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Transcriptomics of mouse hepatocyte maturation and human hepatic reprogramming

ABSTRACT: Here, we chemically induced liver progenitor cells (CLiPs) from mouse hepatocytes using a previously established protocol. To identify central protein kinases (PKs) that potentially promote the maturation of lpc-Hep cells, we profiled the transcriptomes and phosphoproteomes of freshly isolated primary mouse hepatocytes (MHs) and ALBUMIN+ hepatocytes (CLiP-Heps) cells. Based on the algorithm developed by us and experiment verification, we validated three PKs that promote mouse hepatocyte maturation. Then, we use RNA sequencing technology to identify potential regulators during hepatic reprogramming with samples from HDFs 2.25 days (FHH-2.25d) and 5 days (FHH-5d) after FOXA3, HNF1A, and HNF4A (FHH) transduction, as well as HDFs transduced with GFP for 2.25 days (GFP) as the control group. After combined analysis with phosphoproteomic data with the algorithm and experiment verification, we identified 2 PKs that may be involved in hepatic reprogramming regulation. One of the five potential regulator candidates is PIM1, which can promote the progress remarkably with overexpression. Therefore, we next perform another RNA-seq to drive the molecular mechanisms under undergoing the regulation by PIM1. Finally, we revealed that cell cycle and ferroptosis pathways are involved in the regulation via PIM1.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE169702 | GEO | 2022/08/06

REPOSITORIES: GEO

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Phosphoproteome and proteome of mouse hepatocyte maturation and human hepatic reprogramming

Project description:To identify central protein kinases that potentially promote the maturation, we chemically induced liver progenitor cells (CLiPs) from mouse hepatocytes using a previously established protocol, and profiled the phosphoproteome and proteome of freshly isolated primary mouse hepatocytes (MHs) and ALBUMIN+ hepatocytes (CLiP-Hep) cells. To systematically interrogate the early regulatory events of hepatic reprogramming, we profiled the Phosphoproteome and proteome in human dermal fibroblasts (HDFs) at 2.25 days (FHH-2.25d) and 5 days (FHH-5d) after infection of lenti-virus encoding three liver-specific transcription factors, FOXA3, HNF1A and HNF4A (FHH). In this analysis, HDF infected with lenti-virus expressing GFP for 2.25 days (GFP) were used as control.

2022-08-05 | PXD035829 | iProX

Loss of Pim1 Imposes a Hyperadhesive Phenotype on Endothelial Cells

Project description:Background: PIM1 is a constitutively active serine-threonine kinase regulating cell survival and proliferation. Increased PIM1 expression has been correlated with cancer metastasis by facilitating migration and anti-adhesion. Endothelial cells play a pivotal role in these processes by contributing a barrier to the blood stream. Here, we investigated whether PIM1 regulates mouse aortic endothelial cell (MAEC) monolayer integrity. Methods: Pim1-/-MAEC were isolated from Pim1 knockout mice and used in trypsinization-, wound closure assays, electrical cell-substrate sensing, immunostaining, cDNA transfection and as RNA source for microarray analysis. Results: Pim1-/-MAEC displayed decreased migration, slowed cell detachment and increased electrical resistance across the endothelial monolayer. Reintroduction of Pim1- cDNA into Pim1-/-MAEC significantly restored wildtype adhesive characteristics. Pim1-/--MAEC displayed enhanced focal adhesion and adherens junction structures containing vinculin and M-NM-2-catenin, respectively. Junctional molecules such as Cadherin 13 and matrix components such as Collagen 6a3 were highly upregulated in Pim1-/- cells. Intriguingly, extracellular matrix deposited by Pim1-/- cells alone was sufficient to induce the hyperadhesive phenotype in wildtype endothelial cells. Conclusion: Loss of Pim1 induces a strong adhesive phenotype by enhancing endothelial cell-cell and cell-matrix adhesion by the deposition of a specific extracellular matrix. Targeting PIM1 function therefore might be important to promote endothelial barrier integrity. Pim-1-/- mouse aortic endothelial cells were compared to wildtype cells

2012-10-29 | E-GEOD-32059 | biostudies-arrayexpress

Genome-wide analysis of perinatal effect of nitric oxide (NO) donor molsidomine on the kidneys of Fawn-Hooded Hypertensive (FHH) rats at different ages

Project description:Microarray was performed on kidneys in molsidomine-treated FHH rats in order to gain understanding why perinatal treatment with molsidomine in FHH was beneficial in FHH offspring (e.g. lower blood pressure and less renal damage)

2011-07-01 | GSE27725 | GEO

Loss of Pim1 Imposes a Hyperadhesive Phenotype on Endothelial Cells

Project description:Background: PIM1 is a constitutively active serine-threonine kinase regulating cell survival and proliferation. Increased PIM1 expression has been correlated with cancer metastasis by facilitating migration and anti-adhesion. Endothelial cells play a pivotal role in these processes by contributing a barrier to the blood stream. Here, we investigated whether PIM1 regulates mouse aortic endothelial cell (MAEC) monolayer integrity. Methods: Pim1-/-MAEC were isolated from Pim1 knockout mice and used in trypsinization-, wound closure assays, electrical cell-substrate sensing, immunostaining, cDNA transfection and as RNA source for microarray analysis. Results: Pim1-/-MAEC displayed decreased migration, slowed cell detachment and increased electrical resistance across the endothelial monolayer. Reintroduction of Pim1- cDNA into Pim1-/-MAEC significantly restored wildtype adhesive characteristics. Pim1-/--MAEC displayed enhanced focal adhesion and adherens junction structures containing vinculin and β-catenin, respectively. Junctional molecules such as Cadherin 13 and matrix components such as Collagen 6a3 were highly upregulated in Pim1-/- cells. Intriguingly, extracellular matrix deposited by Pim1-/- cells alone was sufficient to induce the hyperadhesive phenotype in wildtype endothelial cells. Conclusion: Loss of Pim1 induces a strong adhesive phenotype by enhancing endothelial cell-cell and cell-matrix adhesion by the deposition of a specific extracellular matrix. Targeting PIM1 function therefore might be important to promote endothelial barrier integrity.

2012-10-29 | GSE32059 | GEO

Comparative transcriptional analysis of lung fibroblasts from young and aged mice identifies PIM1/NFATc1 axis as a driver of persistent fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by the accumulation of myofibroblasts leading to the progressive scarring of the lung. To identify transcriptional gene programs driving persistent fibrosis in aged lungs, we performed a comparative RNA-seq analysis of fibroblasts freshly isolated from young and aged mouse lungs 30 days post-bleomycin injury. We discovered that lung fibroblasts isolated from young animals at this time point post-injury were transcriptionally similar to those isolated from uninjured mice. In contrast, aged lung fibroblasts isolated at the same time point exhibited a sustained pro-fibrotic state characterized by the elevated expression of genes implicated in inflammation, extracellular matrix remodeling, and cell survival. We identified the protein kinase pro-viral integration site of Moloney murine leukemia virus 1 (PIM1) and its direct target Nuclear Factor of Activated T Cells-1 (NFATc1) as putative drivers of the sustained profibrotic gene signatures observed in aged lung fibroblasts post-injury. PIM1 and NFATc1 transcripts were highly enriched in a pathogenic fibroblast population recently discovered in IPF lungs, and their protein expression was detected in fibroblastic foci. Overexpression of PIM1 in normal human lung fibroblasts potentiated their fibrogenic activation and this effect was dependent on NFATc1. Pharmacological inhibition of PIM1 in IPF-derived lung fibroblasts attenuated their activation and sensitized them to apoptotic stimuli. Finally, inhibition of PIM1 strongly reduced the expression of ECM remodeling and pro-survival genes and blocked the secretion of collagen in IPF lung explants ex vivo. Targeting PIM1/NFATc1 axis in pathogenic lung fibroblasts may represent a therapeutic strategy to limit their activation and promote fibrosis resolution in IPF.

2022-01-01 | GSE191208 | GEO

ER71/ETV2-mediated direct reprogramming of human dermal fibroblasts (HDFs) into endothelial-like cells

Project description:Samples 1-6: HDFs transduced with ER71/ETV2 were sorted on KDR expression at day 7. The isolated KDR+ cells together with human umbilical venous endothelial cells (HUVECs) and untransduced HDFs were subjected to genomic gene expression profiling. A significant number of genes related with vessel development and angiogenesis was significantly upregulated in KDR+ cells, compared to control HDFs. These findings strongly argue that ER71/ETV2 directly reprograms human fibroblasts to functional endothelial-like cells, which could be useful for disease investigation as well as autologous cell therapy. Samples 7-12: HDFs transduced with ER71/ETV2 were sorted on KDR expression at day 7. The isolated KDR+ cells were further cultured up to day 93. The further cultured cells together with human umbilical venous endothelial cells (HUVECs) and untransduced HDFs were subjected to genomic gene expression profiling. A significant number of genes related with vessel development and angiogenesis was significantly upregulated in the further cultured cells, compared to control HDFs. These findings strongly argue that ER71/ETV2 directly reprograms human fibroblasts to functional endothelial-like cells, which could be useful for disease investigation as well as autologous cell therapy. Samples 1-6: HDFs transduced with ER71/ETV2 were sorted on KDR expression at day 7. The isolated KDR+ cells together with human umbilical venous endothelial cells (HUVECs) and untransduced HDFs were subjected to genomic gene expression profiling. Samples 7-12: HDFs transduced with ER71/ETV2 were sorted on KDR expression at day 7. The isolated KDR+ cells were further cultured up to day 93. The further cultured cells together with human umbilical venous endothelial cells (HUVECs) and untransduced HDFs were subjected to genomic gene expression profiling.

2013-09-12 | E-GEOD-50801 | biostudies-arrayexpress

scATAC-seq of human dermal fibroblasts reprogrammed with MGT

Project description:scATAC-seq experiments were performed with control (untreated) HDFs, MGT_siControl HDFs, and MGT_siAJSZ HDFs.

2021-09-01 | GSE183121 | GEO

Colibactin causes genomic instability and promotes Wnt independence in primary colon epithelial cells

Project description:Colorectal cancer is driven by a sequential cascade of mutations known as the adenoma-carcinoma sequence. Recent studies have revealed that specific bacterial species present in the colonic microbiota can induce mutations and contribute to this malignancy. Specifically, genotoxic colibactin-producing pks+ Escherichia coli strains can induce DNA double strand breaks (DSBs) and promote tumor development in mouse models of colorectal cancer. Here, we investigated the transformation potential of colibactin by using organoids and polarized monolayers derived from primary murine colon epithelial cells and reveal striking phenotypic changes upon short-term infection. This study demonstrates the direct pro-oncogenic potential of pks+ E. coli, as such transformations in vivo could facilitate colitis-associated colorectal carcinogenesis.

2020-12-03 | GSE140929 | GEO

Proteomic analysis after chronic exposure to 3 different low-dose of IR

Project description:Research describing alteration of Medaka proteome after chronic exposure (190 days) to low-doses (2.25, 21.01 or 204.3 mGy/day) ionizing radiation analyzing the whole-body.

2021-08-10 | PXD025741 | JPOST Repository

Short-term mucosal disruption enables colibactin-producing E. coli to cause long-term perturbation of colonic homeostasis

Project description:Colibactin, a bacterial genotoxin produced by E. coli harboring the pks genomic island, induces cytopathic effects such as DNA breaks, cell cycle arrest and apoptosis. Patients with a colonic dysfunction due to inflammatory bowel disease such as ulcerative colitis have an elevated likelihood of carrying pks+ E. coli in their colon microbiota but it is not clear whether and how they contribute to the pathogenesis of colitis. Using a gnotobiotic mouse model, we show that pks+ E. coli do not affect colonic integrity under homeostatic conditions, with the microbiota remaining separated from the epithelium by a mucus barrier. However, upon chemical disruption of this barrier by DSS, the microbes gain direct access to the epithelium, causing severe epithelial injury, and development of colitis, while mice colonized with an isogenic ΔclbR mutant incapable of producing colibactin suffer significantly less pronounced effects. While ΔclbR-colonized animals show efficient recovery of the mucus barrier and crypt homeostasis, recovery in WT-colonized mice is impaired. Instead, the mucosa remains in a chronic regenerative state characterized by high proliferation and impaired differentiation of enterocytes and goblet cells, preventing the re-establishment of a functional barrier. In turn, pks+ E. coli remain in direct contact with the epithelium, perpetuating the process and triggering chronic mucosal inflammation that morphologically and transcriptionally resembles human ulcerative colitis. It is characterized by high levels of stromal R-spondin 3. Genetic overexpression of R-spondin 3 in colon myofibroblasts is sufficient to mimic this chronic regenerative state, resulting in barrier disruption and expansion of E. coli. Together, our data reveal that pks+ E. coli are pathobionts that upon contact with the epithelium promote severe injury and interfere with recovery, initiating chronic tissue dysfunction and inflammation.

2023-07-10 | GSE205403 | GEO

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