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
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.
Anschrift für die Verfasser
Dr. J. Petersen
Klinik und Poliklinik für Innere
Medizin
Universitätsklinikum Hamburg-Eppendorf
Martinistraße 52
20246 Hamburg
eMail: petersen@hpi.uni-hamburg.de