WO1994002601A1 - Generation d'une foie non natif, par implantation cellulaire, chez un animal presentant une alteration des fonctions hepatiques natives - Google Patents

Generation d'une foie non natif, par implantation cellulaire, chez un animal presentant une alteration des fonctions hepatiques natives Download PDF

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Publication number
WO1994002601A1
WO1994002601A1 PCT/US1993/006830 US9306830W WO9402601A1 WO 1994002601 A1 WO1994002601 A1 WO 1994002601A1 US 9306830 W US9306830 W US 9306830W WO 9402601 A1 WO9402601 A1 WO 9402601A1
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WIPO (PCT)
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native
liver
cells
animal
human
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PCT/US1993/006830
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English (en)
Inventor
Ralph L. Brinster
Richard D. Palmiter
Jay L. Degan
Eric P. Sandgren
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The Trustees Of The University Of Pennsylvania
University Of Washington
Children's Hospital Medical Center
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Application filed by The Trustees Of The University Of Pennsylvania, University Of Washington, Children's Hospital Medical Center filed Critical The Trustees Of The University Of Pennsylvania
Priority to AU47782/93A priority Critical patent/AU676194B2/en
Priority to JP6504654A priority patent/JPH07509363A/ja
Priority to EP93918276A priority patent/EP0652949A4/fr
Publication of WO1994002601A1 publication Critical patent/WO1994002601A1/fr

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0271—Chimeric vertebrates, e.g. comprising exogenous cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the invention relates to non-native functioning liver generation in animals with impaired native liver function, and to (transgenic) animals harboring functioning non-native livers.
  • liver transplantation could be used to treat patients with congenital hepatic enzyme deficiencies to replace liver lost through disease (e.g. viral hepatitis, alcohol-related cirrhosis or fibrosis) , or provide a temporary support system where acute liver dysfunction may be resolved by regeneration over a period of time. Hepatocyte transplantation also offers the opportunity to create animal models with human liver function. Such animals would be very useful for the study of viral infections affecting the liver (e.g.
  • human hepatitis virus or cytomegalovirus infection and/or test the effectiveness and safety of treatment or therapies for such infections. They would also be useful for the study of chemical (e.g. alcohol) toxicity in the human liver and chemical-induced cirrhosis and fibrosis and to test the effectiveness and safety of treatments or therapies for chemical-induced liver damage.
  • chemical e.g. alcohol
  • liver fragments had been carried out as early as the 1930s. However, in most cases the transplanted liver tissue either degenerated or disappeared within a few days or weeks.
  • liver transplant Another currently investigated approach to liver transplant resides in the implantation of new liver cells on scaffolds of biodegradable polymers that are hoped to regenerate into masses and take over at least some of the native liver's functions. Although it has been reported that with this approach liver cells on a matrix can survive and function in rats six months to a year after transplantation, implanted cell survival is low, and, in some animal trials, too much connective tissue grew into the matrix, binding tightly to the polymer and forming scar tissue preventing the liver cells from dispersing through the matrix ("Technology Review" July 1992, pp. 12, 13) .
  • transgenic animal technology has provided the means to create and analyze animal models of genetic diseases affecting virtually any organ to which transgene expression can be directed. Because of its involvement in many diseases of medical importance, the liver has been a frequent target for this type of analysis.
  • transgenes reported to be associated with liver lesions are those encoding growth hormone, which alters hepatocyte size and nuclear characteristics; oncogenes, which induce hepatic tumors; the hepatitis B virus large envelope polypeptide, which induces hepatocellular necrosis and carcinoma formation in adults; transforming growth fact a , which causes both tumors and excessive liver growth; and a variant form of ⁇ 1 -antitrypsin (AAT) , which reproduces some characteristics of AAT deficiency disease in humans, including neonatal and adult hepatitis.
  • growth hormone which alters hepatocyte size and nuclear characteristics
  • oncogenes which induce hepatic tumors
  • the hepatitis B virus large envelope polypeptide which induces hepatocellular necrosis and carcinoma formation in adults
  • transforming growth fact a which causes both tumors and excessive liver growth
  • AAT ⁇ 1 -antitrypsin
  • transgene expression Because of the liver's large synthetic and secretory capability, targeting transgene expression to this organ also serves as a way to determine the systemic influence of overproduction of biologically potent molecules. This approach has previously been used to study the consequences of inappropriate plasminogen activator expression in vivo by introducing into mice a transgene bearing the urokinase-type plasminogen activator (uPA) coding sequence fused to the albumin enhancer/promoter (Heckel et al. Cell (19900 j62:447-456) .
  • uPA urokinase-type plasminogen activator
  • Plasminogen activators catalyze the proteolytic cleavage and activation of plasminogen to plasmin, which in turn degrades fibrin clots (Collen, D. and Lijnen, H.R. (1987) Fibrinolysis and the Control of Hematostasis. In the Molecular Basis of Blood Diseases. G. Stamatoyannopoulos, A.W. Nienhuis, P. Leder, and P.W. Majerus, eds. (Phila. : W.B. Saunders Co.) , pp. 662-688) .
  • uPA also has been implicated in biological processes involving tissue remodeling or destruction, including ovulation, mammary gland involution, and metastasis (Dan ⁇ et al. , Adv. Cancer Res. (1985) 44:149-265; Collen and Lijnen, (1987) supra ; Saksela and Rifkin, Annu. Rev. Cell Biol . (1988) 4:93-126) .
  • Alb-uPA albumin-urokinase type plasminogen activator
  • Alb-uPA expression provides a transgenic mouse in which endogenous transgene-expressing hepatocytes have a selected disadvantage relative to hepatocytes (native or non-native) that are not expressing the transgene.
  • the livers in these mice provide an environment for growth of hepatocytes (native or non-native) that are not expressing the transgene. These cells grow out at the expense of transgene- expressing cells and the result is livers with apparently normal architecture.
  • one object of the invention is to provide a method of correcting defective liver function in an animal host by implanting particular non-native cells (or corresponding tissue) into the liver region of a host animal with impaired native liver function to thereby generate a functioning non-native liver in the host and correct the impaired liver function.
  • Another object of the present invention is to provide transgenic, non-human animals (e.g. rodents such as mice) harboring a transgene that encodes a product that is disadvantageous, but not lethal, to native liver cells and thus impairs native liver function. These transgenic, non-human animals are useful as a host system for non-native (e.g. human) liver.
  • Another object of the present invention is to provide non-human host animals that can both maintain and expand a fully-functioning non-native (e.g. human) liver tissue useful for (1) modeling liver disease, (2) liver tissue banking (e.g. maintenance and expansion of liver tissue for later analysis and re-implantation back into donors) , (3) testing pharmaceuticals for human liver toxicity in vivo, and/or (4) genetic manipulation prior to re-implantation (i.e., hepatocyte-directed gene therapy) .
  • Another object of the invention is to provide a method of generating a functioning non-native liver in a host animal by implanting non-native liver cells (or tissue) into a host animal with a genetically established defective liver function.
  • Another object of the invention is to provide non-human animals harboring a functioning non-native liver.
  • Another object of the invention is to provide a novel method for maintaining full-differentiated, full-functioning donor (e.g. human) hepatocytes in an in vivo setting for genetic manipulation prior to return to the donors .
  • the genetic manipulation could include, for example, introducing expression vectors that direct the production of medically important proteins in the transplant recipient.
  • non-native cells e.g, fetal, neonatal or adult, non-hematopoietic liver stem, progenitor or mature cells; fetal, stem, progenitor or adult bile duct cells; endodermal (e.g. pancreas or gut) cells; (cultured) totipotent stem cells; or cultured animal cells) , or corresponding tissue, into the liver region of a host animal having impaired native liver function, such that the implanted cells (or tissue) colonize the host animal and develop therein a functioning non-native liver.
  • non-native cells e.g, fetal, neonatal or adult, non-hematopoietic liver stem, progenitor or mature cells; fetal, stem, progenitor or adult bile duct cells; endodermal (e.g. pancreas or gut) cells; (cultured) totipotent stem cells; or cultured animal cells) , or corresponding tissue, into the liver region of a host animal having impaired native
  • Suitable host animals therefore include fish, fowl (e.g. chickens, ducks, geese, turkeys, etc.) , or mammals such as rodents (e.g. mice or rats) , guinea pigs, pigs, dogs, cats, rabbits, goats, sheep, horses, ruminants such as cows, monkeys, other non-human primates, as well as humans. Impairment of native liver function in the host animal may have occurred accidentally, e.g.
  • liver deficiency disease such as deficiencies in Factor IX, Factor VIII, LDL receptor, or one of varied metabolic enzymes (e.g. phenylalanine hydroxylase) , or any of the other hundreds of known metabolic diseases that affect the liver.
  • the invention is applied as therapy and/or treatment to such animals, including humans, suffering from liver failure.
  • the invention is used as an alternative to liver transplant to restore liver function.
  • a non-native liver is generated in a non-human animal in which liver insufficiency has been induced to obtain an animal model system with a functioning non-native (e.g. human or other animal) liver.
  • a functioning non-native e.g. human or other animal
  • impairment of native liver function may be purposefully achieved by compromising the native hepatocyte genetically so that they are at a selective disadvantage towards implanted non-native cells (e.g. hepatocytes) .
  • the implanted non-native hepatocytes have a proliferative advantage over the accidentally or purposely disadvantaged native hepatocytes and ultimately replace all of the native hepatocytes in the host .
  • This provides a host harboring substantially few, if any native hepatocytes, but a functioning, substantially non-native, liver generated from the implanted non-native cells. (The liver generated is substantially non-native insofar as it is likely to comprise some non-hepatocyte cells found in the native liver and perhaps some native hepatocytes.)
  • liver insufficiency in a non-human mammal may be achieved in accordance with this embodiment of the present invention with a transgenic, non-human animal harboring a transgene which encodes a product that is disadvantageous, but not immediately lethal, to native liver cells.
  • a transgenic, non-human animal harboring a transgene which encodes a product that is disadvantageous, but not immediately lethal, to native liver cells.
  • any deleterious transgene product may be used that impairs cellular function to the extent that hepatocytes expressing the gene have a distinct growth disadvantage relative to cells that do not express a transgene (e.g. the implanted non-native hepatocytes) .
  • transgene products include any type of plasminogen activator, such as an urokinase-type or tissue-type plasminogen activator, or bacterial plasminogen activators (e.g. strptokinase) or toxins such as an attenuated diphtheria toxin.
  • plasminogen activator such as an urokinase-type or tissue-type plasminogen activator, or bacterial plasminogen activators (e.g. strptokinase) or toxins such as an attenuated diphtheria toxin.
  • Other examples of transgene products useable in accordance with this embodiment of the present invention include agents that adversely affect the metabolism or growth potential of the native liver cells.
  • Illustrative agents are agents which compromise the ability of the native liver cells to transmit growth factor signals (e.g. with dominant and negative transgenes affecting steps in signal transduction pathway) or by producing mutant proteins that clog circulatory pathway(s) .
  • uPA urokinase-type plasminogen activator
  • This white liver tissue contains small hepatocytes with altered rough endoplasmic reticulum morphology but is neither necrotic or fibrotic. Expression of the uPA transgene appears to be deleterious to hepatocytes, but not immediately lethal. This kind of genetic impairment of native liver function provides a suitable format for establishing regenerative liver outgrowths from either donor animals (e.g. humans) or endogenous liver cells that spontaneously cease uPA transgene expression through DNA recombination and loss of all functional copies of the transgene tandem array.
  • heterozygous Alb-uPA mice frequently develop regenerative liver nodules with normal reddish liver color that grow out at expense of surrounding "white” liver tissue and eventually reconstitute the liver.
  • These "red” liver nodules are clonal outgrowth of single hepatocytes based on analysis of the transgene remnants left behind following transgene recombination.
  • Hepatocytes that have deleted all functional transgenes, and lack detectable transgene express acquire a selected advantage and quickly expand and replace the transgene-expressing hepatocytes in the surrounding "white tissue".
  • An embodiment that is an extension of these observations is that non-native (e.g.
  • liver cells can be transplanted into these mice (or their functional equivalent) and, as a result of their inherent growth advantage over native, transgene-expressing liver cells, they grow out to reconstitute the liver at the expense of endogenous liver cells which do die or disappear.
  • a transgene that encodes a product which is disadvantageous, but not immediately lethal, to the liver cells of the host animal is constructed.
  • the resulting fusion construct is inserted using known techniques into fertilized eggs followed by implantation into pregnant or pseudopregnant females.
  • the progeny are then bred to produce offspring which express the construct, and which have impaired native liver function.
  • non-native cells may be used for implantation into the host in accordance with the invention.
  • These cells (or tissue) may be fetal, neonatal and/or adult stem, progenitor and/or mature non-hematopoietic liver cells.
  • non-hematopoietic liver progenitor cells and more preferably non-hematopoietic liver stem cells are used.
  • hepatocytes which constitute about 60% of the mammalian liver, may be used as the liver cells.
  • non-native hepatocytic stem cells which may be used in the invention are distinct from fetal hematopoietic stem cells.
  • Fetal hematopoietic stem cells are precursors to the hematopoietic system, and have previously been used to generate a non-native hematopoietic system in a host.
  • non-native cells which may be used in accordance with the invention include (i) stem, progenitor and/or mature bile duct cells, (ii) endodermal tissue cells such as pancreas or gut cells, (iii) optionally cultured totipotent stem cells including (ES) cells or embryonic carcinoma (EC) cells, and/or (iv) cultured animal cells.
  • totipotent animal stem cells are first cultured under conditions which control their differentiation, such as by using particular growth factors in the cell culture medium, and these cultured cells are then used to colonize the host animal.
  • Totipotent animal stem cells can also (alternatively) be first treated or cultured with growth factors that enhance survival, promote replication, and/or selectively enrich for stem cells.
  • Animal cells (or tissue) from other sources can also be treated by growth factors or other substances to bring about differentiation of a particular cell lineage with characteristics of hepatic stem cells.
  • embryonic stem cells or embryonal carcinoma cells can be stimulated to differentiate by retinoic acid or another inducer. Subsequent differentiation in culture along the endodermal or hepatocyte cell lineage can be achieved by stimulation with growth factors and/or selection, using known techniques and materials.
  • the non-native cells may by genetically engineered (using known techniques) to produce, in vivo in the host, a physiologically effective amount of one or more medically relevant protein and then transplanted in accordance with the present invention.
  • This technique can be used to improve hepatocyte function in an animal, e.g, by producing Factor IX, LDL receptors, phenylalanine hydroxylase, etc. or to produce proteins of systemic value, e.g. Factor VIII, adenosine deaminase, or peptide hormones.
  • non-native cells (or tissue) to be implanted may be isolated from a donor animal, as noted below, and optionally cultured, using known techniques.
  • non-hematopoietic liver stem, progenitor and/or mature cells are first isolated from the terminal or transitional bile ductiles of a mature donor animal other than the host animal, using known techniques.
  • hepatic cells may be isolated from the donor animal using known procedures, e.g. by extraction through a biopsy needle.
  • hepatic cells may be isolated from the donor animal by collagenase perfusion of the portal vein. 1
  • the donor animal used in accordance with the invention may be any one of the donor animal used in accordance with the invention.
  • ⁇ -See, e.g. , Soda et al, Blood (1984) 63., 270-276, or Claunig et al, In Vitro (1981) 17, 913-925. be an animal of the same species or of a different species as compared to the host animal. Generally it is a different individual .
  • the donor animal may be any animal harboring a normal functioning liver or an animal with a congenital or squired liver disease. In a preferred embodiment the donor animal is a human.
  • the non-native cells are then introduced into the host organism in a manner which provides for implantation of a sufficient number of the non-native cells into the liver region of the host animal to permit their development into a non-native liver.
  • the present invention does not require the use of a polymeric matrix for supporting the implanted cells.
  • cells from a variety of sources may be used in accordance with the invention, since such cells are comprised of a mixture of cells of different degree of development (i.e., stem, progenitor and mature cells) . These mixtures contain cells having a sufficiently primitive degree of development so that, when subjected to the biological environment of the host's liver area, these cells will establish a functioning non-native liver.
  • degree of development i.e., stem, progenitor and mature cells
  • other cells may be used to form a new liver.
  • Scarpelli et al in Laboratory Investigation (1990) 6.2:552 reported identifying cells in the pancreas of hamsters, treated with carcinogens, which have the appearance of hepatocytes. These cells and others may form functional hepatocytes when placed in the appropriate environment (e.g. a failing liver) in accordance with the present invention. Implantation into the host animal's liver area may be achieved using different techniques.
  • additional adjuvants to promote the transplantation of the non-native cells i.e., substances which are known to enhance non-native cell survival and/or division 2
  • additional adjuvants to promote the transplantation of the non-native cells i.e., substances which are known to enhance non-native cell survival and/or division 2
  • additional adjuvants to promote the transplantation of the non-native cells i.e., substances which are known to enhance non-native cell survival and/or division
  • Suitable sites include the abdominal cavity, muscle tissue, kidney, pancreas, celiac artery, fat pads and/or subcutaneous area of the host animal.
  • Preferred sites of administration in accordance with the invention, and which are preferably effectuated by injection, include the portal vein, the spleen, directly into the native liver, and the umbilical vein of the fetal host which leads to the fetal liver.
  • the host and donor are two different animals steps are taken prior to implantation to suppress potential host immune rejection of the implanted non-native cells.
  • This may be achieved in a variety of ways, such as by treating the host animal with cyclosporin or any other material known to suppress the host's immunological system, e.g. agents that are known to selectively destroy subgroups of the immune cell population of the host, such as T-cell destroying antibodies.
  • tolerance in the host can be induced by transferring non-native cells to the thymus of the host before implantation (see, Rosselt et al, Science (1990) 24_9_:1293-1295) , or cells from an animal of the same strain as the host can be used.
  • an immunodeficient host can be used, such as inbred strains of an animal (e.g. SCID mice or nude mice) bred to act as recipients of non-native cells.
  • cells can be introduced together with growth factors or other substances that enhance survival, implantation, and for growth.
  • the recipient for the non-native cells is a transgenic mouse with defective liver function, and human non-hematopoietic liver cells are used to generate the non-native liver.
  • a suitable transgenic mouse is described by Sandgren et al in Cell, (1991) 6_6_:245-256, which is hereby incorporated by reference.
  • the transgenic mouse described in this publication of the inventors exhibits a high expression of albumin-urokinase-type plasminogen activator (Alb-uPA) fusion construct.
  • This mouse with impaired liver function is a good recipient for human non-hematopoietic liver cell implantation (but mice with liver impairment resulting from other causes may be used) .
  • the transgenic mouse with impaired liver function is injected with non-native, preferably human non-hematopoietic liver cells such that the injected human hepatocytic stem cells colonize the native liver at the expense of the endogenous "white tissue" of the transgenic mouse.
  • the human liver cells proliferate to form nodules which ultimately reconstitute the entire native liver of the host with human hepatocytes and establish human liver function. This includes the replacement of most mouse plasma proteins with their corresponding human plasma proteins.
  • the resulting mouse or any other non-human host produced in accordance with the invention is well suited for (1) modeling study of human liver function, including screening pharmaceutical agents for treating human liver disease, (2) modeling human congenital diseases affecting the liver (including those in which the cause is unknown) by implanting patient liver cells into host mice, (3) liver cell banking (e.g. maintenance and expansion of liver tissue for later analysis or re-implantation into the donor) , (4) genetic manipulation of full-functioning, full-differentiated hepatocytes for later re-implantation into donors (i.e., hepatocyte-directed gene therapy such as hepatitis virus resistant human liver cells that express antisense against the virus) , and/or (5) modeling human liver for analysis of therapeutic agents that can promote liver regeneration.
  • hepatocyte-directed gene therapy such as hepatitis virus resistant human liver cells that express antisense against the virus
  • the present invention provides:
  • Therapeutic uses including: (a) re-implantation of healthy liver tissue into donor patients once an infectious agent or diseased tissue has been eliminated, and (b) genetic modification of donor cells and subsequent re-implantation into donor patients (e.g. hepatocyte-directed gene therapy) ;
  • liver for the study of chemical (e.g. alcohol) toxicity in the liver and chemical-induced cirrhosis and fibrosis and to test the effectiveness and safety of treatments or therapies for chemical-induced liver damage;
  • chemical e.g. alcohol
  • liver-derived plasma proteins which comprise >90% of the total plasma proteins

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Abstract

L'invention se rapporte à des animaux présentant une altération des fonctions hépatiques natives, dotés d'un foie non natif fonctionnel développé à partir de cellules non natives implantées, et à un procédé de production de ces animaux.
PCT/US1993/006830 1992-07-24 1993-07-23 Generation d'une foie non natif, par implantation cellulaire, chez un animal presentant une alteration des fonctions hepatiques natives WO1994002601A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU47782/93A AU676194B2 (en) 1992-07-24 1993-07-23 Non-native liver generation in an animal with impaired native liver function by cell implantation
JP6504654A JPH07509363A (ja) 1992-07-24 1993-07-23 生来の肝機能に障害を有する動物における，細胞移植による非生来の肝臓の生成
EP93918276A EP0652949A4 (fr) 1992-07-24 1993-07-23 Generation d'une foie non natif, par implantation cellulaire, chez un animal presentant une alteration des fonctions hepatiques natives.

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US91805092A 1992-07-24 1992-07-24
US918,050 1992-07-24

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WO1994002601A1 true WO1994002601A1 (fr) 1994-02-03

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EP (1) EP0652949A4 (fr)
JP (1) JPH07509363A (fr)
AU (1) AU676194B2 (fr)
CA (1) CA2140785A1 (fr)
IL (1) IL106368A0 (fr)
WO (1) WO1994002601A1 (fr)

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EP0671923A1 (fr) * 1992-10-09 1995-09-20 Advanced Tissue Sciences, Inc. Cellules hepatiques de reserve
WO1996039810A1 (fr) * 1995-06-07 1996-12-19 Novartis Ag Tissu hepatocellulaire humain chez des animaux chimeres presentant un deficit immunitaire
EP0797455A1 (fr) * 1994-12-14 1997-10-01 University Of Washington Vecteurs recombines destines a la reconstitution permanente du foie et traitement de l'hepatite c
WO1999016307A1 (fr) * 1997-09-26 1999-04-08 Cedars-Sinai Medical Center Cobaye animal, in vivo, pour l'expression du virus de l'hepatite c
US5980886A (en) * 1994-12-14 1999-11-09 University Of Washington Recombinant vectors for reconstitution of liver
WO2000040083A1 (fr) * 1999-01-05 2000-07-13 Surrogen, Inc. Animal chimerique avec tissu heterologue greffe et son procede d'obtention
US6132708A (en) * 1997-10-10 2000-10-17 Oregon Health Sciences University Liver regeneration using pancreas cells
WO2001067854A1 (fr) * 2000-03-17 2001-09-20 Kneteman Norman M Modele d'animal chimerique sensible a l'infection par le virus de l'hepatite c humaine
WO2001087059A1 (fr) * 2000-05-19 2001-11-22 Japan Science And Technology Corporation Animal chimerique
US6525242B1 (en) 1999-11-02 2003-02-25 The University Of Connecticut Propagation of human hepatocytes in non-human mammals
WO2004006664A1 (fr) * 2002-07-16 2004-01-22 Japan Science And Technology Agency Modele animal porteur de tissu hepatique non cancereux greffe, et procede permettant de produire cet animal
EP1496110A1 (fr) * 2002-03-25 2005-01-12 Japan Science and Technology Agency Procede assurant la proliferation des hepatocytes humains et procede d'obtention d'hepatocytes humains
US6864402B1 (en) 1998-09-18 2005-03-08 Albert Einstein College Of Medicine Of Yeshiva University Chronic hepatitis virus infection and clonal hepatocellular carcinoma in mouse repopulated livers
US6995299B2 (en) 1999-11-02 2006-02-07 University Of Connecticut Propagation of human hepatocytes in non-human animals
WO2006019162A1 (fr) * 2004-08-20 2006-02-23 Daiichi Pure Chemicals Co., Ltd. Procédé de présomption du métabolisme de médicament dans le foie humain et fonction hépatique
US7273963B2 (en) 2004-08-20 2007-09-25 Kmt Hepatech, Inc. Malarial animal model having a chimeric human liver
US11172657B2 (en) 2017-09-19 2021-11-16 Pormedtec Co., Ltd. Method for developing organ that lacks specific functional cell

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Title
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Cancer Research, Volume 50, issued 01 July 1990, SELL, "Is there a Liver Stem Cell", pages 3811-3815, see entire article. *
Cell, Volume 66, issued 26 July 1991, SANDGREN et al., "Complete Hepatic Regeneration After Somatic Deletion of an Albumin-Plasminogen Activator Transgene", pages 245-256, see entire article. *
Laboratory Investigation, Volume 65, No. 6, issued 1991, MODIS et al., "Hepatocytes Modulate the Hepatic Microvascular Phenotype", pages 661-670, see entire article. *
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Science, Volume 233, issued 12 September 1986, DEMETRIOU et al., "Replacement of Liver Function in Rats by Transplantation of Microcarrier-Attached Hepatocytes", pages 1190-1192, see entire article. *
See also references of EP0652949A4 *

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0671923A1 (fr) * 1992-10-09 1995-09-20 Advanced Tissue Sciences, Inc. Cellules hepatiques de reserve
EP0671923A4 (fr) * 1992-10-09 1996-08-21 Advanced Tissue Sciences Inc Cellules hepatiques de reserve.
US6107027A (en) * 1994-12-14 2000-08-22 University Of Washington Ribozymes for treating hepatitis C
EP0797455A1 (fr) * 1994-12-14 1997-10-01 University Of Washington Vecteurs recombines destines a la reconstitution permanente du foie et traitement de l'hepatite c
US5980886A (en) * 1994-12-14 1999-11-09 University Of Washington Recombinant vectors for reconstitution of liver
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EP0797455A4 (fr) * 1994-12-14 2001-11-07 Univ Washington Vecteurs recombines destines a la reconstitution permanente du foie et traitement de l'hepatite c
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AU4778293A (en) 1994-02-14
CA2140785A1 (fr) 1994-02-03
AU676194B2 (en) 1997-03-06
IL106368A0 (en) 1993-11-15
EP0652949A4 (fr) 1996-08-21
EP0652949A1 (fr) 1995-05-17
JPH07509363A (ja) 1995-10-19

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