Stepwise reprogramming of liver cells to a pancreas progenitor state by the transcriptional regulator Tgif2

The development of a successful lineage reprogramming strategy of liver to pancreas holds promises for the treatment and potential cure of diabetes. The liver is an ideal tissue source for generating pancreatic cells, because of its close developmental origin with the pancreas and its regenerative ability. Yet, the molecular bases of hepatic and pancreatic cellular plasticity are still poorly understood. Here, we report that the TALE homeoprotein TGIF2 acts as a developmental regulator of the pancreas versus liver fate decision and is sufficient to elicit liver-to-pancreas fate conversion both ex vivo and in vivo. Hepatocytes expressing Tgif2 undergo extensive transcriptional remodelling, which represses the original hepatic identity and, over time, induces a pancreatic progenitor-like phenotype. Consistently, in vivo forced expression of Tgif2 activates pancreatic progenitor genes in adult mouse hepatocytes. This study uncovers the reprogramming activity of TGIF2 and suggests a stepwise reprogramming paradigm, whereby a ‘lineage-restricted’ dedifferentiation step precedes the identity switch

Modulation of cell surface expression of liver carbohydrate receptors during in vivo induction of apoptosis with lead nitrate

Cell surface expression of carbohydrate receptors (i.e. mannose and galactose receptors) and phagocytosis of apoptotic cells by sinusoidal liver cells was studied. Binding sites and phagocytic activity were quantified at different time intervals (1, 3, 5, 7, 9, 11, 13, 15, 20, 30, 40 and 60 days) after the in vivo administration to rats of a potent liver mitogen, lead nitrate, that also induces apoptosis. The number and distribution of binding sites was receptor and cell-type dependent during the days following the metal injection. The use of competing saccharides in inhibition uptake experiments suggests that sinusoidal liver cells actively phagocytose apoptotic hepatocytes and circulating apoptotic cells by using both receptors. In particular, Kupffer cells at 5 and 15 days after the lead nitrate injection are very active in internalizing apoptotic cells (two- to threefold control). However, phagosomes containing apoptotic hepatocytes are often seen inside the cytoplasm of parenchymal and endothelial cells

Lead nitrate-induced proliferation and death (apoptosis) in liver, kidney, and spleen of rats

Among the many circumstances in which apoptosis plays a role, there is the reduction of cell number during regression of organ hyperplasia due to mitogens. The present study investigates whether a single intravenous injection of lead nitrate to rat could exert a proliferative stimulus in a number of organs (i.e., liver, kidney, spleen, intestine, stomach, brain, and heart), and, as well, looks at the fate of the cells generated by the mitogenic stimulus. Microscopic analysis revealed that liver, spleen, and kidney are affected by metal intoxication, while intestine, stomach, brain, and heart are partially or totally resistent to the treatment. Proliferation of the hepatic, renal, and splenic tissues was observed within a few days of treatment, followed by regression of hyperplasia due to apoptosis. The appearance of apoptotic cells was never observed during proliferation or at restoration of the organ mass. In the tissue sections, apoptotic cells were observed both in the extracellular spaces and inside the cytoplasm of the healthy ones, as a result of their phagocytosis