Activin-driven fate determination is pivotal for liver progenitor cells to take over hepatocytic function in in ACLF
Tao LinShan WangRilu FengChangzhou ShaoXiaodong YuanFranziska WandrerHeike BantelAlexander MarxMPA EbertHuiguo DingSteven DooleyHonglei Weng
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Liver progenitor cell (LPC) differentiation into mature hepatocytes determines survival and recovery of patients with acute-on-chronic liver failure (ACLF), who suffer from massive hepatic necrosis. Interestingly, even in irreversible ACLF, LPCs differentiate towards hepatocytes. However, these LPC-derived hepatocytes do not provide sufficient hepatocytic function, as required for systemic homeostasis. This study demonstrates a crucial role of Activin-dependent lineage-determining transcription factor HNF4a in the maintenance of key hepatocyte function.Keywords:
Progenitor
Homeostasis
Cell fate determination
Sinusoid
Abstract Three structurally distinct zones are present in the liver sinusoid. The endothelium and basement (boundary) membrane of the portal vein extend uninterruptedly into the peripheral zone. The intermediate zone, comprising 90% or more of the length of the sinusoid, possesses a fenestrated lining and no basement membrane. The short central zone has unfenestrated endothelium and a basement membrane. Both are continuous with those of the central vein. The space of Dissé encircles all three zones of the sinusoid. It contains fat storage cells, perisinusoidal cells, numerous microvillae of liver cells and reticular fibers. These fibers are bundles of unit collagen fibers enclosed by cytoplasm of nearby cells. The space of Dissé is continuous with the tissue space at both ends of the sinusoid. The liver cells lack a basement membrane whether they abut on the space of Dissé or on the tissue space proper. The unique feature of liver fine structure is the combination of fenestrations and lack of basement membranes in the intermediate zone of the sinusoid. Blood plasma is thereby afforded intimate contact with the parenchymal cells and has access to the tissue space at both ends of the sinusoid. This structural situation fits the known facts of liver function.
Sinusoid
Perisinusoidal space
Reticular connective tissue
Parenchyma
Lobules of liver
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This article introduces a method for the generation of the sinusoid for control by stepping motor.In order to generate the sinusoid for testing control,the normal sinusoid is changed into time data of the timer by software.According to the data of the timer,the singlechip turns the electromotor by the law of sinusoid.The parameters of sinusoid control signal are optional.
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Timer
Stepper motor
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The livers of rats subjected to end-to-side portacaval anastomoses were studied 3 to 5 months postoperatively by in vivo and electron microscopy. Compared with sham-operated controls, the livers of portacaval anastomoses animals contained dilated, tortuous networks of sinusoids. The velocity of blood flow in these vessels tended to be slower and more variable than controls, but always progressed toward the hepatic venules. Blood entered the sinusoids from portal venules and from arteriosinus twigs which terminated in the initial segments of some of the sinusoids at the periphery of the lobule. Together, the arteriosinus twigs and the short, initial segments of these sinusoids formed functional arterioportal anastomoses. These, in combination with the lack of portal venous flow, resulted in retrograde blood flow in portal venules. Nevertheless, blood still flowed from these portal venules into the sinusoids unless the sinusoid was fed by an arteriosinus twig. In addition to these microcirculatory alterations, the number of Kupffer cells that phagocytized latex particles was less in the animals with portacaval anastomoses, as was the number of particles ingested by these cells. Scanning and transmission electron microscopy confirmed the paucity of Kupffer cells. Those seen appeared inactive since they were flattened, exhibited few microplicae and filopodia and contained few latex particles. The endothelial cells of the sinusoid lining were perforated by increased numbers of large fenestrate which may be a reflection of elevated intrasinusoid pressures generated by the expanded arterialization of the sinusoid bed. The observed dilated sinusoid network interspersed by narrowed plates of hepatocytes is also consistent with this hypothesis. Finally, scattered nodular foci were observed which contained enlarged hepatocytes, narrow sinusoids, active Kupffer cells, and more normal rates of blood flow. Such sites may represent attempts by the liver to regenerate its normal architecture.
Portacaval anastomosis
Portacaval shunt
Liver circulation
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In adult tissues, multi-potent progenitor cells are some of the most primitive members of the developmental hierarchies that maintain homeostasis. That progenitors and their more mature progeny share identical genomes, suggests that fate decisions are directed by interactions with extrinsic soluble factors, ECM, and other cells, as well as physical properties of the ECM. To understand regulation of fate decisions, therefore, would require a means of understanding carefully choreographed combinatorial interactions. Here we used microenvironment protein microarrays to functionally identify combinations of cell-extrinsic mammary gland proteins and ECM molecules that imposed specific cell fates on bipotent human mammary progenitor cells. Micropatterned cell culture surfaces were fabricated to distinguish between the instructive effects of cell-cell versus cell-ECM interactions, as well as constellations of signaling molecules; and these were used in conjunction with physiologically relevant 3 dimensional human breast cultures. Both immortalized and primary human breast progenitors were analyzed. We report on the functional ability of those proteins of the mammary gland that maintain quiescence, maintain the progenitor state, and guide progenitor differentiation towards myoepithelial and luminal lineages.
Cell fate determination
Progenitor
Cell type
Cell Signaling
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Objective To inquiry pathological changes of endotheliocytes of hepatic sinusoid while reperfusion and rejection occurred after liver transplantation.Methods We stained liver specimen sampled termly with monoclonal antibodies to endotheliocytes of hepatic sinusoid in rat.Results ICAM 1 was stained markedly in hepatic sinusoid at 4th day,but we didn't find laminine and Ⅷ associated antigen during experiment.Clearly ICAM 1 stained was found in highly rejected group(ACI LEW)from the first day after transplantation.In the medium group (BN LEW),we detected that ICAM 1 was stained at 1st day after transplantation,and Ⅷ associated antigen was found in hepatic sinusoid.Conclusion The liver injury resulted from chronic rejection not only destroy hepatic artery but also injure hepatic sinusoid.
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Perisinusoidal space
Lumen (anatomy)
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Summary Correct nervous system development depends on the timely differentiation of progenitor cells into neurons. While the output of progenitor differentiation is well investigated at the population and clonal level, the possibilities and constraints for fate decisions of specific progenitors over development are less explored. Particularly little is known about their variability and competence plasticity. To fill this gap, we here use long-term live imaging to follow the outcome of progenitor divisions in the zebrafish retina. We find that neurogenic Atoh7 expressing progenitors produce different neuronal types over development with time-dependent probabilities. Interestingly, deterministic and probabilistic fate decisions co-exist in the same lineage. While interference with the deterministic fate affects lineage progression, interference with fate probabilities of the stochastic lineage branch results in a broader range of fate possibilities than seen in controls. When tissue development is challenged, Atoh7 expressing progenitors can produce any neuronal type, arguing against the concept of fixed competence windows. Stochastic modelling of fate probabilities in challenged conditions revealed a simple gene regulatory network able to recapitulate the observed competence changes during development. Based on our results, we postulate that fate plasticity could be involved in robust retinal development, a concept possibly applicable to other tissues.
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Progenitor
Lineage (genetic)
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Aims: Hepatocytes are in tight contact with the hepatic stellate cells (HSC) of the liver sinusoid and with the myofibroblasts (rMF) of the pericentral and perivenous area. Hepatocyte-derived signals may influence the behaviour of these cells.
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Hepatic stellate cell
Primary culture
Differential effects
Myofibroblast
Primary (astronomy)
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