Embryonic Ductal Plate Cells Give Rise to Cholangiocytes, Periportal Hepatocytes, and Adult Liver Progenitor Cells

Abstract

Background & Aims Embryonic biliary precursor cells form a periportal sheet called the ductal plate, which is progressively remodeled to generate intrahepatic bile ducts. A limited number of ductal plate cells participate in duct formation; those not involved in duct development are believed to involute by apoptosis. Moreover, cells that express the SRY-related HMG box transcription factor 9 (SOX9), which include the embryonic ductal plate cells, were proposed to continuously supply the liver with hepatic cells. We investigated the role of the ductal plate in hepatic morphogenesis. Methods Apoptosis and proliferation were investigated by immunostaining of mouse and human fetal liver tissue. The post-natal progeny of SOX9-expressing ductal plate cells was analysed after genetic labeling, at the ductal plate stage, by Cre-mediated recombination of a ROSA26RYFP reporter allele. Inducible Cre expression was induced by SOX9 regulatory regions, inserted in a bacterial artificial chromosome. Livers were studied from mice under normal conditions and during diet-induced regeneration. Results Ductal plate cells did not undergo apoptosis and showed limited proliferation. They generated cholangiocytes lining interlobular bile ducts, bile ductules and canals of Hering, as well as periportal hepatocytes. Oval cells that appeared during regeneration also derived from the ductal plate. We did not find that liver homeostasis required a continuous supply of cells from SOX9-expressing progenitors. Conclusions The ductal plate gives rise to cholangiocytes lining the intrahepatic bile ducts, including its most proximal segments. It also generates periportal hepatocytes and adult hepatic progenitor cells.

In vivo reprogramming of Sox9 + cells in the liver to insulin-secreting ducts

“…We have confirmed this with the use of a Sox9-CreER mouse strain (19). It has been shown that Sox9 is up-regulated in adult hepatocytes by tamoxifen, making it difficult to label Sox9 + cells in adulthood (19).…”

“…Moreover the experiments with the Sox9-CreER; mTmG mice show that they arise from cells labeled for Sox9 expression at the ductal plate stage of development. These are probably small bile ducts (22,23) but the cells of origin might also be hepatoblastlike progenitor cells, thought to be in the periportal region associated with small bile ducts (26,27) or perhaps they derive from the peribiliary glands, which are associated with larger bile ducts and are reported to contain cells expressing markers characteristic of embryonic endoderm (18,19,(28)(29)(30)(31)(32).…”

“…It has been shown that Sox9 is up-regulated in adult hepatocytes by tamoxifen, making it difficult to label Sox9 + cells in adulthood (19). However, this problem does not exist in fetal animals and we were able to obtain mice with labeled biliary systems by administering tamoxifen in late pregnancy.…”

“…These arise in the second half of gestation from structures called ductal plates, which form around the portal veins (17). The Sox9 gene is expressed in early cells of the ductal plates and its expression persists in small but not large bile ducts after birth (18,19).…”

Human hepatic organoids for the analysis of human genetic diseases

“…ALGS patients are born with an intact biliary system (51), but the ratio of bile ducts to liver tissue quickly declines with age after birth, which leads to cholestasis and presentation with ALGS liver disease (7,52,53). The proximal branches of the biliary tree are formed in embryonic liver from a single layer of bipotent precursor cells that surround the portal vein (the ductal plate), which are progressively remodeled to generate intrahepatic bile ducts (54), and this requires an interaction with surrounding mesodermal tissues (55). However, the liver enlarges 3-fold during the postnatal period, which is when ALGS liver abnormalities first appear.…”