Establishment of heterotropic liver tissue mass with direct link to the host liver following implantation of hepatocytes transfected with vascular endothelial growth factor gene in mice.
One of the major goals of tissue engineering is to establish an integrated organ in vivo. We have previously shown that transfection of vascular endothelial growth factor (VEGF) gene into hepatocytes promotes tissue formation by engrafted cells. Here we show that tissue growth was significantly enhanced by co-transplantation of hepatocyte growth factor (HGF) and tumor necrosis factor-alpha (TNF alpha) gene transfected hepatocytes with VEGF-gene transfected cells, but tissue islands were scattered nonspecifically in the abdomen of mice. The result brought us forward to the next step to establish an integrated mass and structural formation of liver tissue. We entrapped VEGF gene transfected hepatocytes in a nylon mesh bag and intraperitoneally engrafted close to the liver. Three weeks later, the bag was covered by a thick network of blood vessels, compared to the control. Histological examination showed that the blood vessels penetrated the parenchyma of the engrafted bag and formed a well-developed vessel network in the region. The use of hepatocytes from lacZ transgenic mice and PCR analysis demonstrated survival and albumin production by hepatocytes in the engrafted bag. Our model can potentially be developed into a heterotropic artificial liver with direct access to the host blood circulation.
Ajioka
I
I
Department of Biomolecular Engineering, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
Nishio
R
R
Ikekita
M
M
Akaike
T
T
Sasaki
M
M
Enami
J
J
Watanabe
Y
Y
D000199:Actins / Q000096:biosynthesis; D000418:Albumins / Q000096:biosynthesis; D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology; D001698:Biomedical Engineering; D002470:Cell Survival / Q000187:drug effects; D020099:Coated Materials, Biocompatible / Q000737:chemistry; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000494:pharmacology; D022781:Hepatocytes / Q000637:transplantation*; D006801:Humans; D007763:Lac Operon / Q000502:physiology; D008099:Liver / Q000098:blood supply* / Q000502:physiology*; D008222:Lymphokines / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011994:Recombinant Proteins; D013499:Surface Properties; D014162:Transfection; D016042:Transplantation, Heterotopic / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000199:Actins; D000418:Albumins; D001672:Biocompatible Materials; D020099:Coated Materials, Biocompatible; D016228:Endothelial Growth Factors; D008222:Lymphokines; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017228:Hepatocyte Growth Factor