang L, Shen B, Yin S, Liu W, Cui L, Li N: A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res. 2008, 18: 846-857. 10.1038/cr.2008.80.CrossRefPubMed

56.

Nasef A, Mazurier C, Bouchet S, Francois S, Chapel A, Thierry D, Gorin NC, Fouillard L: Leukemia inhibitory factor: Role in human mesenchymal stem cells mediated immunosuppression. Cell Immunol. 2008, 253: 16-22. 10.1016/j.cellimm.2008.06.002.CrossRefPubMed

57.

Casiraghi F, Azzollini N, Cassis P, Imberti B, Morigi M, Cugini D, Cavinato RA, Todeschini M, Solini S, Sonzogni A, Perico N, Remuzzi G, Noris M: Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol. 2008, 181: 3933-3946.CrossRefPubMed

58.

Chabannes D, Hill M, Merieau E, Rossignol J, Brion R, Soulillou JP, Anegon I, Cuturi MC: A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood. 2007, 110: 3691-3694. 10.1182/blood-2007-02-075481.CrossRefPubMed

59.

Popp FC, Eggenhofer E, Renner P, Slowik P, Lang SA, Kaspar H, Geissler EK, Piso P, Schlitt HJ, Dahlke MH: Mesenchymal stem cells can induce long-term acceptance of solid organ allografts in synergy with low-dose mycophenolate. Transpl Immunol. 2008, 20: 55-60. 10.1016/j.trim.2008.08.004.CrossRefPubMed

60.

Sbano P, Cuccia A, Mazzanti B, Urbani S, Giusti B, Lapini I, Rossi L, Abbate R, Marseglia G, Nannetti G, Torricelli F, Miracco C, Bosi A, Fimiani M, Saccardi R: Use of donor bone marrow mesenchymal stem cells for treatment of skin allograft rejection in a preclinical rat model. Arch Dermatol Res. 2008, 300: 115-124. 10.1007/s00403-007-0827-9.CrossRefPubMed

61.

Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A, Miller L, Guetta E, Zipori D, Kedes LH, Kloner RA, Leor J: Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution. Circulation. 2003, 108: 863-868. 10.1161/01.CIR.0000084828.50310.6A.CrossRefPubMed

62.

Jacobsen PF, Daly J: A method for distinguishing human and mouse cells in solid tumors using in situ hybridization. Exp Mol Pathol. 1994, 61: 212-220. 10.1006/exmp.1994.1038.CrossRefPubMed

63.

Nicklas JA, Buel E: Development of an Alu-based, real-time PCR method for quantitation of human DNA in forensic samples. J Forensic Sci. 2003, 48: 936-944.PubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/10/56/prepub

Title: Therapeutic potential of transplanted placental mesenchymal stem cells in treating Chinese miniature pigs with acute liver failure
Authors: Hongcui Cao
Jinfeng Yang
Jiong Yu
Qiaoling Pan
Jianzhou Li
Pengcheng Zhou
Yanyuan Li
Xiaoping Pan
Jun Li
Yingjie Wang
Lanjuan Li
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: BMC Medicine / Issue 1/2012
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/1741-7015-10-56

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Therapeutic potential of transplanted placental mesenchymal stem cells in treating Chinese miniature pigs with acute liver failure

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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