Zelltherapie in der Hepatologie[*]

Zusammenfassung

In den letzten 10 Jahren konnten große Fortschritte auf dem Gebiet der Leberzelltransplantation und des leberspezifischen Gentransfers erreicht werden. Tierexperimentelle Untersuchungen haben gezeigt, dass neues Lebergewebe sowohl aus transplantierten primären Hepatozyten als auch aus Stammzellen des Knochenmarks entstehen kann. Dies hat wesentlich zu unserem Verständnis der Organogenese und Hepatozytenbiologie beigetragen. Weiterhin sind mithilfe der Leberzelltransplantation neue Kleintiermodelle zum Studium der Virushepatitis entwickelt worden. In der Klinik bietet das Verfahren ein breites Spektrum potenzieller Anwendungsgebiete, insbesondere bei der Therapie erblicher Stoffwechselerkrankungen. Der therapeutische Nutzen transplantierter Hepatozyten konnte erstmals 1998 bei einer Patientin mit Crigler-Najjar-Syndrom Typ I belegt werden. Weitere Studien im Bereich der Grundlagenforschung und Klinik erscheinen gerechtfertigt, um den Stellenwert der Zelltherapie in der Hepatologie zu evaluieren.

Current status of cell-based therapies in liver diseases

Major strides have been made during the past 10 years in the fields of liver cell transplantation and liver-directed gene therapy. Pre-clinical studies in animals have shown that primary hepatocytes transplanted into the liver as well as intravenously transfused bone marrow stem cells can generate new liver tissue. Such cell transplantation studies have contributed to our understanding of organogenesis and hepatocyte biology. Furthermore, transplantation of xenogenic hepatocytes has led to the development of new small animal models for studying viral hepatitis. In the clinical setting, liver cell transplantation offers a wide range of potential therapeutic applications, especially in metabolic diseases. In particular, the case of a patient with Crigler-Najjar Syndrome Type I clearly demonstrated the long-term viability of transplanted hepatocytes with stable metabolic function. Further studies are warranted to assess the full potential of cell- based therapies and their clinical application.

Schlüsselwörter

Hepatozyten - Stammzellen - Progenitorzellen - Transplantation - Gentherapie - Hepatitis B - Organogenese - Hepatozytenbiologie

Key words

Hepatocytes - Stem Cells - Progenitor Cells - Transplantation - Gene Therapy - Hepatitis B - Hepatocyte Biology

1 Teile dieses Manuskripts sind im Rahmen des Forschungsforums Nummer 11 auf der DGVS-Tagung Gastroenterologie 2000 in Hamburg präsentiert worden.

Literatur

• 1 Gupta S, Bhargava K K, Novikoff P M. Mechanisms of cell engraftment during liver repopulation with hepatocyte transplantation.  Semin Liver Dis. 1999;  19 15-26
• 2 Gupta S, Gorla G R, Irani A N. Hepatocyte transplantation: Emerging insights into mechanisms of liver repopulation and their relevance to potential therapies.  J Hepatol. 1999;  30 162-170
• 3 Gupta S, Rogler C E. Lessons from genetically engineered animal models. VI. Liver repopulation systems and study of pathophysiological mechanisms in animals.  Am J Physiol. 1999;  277 G1097-G1102
• 4 Gupta S, Rayvanshi P, Sokhi P. et al . Entry and integration of transplanted hepatocytes in liver plates occur by disruption of hepatic sinusoidal endothelium.  Hepatology. 1999;  29 509-519
• 5 Overturf K, Al-Dhalimy M, Tanguay R. et al . Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I.  Nat Genet. 1996;  12 266-273
• 6 Rogler L E. Selective bipotential differentiation of mouse embryonic hepatoblasts in vitro.  Am J Pathol. 1997;  150 591-601
• 7 Dabeva M D, Petkov P M, Sandhu J. et al . Proliferation and differentiation of fetal liver epithelial progenitor cells after transplantation into adult rat liver.  Am J Pathol. 2000;  156 2017-2031
• 8 Grisham J W, Thorgeirsson S S. Oval cells. Potten CS Stem cells San Diege, Ca; Academic Press 1997: 213-248
• 9 Petersen B E, Bowen W C, Patrene K D. et al . Bone marrow as a potential cell source of hepatic oval cells.  Science. 1999;  284 1168-1172
• 10 Lagasse E, Connors H, Al-Dhalimy M. et al . Purified hemapoietic stem cells can differentiate into hepatocytes in vivo.  Nature Med. 2000;  6 1229-1234
• 11 Theise N D, Badve S, Saxena R. et al . Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation.  Hepatology. 2000;  31 235-240
• 12 Ferrari G, De Cusella-Angelis G, Coletta M. et al . Muscle regeneration by bone marrow derived myogenic progenitors.  Science. 1999;  284 1168-1170
• 13 Alison M R, Poulsom R, Jeffery R. et al . Hepatocytes from nonhepatic adult stem cells.  Nature. 2000;  406 257
• 14 Theise N D, Nimmakayalu M, Gardner R. et al . Liver from bone marrow in humans.  Hepatology. 2000;  32 11-16
• 15 Prockop D J. Marrow stromal cells as stem cells for non-hematopoietic tissue.  Science. 1997;  276 71-74
• 16 Bjornson C R, Rietze L R, Reynolds B A, Magli M C, Vescovi A L. Turning brain into blood; a hematopoietic fate adopted by adult neural stem cells in vivo.  Science. 1999;  283 534-537
• 17 Jackson K A, Mi T, Goodell M A. Hematopoietic stem cells isolated from murine sceletal muscle.  Proc Natl Acad Sci USA. 1999;  96 14 482-14 486
• 18 Jamal H Z, Weglarz T C, Sandgren E P. Cryopreserved mouse hepatocytes retain regenerative capacity in vivo.  Gastroenterology. 2000;  118 390-394
• 19 Dandri M , Burda M R, Gocht A . et al . Woodchuck hepatocytes remain permissive for hepadnavirus infection and mouse hiver repopulation after cryopreservation.  Hepatology. 2001;  34 824-833
• 20 Kobayashi N, Fujiwara T, Westerman K A. et al . Prevention of acute liver failure in rats with reversibly immortalized human hepatocytes.  Science. 2000;  287 1258-1262
• 21 Klug M G, Soonpa M H, Koh G Y, Field L J. Genetically selected cardiomyocytes from differentiating embryonic stem cells from stable intracardiac grafts.  J Clin Invest. 1996;  98 216-224
• 22 Strom S C, Chowdhury J R, Fox I J. Hepatocyte transplantation for the treatment of human disease.  Semin Liver Dis. 1999;  19 39-48
• 23 Braun K M, Degen J L, Sandgren E P. Hepatocyte transplantation in a model of toxin-induced liver disease: Variable therapeutic effect during replacement of damaged parenchyma by donor cells.  Nat Med. 2000;  6 320-326
• 24 Petersen J, Dandri M, Gupta S, Rogler C E. Liver repopulation with xenogenic hepatocytes in B and T cell deficient mice leads to chronic hepadnavirus infection and hepatocellular carcinoma.  Proc Natl Acad Sci USA. 1998;  95 310-315
• 25 Overturf K, Al-Dhalimy M, Tanguay R. et al . Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I.  Nat Genet. 1996;  12 266-273
• 26 Mignon A, Guidotti J E, Mitchell C. et al . Selective repopulation of normal mouse liver by FAS/CD95-resistant hepatocytes.  Nat Med. 1998;  4 1185-1188
• 27 Lagasse E, Connors H, Al-Dhalimy M. et al . Purified hematopoietic stem cells can differentiate into hepatocytes in vivo.  Nat Med. 2000;  6 1229-1234
• 28 Ohashi K, Marion P L, Nakai H. et al . Sustained survival of human hepatocytes in mice: A model for in vivo infection with human hepatitis B and hepatitis delta viruses.  Nat Med. 2000;  6 327-331
• 29 Ilan E, Burakova T, Dagan S. et al . The hepatitis B virus-trimera mouse: A model for human HBV infection and evaluation of anti-HBV therapeutic agents.  Hepatology. 1999;  29 553-562
• 30 Dandri M, Burda M R, Török E. et al . Repopulation of mouse liver with human hepatocytes and in vivo infection with Hepatitis B virus.  Hepatology. 2001;  33 981-988
• 31 Grompe M. Therapeutic liver repopulation for the treatment of metabolic liver diseases.  Human Cell. 1999;  12 171-180
• 32 Fox I J, Chowdhury J R, Kaufman S S. et al . Treatment of the Crigler Najjar syndrome type I with hepatocyte transplantation - see comments.  N Engl J Med. 1998;  338 1422-1426

1 Teile dieses Manuskripts sind im Rahmen des Forschungsforums Nummer 11 auf der DGVS-Tagung Gastroenterologie 2000 in Hamburg präsentiert worden.

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