Restricted accessResearch articleFirst published online 2010-10
Treatment of Acute Hepatic Failure in Mice by Transplantation of Mixed Microencapsulation of Rat Hepatocytes and Transgenic Human Fetal Liver Stromal Cells
Microencapsulation-mediated cell therapy overcomes the immune incompatibility between donor and recipient in transplantation. The aim of this study was to investigate the effects of transplantation of microcapsules containing a mixture of rat hepatocytes and human fetal liver stromal cells (hFLSCs), engineered to produce basic fibroblast growth factor (bFGF), on acute liver failure (ALF) in mice. In vitro experiments showed that different combinations of microencapsulated rat's hepatocytes and stromal cells survive, grow, and function better in three-dimensional conditions. The metabolic activity of rat hepatocytes co-microencapsulated with hFLSCs, particularly when engineered to produce bFGF (FLSCs/bFGF), is significantly higher than that of microcapsules with rat hepatocytes alone. Intraperitoneal transplantation of the encapsulated hepatocytes with FLSCs/bFGF increased the survival rate and improved liver function of an ALF mouse model induced by a 70% partial hepatectomy in BALB/C mice. Moreover, dramatic liver regeneration was observed 2 days after transplantation in the group that received intraperitoneal transplantations of encapsulated hepatocytes with FLSCs/bFGF. Therefore, transplantation of encapsulated hepatocytes and hFLSCs/bFGF may be a promising strategy to treat ALF or related liver diseases.
Get full access to this article
View all access options for this article.
References
1.
BrianE.M., ChristineM.T., LindaM.C., ClaudyM.Overview of extracorporeal liver support systems and clinical results. Ann N Y Acad Sci, 875:310. 1999.
2.
IjimaH., NakazawaK., FunatsuK.Development of a hybrid artificial liver. Organ Biol, 5:35. 1998.
3.
DodsonS.F., IssaS., BonhamA.Liver transplantation for chronic hepatitis. Surg Clin North Am, 79:131. 1999.
4.
GordonR.D., FungJ., TzakisA.G., TodoS., StieberA., BronstherO., MartinM., Van ThielD.H., StarzlT.E.Liver transplantation at the University of Pittsburgh from 1984 to 1990. Clin Transplant, 177:105. 1991.
5.
SchraaE.O., MarquetR.L., IjzermansJ.N.M.The fourth barrier. Curr Med Res Opin, 15:327. 1999.
6.
SimK.H., MarinovA., LevyG.A.Xenotransplantation: a potential solution to the critical organ donor shortage. Can J Gastroenterol, 13:311. 1999.
7.
StrainA.J., NeubergerJ.M.A bioartificial liver—state of the art. Science, 295:1005. 2002.
8.
DemetriouA.A., BrownR.S.Jr., BusuttilR.W., FairJ., McGuireB.M., RosenthalP., Am EschJ.S.2nd., LerutJ., NybergS.L., SalizzoniM., FaganE.A., de HemptinneB., BroelschC.E., MuracaM., SalmeronJ.M., RabkinJ.M., MetselaarH.J., PrattD., De La MataM., McChesneyL.P., EversonG.T., LavinP.T., StevensA.C., PitkinZ., SolomonB.A.Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure. Ann Surg, 239:660. 2004.
9.
MeiJ., SgroiA., MaiG., BaertschigerR., Gonelle-GispertC., Serre-BeinierV., MorelP., BühlerL.H.Improved survival of fulminant liver failure by transplantation of microencapsulated cryopreserved porcine hepatocytes in mice. Cell Transplant, 18:101. 2009.
10.
WenL., CalmusY., HoningerJ., ContiF., CapeauJ., WeillB., NordlingerB.Encapsulated xenogeneic hepatocytes remain functional after peritoneal implantation despite immunization of the host. J Hepatol, 29:960. 1998.
11.
PatzerJ.F.2nd., MazariegosG.V., LopezR., MolmentiE., GerberD., RiddervoldF., KhannaA., YinW.Y., ChenY., ScottV.L., AggarwalS., KramerD.J., WagnerR.A., ZhuY., FulmerM.L., BlockG.D., AmiotB.P.Novel bioartificial liver support system: preclinical evaluation. Ann N Y Acad Sci, 875:340. 1999.
12.
AokiT., UmeharaY., FerraressoC., SugiyamaN., MiddletonY., AvitalI., InderbitzinD., DemetriouA.A., RozgaJ.Intrasplenic transplantation of encapsulated cells: a novel approach to cell therapy. Cell Transplant, 11:553. 2002.
13.
CanapleL., NurdinN., AngelovaN., HunkelerD., DesvergneB.Development of a coculture model of encapsulated cells. Ann NY Acad Sci, 944:350. 2001.
PeiH., YangY., XiJ., BaiZ., YueW., NanX., BaiC., WangY., PeiX.Lineage restriction and differentiation of human embryonic stem cells into hepatic progenitors and zone 1 hepatocytes. Tissue Eng Part C Methods, 15:1. 2009.
18.
SeglenP.O.Preparation of isolated rat liver cells. Methods Cell Biol, 13:29. 1976.
19.
HigginsG.M., AndersonR.M.Experimental pathology of the liver. Arch Pathol, 12:186. 1931.
20.
CaiZ., ShiZ., ShermanM., SunA.M.Development and evaluation of a system of microencapsulation of primary rat hepatocytes. Hepatology, 10:855. 1989.
CombalbertJ., FabreI., FabreG., DaletI., DerancourtJ., CanoJ.P., MaurelP.Metabolism of cyclosporine A. IV. Purification and identification of the rifampicin-inducible human liver cytochrome P-450 (cyclosporine A oxidase) as a product of P450IIIA gene subfamily. Drug Metab Dispos, 17:197. 1989.
23.
HayD.C., ZhaoD., RossA., MandalamR., LebkowskiJ., CuiW.Direct differentiation of human embryonic stem cells to hepatocyte-like cells exhibiting functional activities. Cloning Stem Cells, 9:51. 2007.
24.
AmbrosinoG., VarottoS., BassoS.M., CecchettoA., CarraroP., NasoA., De SilvestroG., PlebaniM., AbatangeloG., DonatoD., CestroneA., GironG., D'AmicoD.F.Hepatocyte transplantation in the treatment of acute liver failure: microencapsulated hepatocytes versus hepatocytes attached to an autologous biomatrix. Cell Transplant, 12:43. 2003.
ArkadopoulosN., LiljaH., SuhK.S., DemetriouA.A., RozgaJ.Intrasplenic transplantation of allogeneic hepatocytes prolongs survival in anhepatic rats. Hepatology, 28:1365. 1998.
27.
StromS.C., FisherR.A., ThompsonM.T., SanyalA.J., ColeP.E., HamJ.M., PosnerM.P.Hepatocyte transplantation as a bride to orthotopic liver transplantation in terminal liver failure. Transplantation, 63:559. 1997.
28.
HamazakiK., DoiY., KoideN.Microencapsulated multicellular spheroid of rat hepatocytes transplanted intraperitoneally after 90% hepatectomy. Hepatogastroenterology, 49:1514. 2002.
29.
BenoistS., SarkisR., BarbuV., HonigerJ., BaudrimontM., LakehalF., BecquemontL., DeleloR., HoussetC., BalladurP., CapeauJ., NordlingerB.Survival and functions of encapsulated porcine hepatocytes after allotransplantation or xenotransplantation without immunosuppression. Surgery, 129:607. 2001.
30.
WenL., GrudéP., ContiF., HonigerJ., CapeauJ., NordlingerB., WeillB., CalmusY.Suppression of humoral immunization against encapsulated xenogeneic hepatocytes and prolongation of their function by 2-week cyclosporine treatment in the rat. Surgery, 127:301. 2000.
31.
DixitV., DarvasiR., ArthurM., BrezinaM., LewinK., GitnickG.Restoration of liver function in Gunn rats without immunosuppression using transplanted microencapsulated hepatocytes. Hepatology, 12:13. 1990.
32.
UmeharaY., HakamadaK., SeinoK., AokiK., ToyokiY., SasakiM.Improved survival and ammonia metabolism by intraperitoneal transplantation of microencapsulated hepatocytes in totally hepatectomized rats. Surgery, 130:513. 2001.
BaruchY., ShoshanyG., NeufeldG., EnatR.Basic fibroblast growth factor is hepatotropic for rat liver in regeneration. J Hepatol, 3:23. 1995.
35.
KawasakiT., TamuraS., KisoS., DoiY., YoshidaY., KamadaY., SaekiA., SajiY., MatsuzawaY.Effects of growth factors on the growth and differentiation of mouse fetal liver epithelial cells in primary cultures. J Gastroenterol Hepatol, 6:20. 2005.
36.
CharlotteE., WinK.M., PreauxA.M., MavierP., DhumeauxD., ZafraniE.S., RosenbaumJ.Immunolocalization of heparin binding growth factors (HBGF) types 1 and 2 in rat liver: selective hyperexpression of HBGF-2 in carbon tetrachloride induced fibrosis. J Pathol, 169:6. 1993.
37.
LeeH., CusickR.A., BrowneF., Ho KimT., MaP.X., UtsunomiyaH., LangerR., VacantiJ.P.Local delivery of basic fibroblast growth factor increases both angiogenesis and engraftment of hepatocytes in tissue-engineered polymer devices. Transplantation, 10:73. 2002.
38.
OgawaK., AsonumaK., InomataY., KimI., IkadaY., TabataY., TanakaK.The efficacy of prevascularization by basic FGF for hepatocyte transplantation using polymer devices in rats. Cell Transplant, 8:10. 2001.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
