Liver tissue engineering at extrahepatic sites in mice as a potential new therapy for genetic liver diseases
Liver tissue engineering using hepatocyte transplantation has been proposed as an alternative to whole-organ transplantation or liver-directed gene therapy to correct various types of hepatic insufficiency. Hepatocytes are not sustained when transplanted under the kidney capsule of syngeneic mice. H...
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Published in | Hepatology (Baltimore, Md.) Vol. 41; no. 1; pp. 132 - 140 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
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Hoboken, NJ
Wiley
2005
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Abstract | Liver tissue engineering using hepatocyte transplantation has been proposed as an alternative to whole-organ transplantation or liver-directed gene therapy to correct various types of hepatic insufficiency. Hepatocytes are not sustained when transplanted under the kidney capsule of syngeneic mice. However, when we transplanted hepatocytes with the extracellular matrix components extracted from Engelbreth-Holm-Swarm cells, hepatocytes survived for at least 140 days and formed small liver tissues. Liver engineering in hemophilia A mice reconstituted 5% to 10% of normal clotting activity, enough to reduce the bleeding time and have a therapeutic benefit. Conversely, the subcutaneous space did not support the persistent survival of hepatocytes with Engelbreth-Holm-Swarm gel matrix. We hypothesized that establishing a local vascular network at the transplantation site would reduce graft loss. To test this idea, we provided a potent angiogenic agent before hepatocyte transplantation into the subcutaneous space. With this procedure, persistent survival was achieved for the length of the experiment (120 days). To establish that these engineered liver tissues also retained their native regeneration potential in vivo, we induced two different modes of proliferative stimulus to the naive liver and confirmed that hepatocytes within the extrahepatic tissues regenerated with activity similar to that of naive liver. In conclusion, our studies indicate that liver tissues can be engineered and maintained at extrahepatic sites, retain their capacity for regeneration in vivo, and used to successfully treat genetic disorders. |
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AbstractList | Liver tissue engineering using hepatocyte transplantation has been proposed as an alternative to whole-organ transplantation or liver-directed gene therapy to correct various types of hepatic insufficiency. Hepatocytes are not sustained when transplanted under the kidney capsule of syngeneic mice. However, when we transplanted hepatocytes with the extracellular matrix components extracted from Engelbreth-Holm-Swarm cells, hepatocytes survived for at least 140 days and formed small liver tissues. Liver engineering in hemophilia A mice reconstituted 5% to 10% of normal clotting activity, enough to reduce the bleeding time and have a therapeutic benefit. Conversely, the subcutaneous space did not support the persistent survival of hepatocytes with Engelbreth-Holm-Swarm gel matrix. We hypothesized that establishing a local vascular network at the transplantation site would reduce graft loss. To test this idea, we provided a potent angiogenic agent before hepatocyte transplantation into the subcutaneous space. With this procedure, persistent survival was achieved for the length of the experiment (120 days). To establish that these engineered liver tissues also retained their native regeneration potential in vivo, we induced two different modes of proliferative stimulus to the naive liver and confirmed that hepatocytes within the extrahepatic tissues regenerated with activity similar to that of naive liver. In conclusion, our studies indicate that liver tissues can be engineered and maintained at extrahepatic sites, retain their capacity for regeneration in vivo, and used to successfully treat genetic disorders. |
Author | YAMANOUCHI, Masaki DAKE, Michael D WAUGH, Jacob M KUGE, Hiroyuki NAKAJIMA, Yoshiyuki NAKA, Hiroyuki KAY, Mark A OHASHI, Kazuo YOKOYAMA, Takashi YOSHIOKA, Akira |
Author_xml | – sequence: 1 givenname: Kazuo surname: OHASHI fullname: OHASHI, Kazuo organization: Department of Pediatrics and Genetics, Department of Radiology, Stanford University Medical Center, Stanford, CA, United States – sequence: 2 givenname: Jacob M surname: WAUGH fullname: WAUGH, Jacob M organization: Department of Cardiovascular and Interventional Radiology, Department of Radiology, Stanford University Medical Center, Stanford, CA, United States – sequence: 3 givenname: Michael D surname: DAKE fullname: DAKE, Michael D organization: Department of Cardiovascular and Interventional Radiology, Department of Radiology, Stanford University Medical Center, Stanford, CA, United States – sequence: 4 givenname: Takashi surname: YOKOYAMA fullname: YOKOYAMA, Takashi organization: First Department of Surgery, Nara Medical University, Nara, Japan – sequence: 5 givenname: Hiroyuki surname: KUGE fullname: KUGE, Hiroyuki organization: First Department of Surgery, Nara Medical University, Nara, Japan – sequence: 6 givenname: Yoshiyuki surname: NAKAJIMA fullname: NAKAJIMA, Yoshiyuki organization: First Department of Surgery, Nara Medical University, Nara, Japan – sequence: 7 givenname: Masaki surname: YAMANOUCHI fullname: YAMANOUCHI, Masaki organization: Department of Pediatrics, Nara Medical University, Nara, Japan – sequence: 8 givenname: Hiroyuki surname: NAKA fullname: NAKA, Hiroyuki organization: Department of Pediatrics, Nara Medical University, Nara, Japan – sequence: 9 givenname: Akira surname: YOSHIOKA fullname: YOSHIOKA, Akira organization: Department of Pediatrics, Nara Medical University, Nara, Japan – sequence: 10 givenname: Mark A surname: KAY fullname: KAY, Mark A organization: Department of Pediatrics and Genetics, Department of Radiology, Stanford University Medical Center, Stanford, CA, United States |
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Keywords | Prognosis Hepatic disease Hemopathy Extract Bleeding time Kidney Tissue Liver failure Hepatocyte Blood vessel Network Graft Extracellular matrix Subcutaneous Rodentia Capsule Survival Hemophilia A Genetic disease Regeneration Vertebrata Mammalia Treatment Mouse Animal Digestive diseases Gene therapy Coagulopathy Organ Liver transplantation |
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SubjectTerms | alpha 1-Antitrypsin - genetics alpha 1-Antitrypsin - metabolism Angiogenic Proteins - administration & dosage Angiogenic Proteins - therapeutic use Animals Biological and medical sciences Cell Survival Factor VIII - metabolism Fibroblast Growth Factor 1 - administration & dosage Fibroblast Growth Factor 1 - therapeutic use Fundamental and applied biological sciences. Psychology Gastroenterology. Liver. Pancreas. Abdomen Hemophilia A - blood Hemophilia A - surgery Hemophilia A - therapy Hepatocytes - metabolism Hepatocytes - transplantation Humans Liver - pathology Liver - physiopathology Liver Regeneration Liver, biliary tract, pancreas, portal circulation, spleen Liver. Bile. Biliary tracts Liver. Biliary tract. Portal circulation. Exocrine pancreas Medical sciences Mice Mice, Inbred Strains Mice, Transgenic Microspheres Other diseases. Semiology Preoperative Care Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases Surgery of the digestive system Tissue Engineering Transplantation, Heterotopic Vertebrates: digestive system |
Title | Liver tissue engineering at extrahepatic sites in mice as a potential new therapy for genetic liver diseases |
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