Hematopoietic Microenvironment in the Fetal Liver: Roles of Different Cell Populations

Payushina, O. V.

doi:10.5402/2012/979480

Cited by 17 publications

(11 citation statements)

References 80 publications

(110 reference statements)

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“…Hematopoietic cells (clusters of small cells with basophilic nuclei) were evident in the livers of SD rats on PND 0 and PND 5 but were absent at PND 10 (Figure 1A). This observation is consistent with the hematopoietic nature of the perinatal liver 25 . The portal vein, hepatic artery and bile ducts (the portal triad) were readily identifiable in livers from SD rats from PND 10 onward and did not change in appearance through PND 90 (Figure 1A).…”

Section: Resultssupporting

confidence: 90%

Increased YAP Activation Is Associated With Hepatic Cyst Epithelial Cell Proliferation in ARPKD/CHF

et al. 2017

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Autosomal recessive polycystic kidney disease/congenital hepatic fibrosis (ARPKD/CHF) is a rare but fatal genetic disease characterized by progressive cyst development in the kidneys and liver. Liver cysts arise from aberrantly proliferative cholangiocytes accompanied by pericystic fibrosis and inflammation. Yes associated protein (YAP), the downstream effector of the Hippo signaling pathway, is implicated in human hepatic malignancies such as hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma, but its role in hepatic cystogenesis in CHF/ARPKD is unknown. We studied the role of the YAP in hepatic cyst development using polycystic kidney (PCK) rats, an orthologous model of ARPKD, and in human ARPKD/CHF patients. The liver cyst wall epithelial cells (CWECs) in PCK rats were highly proliferative and exhibited expression of YAP. There was increased expression of YAP target genes, Cyclin D1 and Ctgf (connective tissue growth factor), in PCK rat livers. Extensive expression of YAP and its target genes was also detected in human ARPKD/CHF liver samples. Finally, pharmacological inhibition of YAP activity with verteporfin and short-hairpin (sh) RNA-mediated knockdown of YAP expression in isolated liver CWECs significantly reduced their proliferation. These data indicate that increased YAP activity, possibly through dysregulation of the Hippo signaling pathway, is associated with hepatic cyst growth in ARPKD/CHF.

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Section: Resultssupporting

confidence: 90%

Increased YAP Activation Is Associated With Hepatic Cyst Epithelial Cell Proliferation in ARPKD/CHF

et al. 2017

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“…Gata4 KO mice exhibit impaired hematopoiesis, a somewhat surprising result considering that the G2‐Cre transgene does not target the hematopoietic stem cell compartment. Therefore, impaired hematopoiesis in Gata4 KO mice must be secondary to loss of GATA4 activity in HSCs and/or ECs, which have been shown to be important components of the hematopoietic microenvironment …”

Section: Discussionmentioning

confidence: 99%

“…Therefore, impaired hematopoiesis in Gata4 KO mice must be secondary to loss of GATA4 activity in HSCs and/or ECs, which have been shown to be important components of the hematopoietic microenvironment. 27 The phenotype of Gata4-deficient fetal livers resembles the fibrogenic process that occurs in adult liver in response to external injury. Mutant fetal livers display increased expression and accumulation of ECM proteins involved in adult liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

GATA4 loss in the septum transversum mesenchyme promotes liver fibrosis in mice

et al. 2014

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The zinc finger transcription factor GATA4 controls specification and differentiation of multiple cell types during embryonic development. In mouse embryonic liver, Gata4 is expressed in the endodermal hepatic bud and in the adjacent mesenchyme of the septum transversum. Previous studies have shown that Gata4 inactivation impairs liver formation. However, whether these defects are caused by loss of Gata4 in the hepatic endoderm or in the septum transversum mesenchyme remains to be determined. In this study, we have investigated the role of mesenchymal GATA4 activity in liver formation. We have conditionally inactivated Gata4 in the septum transversum mesenchyme and its derivatives by using Cre/loxP technology. We have generated a mouse transgenic Cre line, in which expression of Cre recombinase is controlled by a previously identified distal Gata4 enhancer. Conditional inactivation of Gata4 in hepatic mesenchymal cells led to embryonic lethality around mouse embryonic stage 13.5, likely as a consequence of fetal anemia. Gata4 knockout fetal livers exhibited reduced size, advanced fibrosis, accumulation of extracellular matrix components and hepatic stellate cell (HSC) activation. Haploinsufficiency of Gata4 accelerated CCl4‐induced liver fibrosis in adult mice. Moreover, Gata4 expression was dramatically reduced in advanced hepatic fibrosis and cirrhosis in humans. Conclusions: Our data demonstrate that mesenchymal GATA4 activity regulates HSC activation and inhibits the liver fibrogenic process. (Hepatology 2014;59:2358–2370)

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“…These results strongly indicate that in PDE2A −/− embryos, the absence of PDE2A induces apoptosis in cells of different lineages that overall forms the liver niche. In mouse embryos between E11.5 and E16.5, the liver is the primary hematopoietic organ [14,15]. Blood smears obtained from E14.5 normal peripheral blood display a great number of mature non-nucleated erythroid cells, which are mainly liver derived.…”

Section: Hepatoblasts Endothelial and Stromal Cells Undergo Apotosismentioning

confidence: 99%

PDE2A Is Indispensable for Mouse Liver Development and Hematopoiesis

Barbagallo

Rotilio

Assenza

et al. 2020

IJMS

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Phosphodiesterase 2A (PDE2A) is a cAMP-cGMP hydrolyzing enzyme essential for mouse development and the PDE2A knockout model (PDE2A−/−) is embryonic lethal. Notably, livers of PDE2A−/− embryos at embryonic day 14.5 (E14.5) have extremely reduced size. Morphological, cellular and molecular analyses revealed loss of integrity in the PDE2A−/− liver niche that compromises the hematopoietic function and maturation. Hematopoietic cells isolated from PDE2A−/− livers are instead able to differentiate in in vitro assays, suggesting the absence of blood cell-autonomous defects. Apoptosis was revealed in hepatoblasts and at the endothelial and stromal compartments in livers of PDE2A−/− embryos. The increase of the intracellular cAMP level and of the inducible cAMP early repressor (ICER) in liver of PDE2A−/− embryos might explain the impairment of liver development by downregulating the expression of the anti-apoptotic gene Bcl2. In summary, we propose PDE2A as an essential gene for integrity maintenance of liver niche and the accomplishment of hematopoiesis.

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Hematopoietic Microenvironment in the Fetal Liver: Roles of Different Cell Populations

Cited by 17 publications

References 80 publications

Increased YAP Activation Is Associated With Hepatic Cyst Epithelial Cell Proliferation in ARPKD/CHF

Increased YAP Activation Is Associated With Hepatic Cyst Epithelial Cell Proliferation in ARPKD/CHF

GATA4 loss in the septum transversum mesenchyme promotes liver fibrosis in mice

PDE2A Is Indispensable for Mouse Liver Development and Hematopoiesis

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