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§¶
From the Marion Bessin Liver Research Center,*
the Division of Gastroenterology, Hepatology and
Nutrition,
and the Departments of
Medicine,
Cell
Biology,§
and
Pathology,¶
Albert Einstein College of Medicine,
Bronx, New York; the Department of
Gastroenterology,||
Tel Aviv
Sourasky Medical Center, Tel Aviv, Israel; and the Istituto di
Patologia Sperimentale,**
Ospedale Oncologico "A
Businco", University of Cagliari, Cagliari, Italy
To identify cells that have the ability to proliferate and
differentiate into all epithelial components of the liver
lobule, we isolated fetal liver epithelial cells (FLEC) from ED
14 Fischer (F) 344 rats and transplanted these cells in conjunction
with two-thirds partial hepatectomy into the liver of normal and
retrorsine (Rs) treated syngeneic dipeptidyl peptidase IV mutant
(DPPIV-) F344 rats. Using dual label
immunohistochemistry/in situ hybridization,
three subpopulations of FLEC were identified: cells expressing both
-fetoprotein (AFP) and albumin, but not CK-19; cells
expressing CK-19, but not AFP or albumin, and cells
expressing AFP, albumin, and cytokeratins-19 (CK-19).
Proliferation, differentiation, and expansion of
transplanted FLEC differed significantly in the two models. In normal
liver, 1 to 2 weeks after transplantation, mainly cells
with a single phenotype, hepatocytic (expressing AFP and
albumin) or bile ductular (expressing only CK-19), had
proliferated. In Rs-treated rats, in which the proliferative
capacity of endogenous hepatocytes is impaired, transplanted
cells showed mainly a dual phenotype (expressing both AFP/albumin and
CK-19). One month after transplantation, DPPIV+
FLEC engrafted into the parenchyma exhibited an hepatocytic phenotype
and generated new hepatic cord structures. FLEC, localized in
the vicinity of bile ducts, exhibited a biliary epithelial
phenotype and formed new bile duct structures or were incorporated into
pre-existing bile ducts. In the absence of a proliferative
stimulus, ED 14 FLEC did not proliferate or differentiate. Our
results demonstrate that 14-day fetal liver contains lineage committed
(unipotential) and uncommitted (bipotential) progenitor cells
exerting different repopulating capacities, which are affected
by the proliferative status of the recipient liver and the host site
within the liver where the transplanted cells become engrafted. These
findings have important implications in future studies directed toward
liver repopulation and ex vivo gene
therapy.
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