- Hepatic Stem Cells: In Search of
The cellular plasticity associated with various fetal tissuesmakes embryonic development an ideal place to search for stem/progenitorcell populations. During embryogenesis, the liver arises fromthe gut tube as an out-pouching, referred to as the liver bud.The liver bud begins to grow and differentiate, and subsequentcellular contact with the cardiac mesoderm and the productionof fibroblast growth factors (FGFs) in the local environmentinduces the endoderm toward hepatic development . The septumtransversum, another mesodermal derivative, also contributesto this process of hepatic differentiation. The septum transversumis in close proximity to the developing ventral foregut andproduces bone morphogenic proteins that contribute to the differentiationprocess from endoderm to the future liver .
As the liver bud grows, the cellular constituent of the liveris composed of hepatoblasts. Hepatoblasts are defined as theprecursors for hepatocytes as well as for cholangiocytes, thecells that form the biliary ductal system of the liver .The hepatoblasts have been characterized with various markers,including albumin, -fetoprotein, cytokeratin 17 (CK 17), andCK 19 [15, 16]. During the developmental process, the architectureof the mature liver becomes apparent with the differentiationof the hepatoblasts into hepatocytes and sinusoid formation.Examination of the various cell types in the 14-day-old fetalrat liver reveals three distinct cell populations: those solelyexpressing hepatocyte markers, such as -fetoprotein and albumin;a second population expressing biliary cell markers, such ascytokeratin; and a third population of cells expressing bothhepatic and biliary markers . This latter population isbipotent, capable of developing into biliary or hepatic celllines, and is thus thought of as the fetal source of hepaticprogenitor cells . Sandhu et al. transplanted rat fetalliver epithelial cells of varying ages into adult livers. Theydemonstrated that fetal liver epithelial cells from embryonicday (ED) 12–14 engrafted and were capable of forming bothhepatocytes and cholangiocytes . However, fetal liver epithelialcells from ED18 were only capable of producing hepatocytes,suggesting that they had lost their bipotent capacity .
Investigators studying the characterization of the stem cellcompartment in the fetal liver have focused on defining markersassociated with stem cells as well as those associated withhepatic cells and then identifying which cells possess a combinationof the markers. Petersen et al. demonstrated Thy-1, a markerof hematopoietic stem cells,  on specific populations offetal hepatocytes . These authors also established thata Thy-1-positive cell population also expressed CK-18, a hepatocyticmarker, within the fetal liver. Hepatic progenitor cells havealso been reported to express c-kit, a stem cell marker, alongwith CD34 and Thy-1 . Using c-kit as a marker, along with6- and ß1-integrin subunits, Suzuki et al. facilitatedflow-cytometric separation of progenitor type cells from otherhepatocytes in the developing mouse liver [8, 22].
The origin of the fetal hepatic stem cell populations has beena controversial topic. Early in development the fetal liveris the major location of hematopoiesis . It has been shownthat these hematopoietic cells release signals that direct theliver to grow and differentiate . Eventually, the functionof hematopoiesis is shifted out of the liver to the bone marrow.However, there is a question of whether some of the transienthematopoietic stem cells remain behind to form the hepatic stemcell compartment. Those investigators favoring this line ofreasoning point out that hepatic progenitor cells can sharecell surface markers associated with hematopoietic stem cells(such as CD34 [25, 26], Thy-1 , and c-kit ). However,there is a growing body of work that suggests that the hepaticprogenitor cells are an independent stem cell population, distinctfrom the hematopoietic stem cell population. Nierhoff et al.separated a highly enriched population of fetal hepatic progenitorcells using a Sca1+ antibody . These cells expressed bothhepatic and biliary markers (AFP and cytokeratin markers, respectively)but did not express c-kit or CD34 . However, in a conflictingstudy, Minguet et al. showed that neither the c-kit-negativeembryonic cells nor the positive fraction could differentiateinto hepatocytes. Interestingly, it was the c-kit (+low) fractionthat comprised the hepatic stem cells that differentiate intomature liver cells . In a separate study, embryonic hepaticprogenitors cultured in the presence of FGF expressed increasedlevels of c-kit, ck-19, and -fetoprotein . The subject ofmarkers is controversial and remains an area of active study.Current efforts at delineating the origin of the fetal progenitorcell population have also included short-term labeling techniques.Tremblay et al. harvested mouse embryos at various ages andlabeled the cells to observe migration patterns . They foundtwo distinct populations of cells: lateral cells that are constrainedto a specific tissue-fate and position axis, and medial cellsthat migrate along an anterior-posterior axis and contributeto multiple gut tissues . Further work with labeling techniqueswill help us gain understanding into the migration and differentiationof the progenitor cells.
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