Dependence of liver-specific transcription on tissue organization.

Abstract

When the liver is disaggregated and hepatocytes are cultured as a cellular monolayer for 24 h, a sharp decline (80 to 99% decrease) in the transcription of most liver-specific mRNAs, but not common mRNAs, occurs (Clayton and Darnell, Mol. Cell. Biol. 2:1552-1561. A wide variety of culture conditions involving various hormones and substrates and cocultivation with other cells failed to sustain high rates of liver-specific mRNA synthesis in cultured hepatocytes, although they continued to synthesize common mRNAs at normal or elevated rates. In contrast, when slices of intact mouse liver tissue were placed in culture, the transcription of liver-specific genes was maintained at high levels (20 to 100% of normal liver). Furthermore, we found that cells in the liver could be disengaged and immediately reengaged in a tissue-like structure by perfusing the liver with EDTA followed by serum-containing culture medium. Slices of reengaged liver continued to transcribe tissue-specific mRNA sequences at significantly higher rates after 24 h in culture than did individual cells isolated by EDTA perfusion followed by culturing as a monolayer. Therefore we conclude that a mature tissue structure plays an important role in the maintenance of maximum tissue-specific transcription in liver cells.

Embryonic development of the liver†

“…21 Consistent with the proposal that extracellular matrix is a significant determinant of hepatoblast cell fate, it has been demonstrated that the profile of gene expression within primary hepatic cultures is significantly affected by the composition of extracellular matrix. 79,80,118,[120][121][122][123] For example, culture of bipotential mouse embryonic liver cells in matrigel, a soluble basement membrane preparation that includes laminin, collagen IV, heparan sulfate proteoglycans, and entactin, induced them to express biliary epithelial cell markers and form ductile like structures. 83,124 In addition, cells lacking ␤1-integrin, a subunit of a heterodimeric protein complex that contributes to cell-matrix interactions, are unable to colonize the liver, and inhibition of the ␣3-integrin subunit expression blocks extracellular matrixinduced differentiation of a hepatic cell line.…”

“…79 This requires extensive differentiation of parenchymal and nonparenchymal cell types, organization of extracellular matrix, development of the biliary tract, maturation of sinusoidal capillaries and hepatic vasculature, and the conversion of hepatocytes to polarized epithelial cells. The molecular mechanisms underlying liver organogenesis are only now beginning to be deciphered.…”

α3β1-integrin as a critical mediator of the hepatic differentiation response to the extracellular matrix

“…For example, early hepatocyte differentiation begins as foregut endodermal cells enter the new collagenous environment of the surrounding mesenchyme, 1 and the role of the ECM in adult hepatocyte differentiation is well established. [2][3][4][5][6][7][8] Other examples of ECMpromoted differentiation include the differentiation of keratinocytes, 9 gastrulation in Pleurodeles embryos, 10 and the epithelial conversion of kidney mesenchyme 11 (for review, see Adams and Watt 12 ). The ECM is present in all animals from the earliest stages of development and is composed of a mixture of proteins and proteoglycans such as collagens, laminin, and fibronectin.…”

Identification of a rat liver cDNA and mRNA coding for the 28 kDa gap junction protein

“…Fig.4 illustrates a 3-fold increase of the 1.9 kb mRNA during this time interval which corresponds to the previously described increase of the mouse liver gap junction protein under these conditions [16,20]. Possibly the transcription of the gene coding for the 28 kDa gap junction protein is similarly dependent on cell-cell contact or on intact tissue organization as has recently been shown for other liver specific mRNAs [21]. Alternatively transcription of the gap junction gene or the stability of the primary transcript and mRNA may decrease in proliferating hepatocytes.…”