Spatiotemporal expression of HMGB2 regulates cell proliferation and hepatocyte size during liver regeneration
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ABSTRACT:
PROVIDER: PRJNA822301 | ENA |
REPOSITORIES: ENA
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Project description:Liver regeneration is an extraordinarily complex process involving a variety of factors; however, the role of chromatin protein in hepatocyte proliferation is largely unknown. In this study, we investigated the functional role of high-mobility group box 2 (HMGB2), a chromatin protein in liver regeneration using wild-type and HMGB2-knockout (KO) mice. Liver tissues were sampled after 70% partial hepatectomy (PHx), and analyzed by immunohistochemistry using various markers of cell proliferation, including Ki-67, PCNA, cyclin D1, cyclin B1, EdU and pH3S10. In WT mice, hepatocyte proliferation was strongly correlated with the spatiotemporal expression of HMGB2; however, cell proliferation was significantly delayed in hepatocytes of HMGB2-KO mice. Quantitative PCR demonstrated that cyclin D1 and cyclin B1 mRNAs were significantly decreased in HMGB2-KO mice livers. Interestingly, hepatocyte size was significantly larger in HMGB2-KO mice at 36-72 h after PHx, and these results suggest that hepatocyte hypertrophy appeared in parallel with delayed cell proliferation. In vitro experiments demonstrated that cell proliferation was significantly decreased in HMGB2-KO cells. A significant delay in cell proliferation was also found in HMGB2-siRNA transfected cells. In summary, spatiotemporal expression of HMGB2 is important for regulation of hepatocyte proliferation and cell size during liver regeneration.
2022-04-03 | GSE199944 | GEO
Project description:Liver regeneration is an well orchestrated compensatory process that regulated by multiple factors. We recently reported the importance of chromatin protein, a high-mobility group box 2 (HMGB2) in mouse liver regeneration, however, it’s molecular mechanism is not yet understood. In this study, we aimed to study how HMGB2 regulates hepatocyte proliferation during liver regeneration. Wild-type (WT) and HMGB2-knockout (KO) mice were 70% partial hepatectomized (PHx), and liver tissues were analyzed by microarray, immunohistochemistry, qPCR and western blotting. In vivo experimental findings were confirmed by in vitro experiments using HMGB2 gene knockdown in combination with de novo lipogenesis model. In WT mouse, HMGB2-positive hepatocytes were co-localized with cell proliferation markers, whereas, hepatocyte proliferation was significantly decreased in HMGB2-KO mice. Oil red-O staining detected the transient accumulation of lipid droplets at 12-24 h in WT mouse livers, however, decreased amount of lipid droplets were found in HMGB2-KO mouse livers, and it was prolonged until 36 h. Microarray, immunohistochemistry and qPCR results were demonstrated that lipid metabolism related genes were significantly decreased in HMGB2-KO mouse livers. In vitro experiments demonstrated that decreased lipid droplets in HMGB2-knockdown cells correlated with decreased cell proliferation activity. HMGB2 is involved in the regulation of liver regeneration through transient accumulation of lipid droplets in hepatocytes.
2023-10-14 | GSE244551 | GEO
Project description: Not available
| S-EPMC9279446 | biostudies-literature
Project description:Dynamic remodeling of translation programs drives hepatocyte proliferation during liver regeneration
| PRJNA415722 | ENA
Project description:We studied the role of the post-translational modification called O-GlcNAcylation during liver regeneration. Here we generated O-GlcNAc transferase (OGT-KO) and O-GlcNAcase (OGA-KO) hepatocyte-specific knock-out mice. 70% partial hepatectomy (PHX) was performed to induce liver regeneration. We showed that OGA-KO mice had normal liver regeneration whereas OGT-KO mice had a defect in the termination of liver regeneration.
2022-02-25 | GSE188882 | GEO
Project description:The liver is the only organ with the ability to regenerate following surgical or toxicant insults, and partial hepatectomy (PH) serves as an experimental model of liver regeneration (LR). Dynamic changes in gene expression occur from the periportal to pericentral regions of the liver following PH; thus, spatial transcriptomics, combined with a novel computational pipeline (ADViSOR [Analytic Dynamic Visual Spatial Omics Representation]), were employed to gain insights into the spatiotemporal molecular underpinnings of LR. ADViSOR, comprised of time-interval principal component analysis (TI-PCA) and sliding dynamic hypergraphs (sDyHyp), was applied to spatial transcriptomics data on 100 genes assayed serially through LR, including key components of the Wnt/beta-catenin pathway at critical time points after PH. This computational pipeline identified key functional modules demonstrating cell signaling and cell-cell interactions, inferring shared regulatory mechanisms. Specifically, ADViSOR analysis suggested that macrophage-mediated inflammation is a critical component of early LR and confirmed prior studies showing that Ccnd1, a hepatocyte proliferative gene, is regulated by the Wnt/ß-catenin pathway. These findings were subsequently validated through protein localization which provided further confirmation and novel insights into the spatiotemporal changes in the Wnt/beta-catenin pathway during LR. Thus, ADViSOR may yield novel insights in other complex, spatiotemporal contexts.
2023-09-28 | GSE244211 | GEO
Project description:Cholestatic injuries, featured with regional damage around the periportal, cause considerable mortality without curative therapies. It is technically challenging to dissect regional cell-cell interactions and molecular changes to fully understand cholangiopathies. Here, we generated a high-definition atlas of spatiotemporal transcriptome during cholestatic injury and repair. Remarkably, cholangiocytes functioned as a periportal hub by integrating signals from neighboring cells. We also dissected periportal damage, spatial heterogenous reprogramming and zonal regeneration, which appeared to be strongly associated with cholangiocyte. Moreover, spatiotemporal analyses revealed a key inhibitory rheostat for hepatocyte proliferation. Together, our study provides a comprehensive resource that is instrumental to demarcate regional cholestatic injury.
2022-12-02 | GSE219169 | 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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2015-03-19 | BIOMD0000000568 | BioModels
Project description:The recovery of liver mass is mainly mediated by proliferation and enlargement of hepatocytes after partial hepatectomy. Studying the gene expression profiles of hepatocytes after partial hepatectomy will be helpful in exploring the mechanism of liver regeneration. We used microarrays to further highlight the regulatory role of hepatocyte in liver regeneration at gene transcription level.
2014-02-28 | GSE55434 | GEO
Project description:The recovery of liver mass is mainly mediated by proliferation and enlargement of hepatocytes after partial hepatectomy. Studying the gene expression profiles of hepatocytes after partial hepatectomy will be helpful in exploring the mechanism of liver regeneration. We used microarrays to further highlight the regulatory role of hepatocyte in liver regeneration at gene transcription level. Rat liver regeneration after partial hepatectomy (PH) is a good model to study the regulation of cell proliferation. We isolated hepatocytes from regenerating liver at 9 time points (2, 6, 12,24, 30, 36, 72, 120, and 168h) after PH and measured gene expression profiles of hepatocytes from 2h to 168h with rat Genome 230 2.0 gene chip. Each sample corresponding to one time point was hybridized onto one array. The experiment was repeated 3 times for each time point. In total, 10 time points were measured and 0h was used control group. After careful quality control analyses of each chip, Affymetrix GCOS 2.0 software was used to analyze the data. The relevance of gene expression profiles and biological processes was analyzed by bioinformatics and systems biology.
2014-02-28 | E-GEOD-55434 | biostudies-arrayexpress