Prolonged engraftment of human hepatocytes in mice transgenic for the deleted form of human hepatocyte growth factor

Hepatology Research - Tập 37 Số 10 - Trang 854-862 - 2007
Anuradha Krishnan1, Kimberly Viker1, Heleen Rietema1, Marije Telgenkamp1, Bruce E. Knudsen1, Michael Charlton1
1Mayo Clinic and Foundation, Rochester, Minnesota, USA

Tóm tắt

Aim:  Small animal models chimeric for human hepatocytes have provided valuable insights into the biology of hepatotropic viral infection and provided a platform for the study of therapeutic agents. Existing models of human hepatocyte transplantation are limited by phenotypic fragility and impaired immunity. We hypothesized that mice transgenic for human hepatocyte growth factor (HGF), a potent human hepatocyte mitogen, would engraft human hepatocytes in the absence of immunodeficiency.Methods:  A plasmid construct containing the 2.3 kb coding region of the 723 amino acid isoform of HGF cDNA under the transcriptional control of the mouse albumin promoter/enhancer was used to generate transgenic mice. Cryopreserved human hepatocytes were transplanted into nine transgenic and six non‐transgenic mice. Engraftment of human hepatocytes was followed for a period of 12 weeks by immunoblotting for human albumin in mouse serum samples.Results:  In six out of the nine transgenic mice, abundance of human albumin, following an initial decline, increased andpeaked at > 70 days post transplantation, demonstrating sustained engraftment of transplanted human hepatocytes. In all the non‐transgenic mice, post‐transplant human albumin levels declined sequentially without evidence of sustained engraftment. Immunostaining of mouse liver sections indicated the presence of human hepatocytes adjacent to clusters of non‐staining murine hepatocytes.Conclusion:  These results demonstrate that sustained engraftment of human hepatocytes in mice is facilitated by expression of the human dHGF transgene. Human hepatocyte engraftment in this model has been achieved on an immunocompetent strain background and merits further study as a candidate for the study of hepatotropic viral infections.

Từ khóa


Tài liệu tham khảo

10.1016/0092-8674(90)90010-C

10.1016/0092-8674(91)90615-6

10.1073/pnas.92.11.4942

10.1101/gad.7.12a.2298

10.1016/S0002-9440(10)64212-5

10.1089/hum.1997.8.5-513

10.1038/90968

10.1002/hep.21209

10.1038/nbt817

10.1002/hep.20657

10.1073/pnas.0511218103

10.1016/j.bbrc.2004.10.204

10.1016/j.transproceed.2006.02.149

10.1124/dmd.104.002600

10.1002/hep.1840210631

10.1172/JCI115207

Hogan B, 1986, Manipulating the Mouse Embryo: A Laboratory Manual

10.1038/sj.onc.1202379

10.1097/00007890-199505270-00017

10.1002/hep.1840190230

10.1016/S1084952102001313

10.1126/science.276.5309.60

10.1002/hep.20969

10.1034/j.1600-0676.2003.00812.x

10.1016/S0002-9440(10)65574-5

10.1152/ajpgi.1999.276.3.G629

10.1097/00007890-200206150-00020

10.1093/carcin/16.1.139

10.1038/73187

Kokudo N, 1994, Effect of 70% hepatectomy on DNA synthesis in rat hepatocyte isograft into the spleen, Transplant Proc, 26, 3464

10.1016/S0041-1345(00)02154-0

10.1242/jcs.111.2.237

Sugiyama N, 2000, Intraportal administration of low‐dose recombinant human hepatocyte growth factor enhances effects of hepatocellular transplantation, Hepatogastroenterology, 47, 1245

10.1006/bbrc.1994.1523

10.1016/S0014-2999(97)01485-4

10.1006/phrs.2000.0728

10.1097/01.TP.0000160813.37515.97

10.1021/js9800432

10.1152/ajpheart.01320.2005

10.1111/j.1432-2277.2005.00156.x

10.1097/00007890-199706150-00001

10.3748/wjg.v10.i14.2099

10.1002/(SICI)1097-0185(199709)249:1<6::AID-AR2>3.0.CO;2-P

10.1053/jhep.2001.23314

10.1086/338266

10.1016/S0002-9440(10)63352-4

Rabes HM, 1976, Analysis of cell cycle compartments of hepatocytes after partial hepatecomy, Cell Tissue Kinetics, 9, 517

10.1002/hep.510310126

10.1177/096368979500400207

10.1016/S0016-5085(96)70078-1

Wu CH, 2001, Liver cell transplantation – novel animal model for human hepatic viral infections, Croat Med J, 42, 446

Thông tin
Thông tin xuất bản

Hepatology Research

Tập 37 Số 10

854-862

Thông tin tác giả