Identification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion Lumos
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Cell Culture
SUBMITTER: 
Paula Follert
LAB HEAD: Eckhard Lammert
PROVIDER: PXD033942 | Pride | 2023-12-28
REPOSITORIES: Pride
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Project description:Non-alcoholic fatty liver disease (NAFLD) is gaining evermore importance due to rapidly rising incidence rates especially in western countries. As the disease progresses, it can develop into hepatocellular carcinoma. Related metabolic changes have been extensively studied in the past. However, the molecular mechanisms responsible for the development of fatty liver disease remain uncovered. Here we show that the basal phosphorylation of the MET receptor can be used as an indicator for hepatocyte dysregulation in fatty liver disease. Using primary hepatocytes isolated from a preclinical model fed with high-fat, high-sugar diet (Western diet; WD) or standard diet (SD), we find a strong downregulation of the PI3K-AKT pathway and upregulation of the MAPK pathway in the WD derived hepatocytes. By developing a mathematical model of HGF-induced signal transduction, calibrated with quantitative time-resolved measurements of both PI3K-AKT and MAPK pathways, we resolve molecular mechanisms responsible for these alterations. Thereby, we identify the basal MET phosphorylation rate as main driver for the altered signal transduction in WD hepatocytes that even leads to an increased proliferation behavior of the usually quiescent hepatocytes in the absence of growth factors. The adaptation of the dynamic pathway model of HGF signal transduction to patient-derived hepatocytes reveals a patient-specific variability of basal MET phosphorylation levels, which correlates with the clinical outcome of patients after liver surgery. These findings suggest that the dysregulated basal MET phosphorylation could be exploited to assess the health status of the liver and thereby inform estimation of the risk of a patient to suffer from liver failure after surgery.Non-alcoholic fatty liver disease (NAFLD) is gaining evermore importance due to rapidly rising incidence rates especially in western countries. As the disease progresses, it can develop into hepatocellular carcinoma. Related metabolic changes have been extensively studied in the past. However, the molecular mechanisms responsible for the development of fatty liver disease remain uncovered. Here we show that the basal phosphorylation of the MET receptor can be used as an indicator for hepatocyte dysregulation in fatty liver disease. Using primary hepatocytes isolated from a preclinical model fed with high-fat, high-sugar diet (Western diet; WD) or standard diet (SD), we find a strong downregulation of the PI3K-AKT pathway and upregulation of the MAPK pathway in the WD derived hepatocytes. By developing a mathematical model of HGF-induced signal transduction, calibrated with quantitative time-resolved measurements of both PI3K-AKT and MAPK pathways, we resolve molecular mechanisms responsible for these alterations. Thereby, we identify the basal MET phosphorylation rate as main driver for the altered signal transduction in WD hepatocytes that even leads to an increased proliferation behavior of the usually quiescent hepatocytes in the absence of growth factors. The adaptation of the dynamic pathway model of HGF signal transduction to patient-derived hepatocytes reveals a patient-specific variability of basal MET phosphorylation levels, which correlates with the clinical outcome of patients after liver surgery. These findings suggest that the dysregulated basal MET phosphorylation could be exploited to assess the health status of the liver and thereby inform estimation of the risk of a patient to suffer from liver failure after surgery.
2024-01-15 | PXD043007 | Pride
Project description:Non-alcoholic fatty liver disease (NAFLD) is gaining evermore importance due to rapidly rising incidence rates especially in western countries. As the disease progresses, it can develop into hepatocellular carcinoma. Related metabolic changes have been extensively studied in the past. However, the molecular mechanisms responsible for the development of fatty liver disease remain uncovered. Here we show that the basal phosphorylation of the MET receptor can be used as an indicator for hepatocyte dysregulation in fatty liver disease. Using primary hepatocytes isolated from a preclinical model fed with high-fat, high-sugar diet (Western diet; WD) or standard diet (SD), we find a strong downregulation of the PI3K-AKT pathway and upregulation of the MAPK pathway in the WD derived hepatocytes. By developing a mathematical model of HGF-induced signal transduction, calibrated with quantitative time-resolved measurements of both PI3K-AKT and MAPK pathways, we resolve molecular mechanisms responsible for these alterations. Thereby, we identify the basal MET phosphorylation rate as main driver for the altered signal transduction in WD hepatocytes that even leads to an increased proliferation behavior of the usually quiescent hepatocytes in the absence of growth factors. The adaptation of the dynamic pathway model of HGF signal transduction to patient-derived hepatocytes reveals a patient-specific variability of basal MET phosphorylation levels, which correlates with the clinical outcome of patients after liver surgery. These findings suggest that the dysregulated basal MET phosphorylation could be exploited to assess the health status of the liver and thereby inform estimation of the risk of a patient to suffer from liver failure after surgery.
2024-01-15 | PXD041563 | Pride
Project description:Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, non-alcoholic fatty liver disease (NAFLD) is gaining importance. As the disease progresses it can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in NAFLD development, but the molecular mechanisms responsible for disease development remained unresolved. Here, we uncover a strong downregulation of the PI3K-AKT pathway and an upregulation of the MAPK pathway in primary hepatocytes from a preclinical model fed with a Western diet (WD). Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveals a patient-specific variability in basal MET phosphorylation, which correlates with the outcome of patients after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.
2024-01-16 | MODEL2306280002 | BioModels
Project description:Nutrient availability fluctuates in most natural populations, forcing organisms to undergo periods of fasting and re-feeding. It is unknown how dietary change influences liver homeostasis. Here, we show that a switch from ad libitum feeding to intermittent fasting (IF) promotes rapid hepatocyte proliferation. Mechanistically, IF- induced hepatocyte proliferation is driven by the combined action of intestinally produced, systemic endocrine FGF15 and localized WNT signaling. IF proliferation re-establishes a constant liver-to-body-mass ratio during periods of fasting and re-feeding, a process termed the hepatostat. This study provides the first example of dietary influence on adult hepatocyte proliferation, and challenges the widely held view that liver tissue is mostly quiescent unless chemically or mechanically injured.
2022-08-01 | ST002263 | MetabolomicsWorkbench
Project description:Liver models that closely mimic the in vivo microenvironment are central for understanding liver functions, capabilities, and intercellular communication processes. Whereas hepatocyte monolayers de-differentiate after only a few days in culture, constructs consisting of hepatocytes and non-parenchymal cells (NPC) separated by a polyelectrolyte multilayer (PEM) provide maintenance of hepatic phenotypes. To better understand the mechanisms and processes that underlie organotypic liver model function, hepatocyte protein abundances in the presence and absence of liver sinusoidal endothelial cells (LSECs) were compared to hepatocyte monolayers. The presence of the PEM led to increases in proteins associated with hepatocyte lipid metabolism, with mitochondrial-based β-oxidation and peroxisomal proteins found in higher abundance. It was also demonstrated that the presence of LSECs modulates levels of carboxylesterases and other phase I and phase II enzymes. These results are discussed in relation to intercellular signaling and hepatocyte function.
2017-07-06 | PXD002491 | Pride
Project description:Gap junction-mediated cell-cell interactions are highly conserved and play essential roles in cell survival, proliferation, differentiation and patterning. We report that Connexin 32 (Cx32)-mediated gap junctional intercellular communication (GJIC) is necessary for human embryonic stem cell-derived hepatocytes (hESC-Heps) during step-wise hepatic lineage restriction and maturation. Vitamin K2, previously shown to promote Cx32 expression in mature hepatocytes, up-regulated Cx32 expression and GJIC activation during hepatic differentiation and maturation, resulting in significant increases of hepatic markers expression and hepatocyte functions. In contrast, negative Cx32 regulator 2-aminoethoxydiphenyl borate blocked hESC-to-hepatocyte maturation and muted hepatocyte functions through disruption of GJIC activities. Dynamic gap junction organization and internalization are phosphorylation-dependent and the p38 mitogen-activated protein kinases pathway (MAPK) can negatively regulate Cxs through phosphorylation-dependent degradation of Cxs. We found that p38 MAPK inhibitor SB203580 improved maturation of hESC-Heps correlating with up-regulation of Cx32; by contrast, the p38 MAPK activator, anisomycin, blocked hESC-Heps maturation correlating with down-regulation of Cx32. These results suggested that Cx32 is essential for cell-cell interactions that facilitate driving hESCs through hepatic-lineage maturation. Regulators of both Cx32 and other members of its pathways maybe used as a promising approach on regulating hepatic lineage restriction of pluripotent stem cells and optimizing their functional maturation.
2017-02-12 | GSE76098 | GEO
Project description:Mueller2015 - Hepatocyte proliferation, T160
phosphorylation of CDK2
This model is described in the article:
T160-phosphorylated CDK2
defines threshold for HGF-dependent proliferation in primary
hepatocytes.
Mueller S, Huard J, Waldow K, Huang
X, D'Alessandro LA, Bohl S, Börner K, Grimm D, Klamt S,
Klingmüller U, Schilling M.
Mol. Syst. Biol. 2015; 11(3): 795
Abstract:
Liver regeneration is a tightly controlled process mainly
achieved by proliferation of usually quiescent hepatocytes. The
specific molecular mechanisms ensuring cell division only in
response to proliferative signals such as hepatocyte growth
factor (HGF) are not fully understood. Here, we combined
quantitative time-resolved analysis of primary mouse hepatocyte
proliferation at the single cell and at the population level
with mathematical modeling. We showed that numerous G1/S
transition components are activated upon hepatocyte isolation
whereas DNA replication only occurs upon additional HGF
stimulation. In response to HGF, Cyclin:CDK complex formation
was increased, p21 rather than p27 was regulated, and Rb
expression was enhanced. Quantification of protein levels at
the restriction point showed an excess of CDK2 over CDK4 and
limiting amounts of the transcription factor E2F-1. Analysis
with our mathematical model revealed that T160 phosphorylation
of CDK2 correlated best with growth factor-dependent
proliferation, which we validated experimentally on both the
population and the single cell level. In conclusion, we
identified CDK2 phosphorylation as a gate-keeping mechanism to
maintain hepatocyte quiescence in the absence of HGF.
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BIOMD0000000568.
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2024-09-02 | BIOMD0000000568 | BioModels
Project description:The transcriptional coactivator Yap promotes proliferation and inhibits apoptosis, suggesting that Yap functions as an oncogene. Most oncogenes, however, require a combination of at least two signals to promote proliferation. Here we present evidence that Yap activation is insufficient to promote growth in the otherwise normal tissue. Using a mosaic mouse model, we demonstrate that Yap overexpression in a fraction of hepatocytes does not lead to their clonal expansion, as proliferation is counterbalanced by increased apoptosis. To shift the activity of Yap towards growth, a second signal provided by tissue damage or inflammation is required. In response to liver injury, Yap drives clonal expansion, suppresses hepatocyte differentiation and promotes a progenitor phenotype. These results suggest that Yap activation is insufficient to promote growth in the absence of a second signal thus coordinating tissue homeostasis and repair. Totally sixteen samples
2015-02-07 | E-GEOD-65207 | biostudies-arrayexpress
Project description:Mechanisms underlying human hepatocyte growth in development and regeneration are incompletely understood. In vitro, human fetal hepatocytes (FH) can be robustly grown as organoids, while adult primary human hepatocyte (PHH) organoids remain difficult to expand, suggesting different growth requirements between fetal and adult hepatocytes. Here, we characterize hepatocyte organoid outgrowth using temporal transcriptomic and phenotypic approaches. FHs initiate reciprocal transcriptional programs involving increased proliferation and repressed lipid metabolism upon initiation of organoid growth. We exploited these insights to design maturation conditions for FH organoids, resulting in acquisition of mature hepatocyte morphological traits and increased expression of functional markers. During PHH organoid outgrowth in the same culture condition, the adult transcriptomes initially mimic the fetal transcriptomic signatures, but PHHs rapidly acquire disbalanced proliferation-lipid metabolism dynamics, resulting in steatosis and halted organoid growth. IL6 supplementation, as emerged from the fetal dataset, and simultaneous activation of the metabolic regulator FXR, prevents steatosis and promotes PHH proliferation, resulting in improved expansion of the derived organoids. Single-cell RNA sequencing analyses reveal preservation of their fetal and adult hepatocyte identities in the respective organoid cultures. Our findings uncover mitogen requirements and metabolic differences determining proliferation of hepatocytes changing from development to adulthood.
2024-04-30 | GSE264260 | GEO
Project description:Mechanisms underlying human hepatocyte growth in development and regeneration are incompletely understood. In vitro, human fetal hepatocytes (FH) can be robustly grown as organoids, while adult primary human hepatocyte (PHH) organoids remain difficult to expand, suggesting different growth requirements between fetal and adult hepatocytes. Here, we characterize hepatocyte organoid outgrowth using temporal transcriptomic and phenotypic approaches. FHs initiate reciprocal transcriptional programs involving increased proliferation and repressed lipid metabolism upon initiation of organoid growth. We exploited these insights to design maturation conditions for FH organoids, resulting in acquisition of mature hepatocyte morphological traits and increased expression of functional markers. During PHH organoid outgrowth in the same culture condition, the adult transcriptomes initially mimic the fetal transcriptomic signatures, but PHHs rapidly acquire disbalanced proliferation-lipid metabolism dynamics, resulting in steatosis and halted organoid growth. IL6 supplementation, as emerged from the fetal dataset, and simultaneous activation of the metabolic regulator FXR, prevents steatosis and promotes PHH proliferation, resulting in improved expansion of the derived organoids. Single-cell RNA sequencing analyses reveal preservation of their fetal and adult hepatocyte identities in the respective organoid cultures. Our findings uncover mitogen requirements and metabolic differences determining proliferation of hepatocytes changing from development to adulthood.
2024-04-30 | GSE264261 | GEO