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Hepatology (Baltimore, Md.) Mar 2021Hepatocytes undergo profound metabolic rewiring when primed to proliferate during compensatory regeneration and in hepatocellular carcinoma (HCC). However, the metabolic...
BACKGROUND AND AIMS
Hepatocytes undergo profound metabolic rewiring when primed to proliferate during compensatory regeneration and in hepatocellular carcinoma (HCC). However, the metabolic control of these processes is not fully understood. In order to capture the metabolic signature of proliferating hepatocytes, we applied state-of-the-art systems biology approaches to models of liver regeneration, pharmacologically and genetically activated cell proliferation, and HCC.
APPROACH AND RESULTS
Integrating metabolomics, lipidomics, and transcriptomics, we link changes in the lipidome of proliferating hepatocytes to altered metabolic pathways including lipogenesis, fatty acid desaturation, and generation of phosphatidylcholine (PC). We confirm this altered lipid signature in human HCC and show a positive correlation of monounsaturated PC with hallmarks of cell proliferation and hepatic carcinogenesis.
CONCLUSIONS
Overall, we demonstrate that specific lipid metabolic pathways are coherently altered when hepatocytes switch to proliferation. These represent a source of targets for the development of therapeutic strategies and prognostic biomarkers of HCC.
Topics: Animals; Carcinoma, Hepatocellular; Cell Proliferation; Gene Expression Profiling; Hepatocytes; Humans; Lipid Metabolism; Lipidomics; Lipogenesis; Liver Neoplasms; Male; Metabolic Networks and Pathways; Metabolomics; Mice; Mice, Inbred C57BL
PubMed: 32460431
DOI: 10.1002/hep.31391 -
Der Pathologe Feb 2021Organizing pneumonia (OP) describes a histological pattern of acute or subacute lung damage. Clinically, patients present with cough, fever, and dyspnea. A distinction... (Review)
Review
Organizing pneumonia (OP) describes a histological pattern of acute or subacute lung damage. Clinically, patients present with cough, fever, and dyspnea. A distinction is made between idiopathic or cryptogenic organizing pneumonia (COP) and secondary organizing pneumonia (OP). In COP, neither clinical/radiological nor histological causes can be determined. It is classified as an interstitial idiopathic pneumonia (IIP) according to the criteria of the American Thoracic Society (ATS) and the European Respiratory Society (ERS). Secondary organizing pneumonia has a known triggering mechanism, such as infectious agents, certain medications, or concomitant symptoms of other primary pulmonary diseases and diseases of other organ systems. Common to both forms is the histological picture of intra-alveolar mesenchymal buds. These are myofibroblast proliferates that branch out along the alveolar spaces. They are usually accompanied by a moderate interstitial and alveolar, chronic, and macrophage-rich inflammatory cell infiltrate. The most important differential diagnosis is common interstitial pneumonia (UIP). It also shows fibroblast proliferates, which are, however, located in the interstitium. The correct classification of an IIP as a COP by means of clinical, radiological, and histological findings is essential, since the COP, in contrast to the UIP, responds very well to corticosteroids and therefore has an excellent prognosis compared to the UIP. The course of secondary organizing pneumonia depends on the respective underlying disease. Here it is important for the pathologist to correctly identify potential accompanying histological characteristics in order to be able to provide clues to a possible cause of OP.
Topics: Cryptogenic Organizing Pneumonia; Humans; Lung; Lung Diseases, Interstitial; Pneumonia; Prognosis
PubMed: 33462627
DOI: 10.1007/s00292-020-00903-8 -
Current Cancer Drug Targets 2020Targeting highly proliferating cells is an important issue for many types of aggressive tumors. Proliferating Cell Nuclear Antigen (PCNA) is an essential protein that... (Review)
Review
Targeting highly proliferating cells is an important issue for many types of aggressive tumors. Proliferating Cell Nuclear Antigen (PCNA) is an essential protein that participates in a variety of processes of DNA metabolism, including DNA replication and repair, chromatin organization and transcription and sister chromatid cohesion. In addition, PCNA is involved in cell survival, and possibly in pathways of energy metabolism, such as glycolysis. Thus, the possibility of targeting this protein for chemotherapy against highly proliferating malignancies is under active investigation. Currently, approaches to treat cells with agents targeting PCNA rely on the use of small molecules or on peptides that either bind to PCNA, or act as a competitor of interacting partners. Here, we describe the status of the art in the development of agents targeting PCNA and discuss their application in different types of tumor cell lines and in animal model systems.
Topics: Animals; Antineoplastic Agents; Aptamers, Nucleotide; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Humans; Molecular Targeted Therapy; Neoplasms; Peptides; Proliferating Cell Nuclear Antigen; Small Molecule Libraries
PubMed: 31951183
DOI: 10.2174/1568009620666200115162814 -
Nature Immunology May 2023Resident tissue macrophages (RTMs) are differentiated immune cells that populate distinct niches and exert important tissue-supportive functions. RTM maintenance is...
Resident tissue macrophages (RTMs) are differentiated immune cells that populate distinct niches and exert important tissue-supportive functions. RTM maintenance is thought to rely either on differentiation from monocytes or on RTM self-renewal. Here, we used a mouse model of inducible lung interstitial macrophage (IM) niche depletion and refilling to investigate the development of IMs in vivo. Using time-course single-cell RNA-sequencing analyses, bone marrow chimeras and gene targeting, we found that engrafted Ly6C classical monocytes proliferated locally in a Csf1 receptor-dependent manner before differentiating into IMs. The transition from monocyte proliferation toward IM subset specification was controlled by the transcription factor MafB, while c-Maf specifically regulated the identity of the CD206 IM subset. Our data provide evidence that, in the mononuclear phagocyte system, the ability to proliferate is not merely restricted to myeloid progenitor cells and mature RTMs but is also a tightly regulated capability of monocytes developing into RTMs in vivo.
Topics: Animals; Mice; Monocytes; Macrophages; Cell Differentiation; Lung; Cell Proliferation; MafB Transcription Factor
PubMed: 36928411
DOI: 10.1038/s41590-023-01468-3 -
Immunity Feb 2022T follicular helper (Tfh) cells are defined by a Bcl6CXCR5PD-1 phenotype, but only a minor fraction of these reside in germinal centers (GCs). Here, we examined whether...
T follicular helper (Tfh) cells are defined by a Bcl6CXCR5PD-1 phenotype, but only a minor fraction of these reside in germinal centers (GCs). Here, we examined whether GC-resident and -nonresident Tfh cells share a common physiology and function. Fluorescently labeled, GC-resident Tfh cells in different mouse models were distinguished by low expression of CD90. CD90 GCTfh cells required antigen-specific, MHCII B cells to develop and stopped proliferating soon after differentiation. In contrast, nonresident, CD90 Tfh (GCTfh-like) cells developed normally in the absence of MHCII B cells and proliferated continuously during primary responses. The TCR repertoires of both Tfh subsets overlapped initially but later diverged in association with dendritic cell-dependent proliferation of CD90 GCTfh-like cells, suggestive of TCR-dependency seen also in TCR-transgenic adoptive transfer experiments. Furthermore, the transcriptomes of CD90 and CD90 GCTfh-like cells were enriched in different functional pathways. Thus, GC-resident and nonresident Tfh cells have distinct developmental requirements and activities, implying distinct functions.
Topics: Animals; B-Lymphocytes; Cell Communication; Cell Differentiation; Cell Proliferation; Dendritic Cells; Gene Expression Profiling; Germinal Center; Histocompatibility Antigens Class II; Mice; Programmed Cell Death 1 Receptor; Receptors, Antigen, T-Cell; Receptors, CXCR5; Sphingosine-1-Phosphate Receptors; T Follicular Helper Cells; T-Lymphocyte Subsets; Thy-1 Antigens
PubMed: 35081372
DOI: 10.1016/j.immuni.2021.12.015 -
Environmental Microbiology Nov 2022Methanonatronarchaeia represents a deep-branching phylogenetic lineage of extremely halo(alkali)philic and moderately thermophilic methyl-reducing methanogens belonging...
Methanonatronarchaeia represents a deep-branching phylogenetic lineage of extremely halo(alkali)philic and moderately thermophilic methyl-reducing methanogens belonging to the phylum Halobacteriota. It includes two genera, the alkaliphilic Methanonatronarchaeum and the neutrophilic Ca. Methanohalarchaeum. The former is represented by multiple closely related pure culture isolates from hypersaline soda lakes, while the knowledge about the latter is limited to a few mixed cultures with anaerobic haloarchaea. To get more insight into the distribution and ecophysiology of this enigmatic group of extremophilic methanogens, potential activity tests and enrichment cultivation with different substrates and at different conditions were performed with anaerobic sediment slurries from various hypersaline lakes in Russia. Methanonatronarchaeum proliferated exclusively in hypersaline soda lake samples mostly at elevated temperature, while at mesophilic conditions it coexisted with the extremely salt-tolerant methylotroph Methanosalsum natronophilum. Methanonatronarchaeum was also able to serve as a methylotrophic or hydrogenotrophic partner in several thermophilic enrichment cultures with fermentative bacteria. Ca. Methanohalarchaeum did not proliferate at mesophilic conditions and at thermophilic conditions it competed with extremely halophilic and moderately thermophilic methylotroph Methanohalobium, which it outcompeted at a combination of elevated temperature and methyl-reducing conditions. Overall, the results demonstrated that Methanonatronarchaeia are specialized extremophiles specifically proliferating in conditions of elevated temperature coupled with extreme salinity and simultaneous availability of a wide range of C -methylated compounds and H /formate.
Topics: Phylogeny; Euryarchaeota; Methanosarcinaceae; Lakes; Salinity; RNA, Ribosomal, 16S
PubMed: 35726892
DOI: 10.1111/1462-2920.16108 -
Circulation Research Jun 2020The adult human heart is an organ with low regenerative potential. Heart failure following acute myocardial infarction is a leading cause of death due to the inability...
RATIONALE
The adult human heart is an organ with low regenerative potential. Heart failure following acute myocardial infarction is a leading cause of death due to the inability of cardiomyocytes to proliferate and replenish lost cardiac muscle. While the zebrafish has emerged as a powerful model to study endogenous cardiac regeneration, the molecular mechanisms by which cardiomyocytes respond to damage by disassembling sarcomeres, proliferating, and repopulating the injured area remain unclear. Furthermore, we are far from understanding the regulation of the chromatin landscape and epigenetic barriers that must be overcome for cardiac regeneration to occur.
OBJECTIVE
To identify transcription factor regulators of the chromatin landscape, which promote cardiomyocyte regeneration in zebrafish, and investigate their function.
METHODS AND RESULTS
Using the Assay for Transposase-Accessible Chromatin coupled to high-throughput sequencing (ATAC-Seq), we first find that the regenerating cardiomyocyte chromatin accessibility landscape undergoes extensive changes following cryoinjury, and that activator protein-1 (AP-1) binding sites are the most highly enriched motifs in regions that gain accessibility during cardiac regeneration. Furthermore, using bioinformatic and gene expression analyses, we find that the AP-1 response in regenerating adult zebrafish cardiomyocytes is largely different from the response in adult mammalian cardiomyocytes. Using a cardiomyocyte-specific dominant negative approach, we show that blocking AP-1 function leads to defects in cardiomyocyte proliferation as well as decreased chromatin accessibility at the and loci, which regulate sarcomere disassembly and cardiomyocyte protrusion into the injured area, respectively. We further show that overexpression of the family members and can promote changes in mammalian cardiomyocyte behavior in vitro.
CONCLUSIONS
AP-1 transcription factors play an essential role in the cardiomyocyte response to injury by regulating chromatin accessibility changes, thereby allowing the activation of gene expression programs that promote cardiomyocyte dedifferentiation, proliferation, and protrusion into the injured area.
Topics: Animals; Cells, Cultured; Chromatin; Myocytes, Cardiac; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Regeneration; Sarcomeres; Transcription Factor AP-1; Zebrafish; Zebrafish Proteins
PubMed: 32312172
DOI: 10.1161/CIRCRESAHA.119.316167 -
The Journal of Allergy and Clinical... Jun 2022Mast cells (MCs) are pleiotropic cells that accumulate in the esophagus of patients with eosinophilic esophagitis (EoE) and are thought to contribute to disease...
BACKGROUND
Mast cells (MCs) are pleiotropic cells that accumulate in the esophagus of patients with eosinophilic esophagitis (EoE) and are thought to contribute to disease pathogenesis, yet their properties and functions in this organ are largely unknown.
OBJECTIVES
This study aimed to perform a comprehensive molecular and spatial characterization of esophageal MCs in EoE.
METHODS
Esophageal biopsies obtained from patients with active EoE, patients with EoE in histologic remission, and individuals with histologically normal esophageal biopsies and no history of esophageal disease (ie, control individuals) were subject to single-cell RNA sequencing, flow cytometry, and immunofluorescence analyses.
RESULTS
This study probed 39,562 single esophageal cells by single-cell RNA sequencing; approximately 5% of these cells were MCs. Dynamic MC expansion was identified across disease states. During homeostasis, TPSAB1AREG resident MCs were mainly detected in the lamina propria and exhibited a quiescent phenotype. In patients with active EoE, resident MCs assumed an activated phenotype, and 2 additional proinflammatory MC populations emerged in the intraepithelial compartment, each linked to a proliferating MKI67 cluster. One proinflammatory activated MC population, marked as KITIL1RL1FCER1A, was not detected in disease remission (termed "transient MC"), whereas the other population, marked as CMA1CTSG, was detected in disease remission where it maintained an activated state (termed "persistent MC"). MCs were prominent producers of esophageal IL-13 mRNA and protein, a key therapeutic target in EoE.
CONCLUSIONS
Esophageal MCs comprise heterogeneous populations with transcriptional signatures associated with distinct spatial compartmentalization and EoE disease status. In active EoE, they assume a proinflammatory state and locally proliferate, and they remain activated and poised to reinitiate inflammation even during disease remission.
Topics: Cell Proliferation; Eosinophilic Esophagitis; Humans; Mast Cells; Sequence Analysis, RNA
PubMed: 35304158
DOI: 10.1016/j.jaci.2022.02.025 -
Journal of Leukocyte Biology Nov 2023Monocytes (Mo) and macrophages (Mφ) play important roles in the function of tissues, organs, and systems of all animals during homeostasis, infection, injury, and... (Review)
Review
Monocytes (Mo) and macrophages (Mφ) play important roles in the function of tissues, organs, and systems of all animals during homeostasis, infection, injury, and disease. For decades, conventional wisdom has dictated that Mo and Mφ are end-stage cells that do not proliferate and that Mφ accumulation in tissues is the result of infiltration of Mo from the blood and subsequent differentiation to Mφ. However, reports from the early 1900s to the present describe evidence of Mo and Mφ proliferation in different tissues and contexts. The purpose of this review is to summarize both historical and current evidence for the contribution of Mφ proliferation to their accumulation in different tissues during homeostasis, infection, injury, and disease. Mφ proliferate in different organs and tissues, including skin, peritoneum, lung, heart, aorta, kidney, liver, pancreas, brain, spinal cord, eye, adipose tissue, and uterus, and in different species including mouse, rat, rabbit, and human. Mφ can proliferate at different stages of differentiation with infiltrating Mo-like cells proliferating in certain inflammatory contexts (e.g. skin wounding, kidney injury, bladder and liver infection) and mature resident Mφ proliferating in other inflammatory contexts (e.g. nematode infection, acetaminophen liver injury) and during homeostasis. The pathways involved in stimulating Mφ proliferation also may be context dependent, with different cytokines and transcription factors implicated in different studies. Although Mφ are known to proliferate in health, injury, and disease, much remains to be learned about the regulation of Mφ proliferation in different contexts and its impact on the homeostasis, injury, and repair of different organs and tissues.
Topics: Humans; Female; Mice; Rats; Animals; Rabbits; Monocytes; Macrophages; Cytokines; Homeostasis; Cell Proliferation
PubMed: 37555460
DOI: 10.1093/jleuko/qiad093