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PubMed2026

The role of transposable elements-endogenous retroviruses in embryonic development and regeneration.

Endogenous retroviruses (ERVs) are dynamically regulated across the lifespan and can function as context-dependent components of host gene-regulatory networks. During embryonic development, selected ERV-derived elements are co-opted to support zygotic genome activation, lineage specification, and placental development. In adult tissues, ERV-derived sequences can contribute to tissue and immune homeostasis, whereas potentially disruptive ERV activity is constrained by epigenetic mechanisms. During regeneration and somatic cell reprogramming, ERV and broader transposable-element programs undergo transient, locus-specific remodeling. In aging, the weakening of epigenetic and nuclear restraint can promote aberrant ERV derepression, inflammation, and functional decline. This review summarizes the diverse roles of ERVs across these contexts and discusses the challenges of defining locus-specific functions, resolving repetitive sequences, and developing safe ERV-targeted interventions.

Endogenous Retroviruses↗
PubMed2026

Loss of the Mechanistic Target of Rapamycin Complex 1 Causes a Lethal Alpha-1 Antitrypsin Deficiency-Associated Liver Disease.

BACKGROUND & AIMS: SERPINA1 mutations cause retention of the otherwise secreted alpha-1 antitrypsin and lead to the proteotoxic alpha-1 antitrypsin deficiency-related liver disease. As mechanistic target of rapamycin is a key coordinator of proteostasis, we studied its role in alpha-1 antitrypsin deficiency-related liver disease. METHODS: PiZ mice overexpressing the characteristic SERPINA1 mutation were mated with rodents harboring a hepatocyte specific-ablation of the interaction partners regulatory-associated protein of mechanistic target of rapamycin or rapamycin-insensitive companion of mammalian target of rapamycin, corresponding to mechanistic target of rapamycin complexes 1 or 2, or with mice lacking mechanistic target of rapamycin. Serum proteomics, liver bulk proteomics, spatial proteomics, and metabolomics were applied to characterize molecular and metabolic alterations. RESULTS: At 2 months of age, PiZ-mTORΔhep and PiZ-RaptorΔhep but not PiZ-RictorΔhep mice showed signs of increased liver injury and mortality despite diminished hepatic alpha-1 antitrypsin accumulation. PiZ-RaptorΔhep animals displayed increased levels of the proapoptotic protein C/EBP homologous protein, but C/EBP homologous protein ablation did not rescue the phenotype. Serum proteomics revealed no signs of advanced synthetic liver failure but immature hepatocellular products. Liver bulk proteomics and small metabolite measurement demonstrated a metabolic reprogramming of PiZ-RaptorΔhep mice. Spatial proteomics revealed alterations in liver zonation with increased ammonia levels as the likely cause of death in PiZ-RaptorΔhep animals. CONCLUSIONS: In summary, in alpha-1 antitrypsin deficiency-related proteotoxic liver injury, regulatory-associated protein of mechanistic target of rapamycin preserves a liver zonation, thereby protecting from lethal metabolic dysregulation.

Animals↗
PubMed2026

Feeding the epigenome: EZH2 as a metabolic integrator of cell fate in development and cancer.

Epigenetic regulation is intimately linked to cellular metabolism, enabling environmental and nutritional cues to shape gene expression programs through dynamic modifications of chromatin structure. This metabolism-epigenetics interface is mediated, in part, by the dependence of chromatin-modifying enzymes on key metabolites, including S-adenosylmethionine (SAM), acetyl-CoA, UDP-GlcNAc, and α-ketoglutarate, which serve as substrates or cofactors for DNA and histone modifications. Among these regulators, EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), has emerged as a key mediator linking metabolic state to epigenetic regulation by translating metabolic inputs into changes in chromatin architecture and gene expression. EZH2 governs developmental cell fate through H3K27me3-mediated gene repression and is frequently dysregulated in cancer, where it promotes dedifferentiation, tumor progression, and metabolic reprogramming. Importantly, EZH2 activity is itself modulated by cellular metabolic status through posttranslational modifications, including phosphorylation, acetylation, methylation, ubiquitination, and O-GlcNAcylation, which influence its stability, catalytic activity, and chromatin-binding capacity. These modifications are responsive to nutrient availability and signaling pathways involving glucose, SAM, NAD+, and other metabolic intermediates. Consequently, disruption of this finely tuned regulatory network can contribute to developmental abnormalities, metabolic dysfunction, and oncogenesis. In this review, we examine the molecular mechanisms governing EZH2 regulation and discuss how metabolic control of EZH2 shapes chromatin dynamics, cell fate decisions, and disease pathogenesis. Elucidating how metabolic signals modulate EZH2 activity will advance our understanding of development and disease while uncovering potential therapeutic opportunities to target metabolism-driven epigenetic dysregulation.

Humans↗
PubMed2025

Exogenous BMI1 expression aggravates oral squamous cell carcinomas in tongue epithelia.

Oral squamous cell carcinoma (OSCC) is characterized by aggressiveness and a poor prognosis, in part because most patients are diagnosed during the later stages of the disease. B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), part of polycomb repressive complex 1 (PRC1), is a key transcription factor overexpressed in OSCC. Although increased BMI1 has been linked to tumor formation in mouse models of the disease, the molecular mechanisms have not been elucidated. Here we used a transgenic mouse line (KrTB) that selectively overexpresses BMI1 in the tongue basal epithelial stem cells (SCs) to delineate BMI1 actions during oral tumorigenesis. By tumor pathological classification after 4-nitroquinoline 1-oxide (4-NQO)-induced carcinogenesis we detected more severe tumors in mice with ectopic BMI1 expression. Genome-wide transcriptomics indicated that mRNAs associated with human OSCC, including SOX9, HIF1A, MMP9, INHBB, and MYOF, were further increased by ectopic BMI1 expression in murine tongue epithelia. mRNAs encoding multiple metabolic targets, such as SLC2A1 (GLUT1), PKM, LDHA, and HK2, were also increased upon BMI1 overexpression in 4-NQO-treated tongue epithelia. Furthermore, we detected BMI1, SOX9, and GLUT1 proteins in the infiltrating cells of invasion fronts identified by markers of invasive SCCs. Finally, metabolomic data show that BMI1 overexpression in tongue epithelia promotes glycolysis during 4-NQO-induced carcinogenesis. Thus, our data demonstrate that BMI1 causes OSCC cells to alter cell metabolism, as changes in many of these transcripts are linked to increased glycolysis and metabolic reprograming that occurs during carcinogenesis.

Animals↗
PubMed2026

Spatial profiling of the spleen in mouse and human myelofibrosis reveals complement-driven immune-stromal interactions as a therapeutic target.

Splenomegaly is a defining feature of myelofibrosis, yet the contribution of splenic mesenchymal stroma to disease progression remains unclear. We combined spatial and single-nucleus transcriptomics of patient spleens with spatial and single-cell transcriptomics, as well as imaging analyses, of murine spleens to map extramedullary hematopoiesis niches. Activated red pulp reticular cells localize near hematopoietic stem and progenitor cells, and early disease is characterized by marginal zone disruption with lymphoid depletion preceding stromal remodeling. Trajectory analyses reveal a shift in reticular cells from hematopoiesis-supportive to inflammatory and pro-fibrotic states, driven by macrophage- and megakaryocyte-derived signals that activate complement and induce tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), extracellular matrix, and Thbs1 programs. Non-hematopoietic complement component C3 deficiency or pharmacological C3 inhibition suppresses these pathways, restores splenic architecture, and reduces splenomegaly and bone marrow fibrosis. These findings identify complement-dependent stromal reprogramming as a mechanism governing hematopoietic niches and as a targetable axis in myelofibrosis.

Animals↗
PubMed2026

Multi-omics and experimental validation identify RAPGEF2 as a protective prognostic biomarker in clear cell renal cell carcinoma.

Kidney Renal Clear Cell Carcinoma (KIRC) is characterized by marked molecular heterogeneity and metabolic reprogramming, underscoring the need for reliable biomarkers for prognostic assessment and individualized treatment. RAPGEF2, a guanine nucleotide exchange factor has been implicated in cell adhesion and differentiation, but its role in KIRC remains unclear. In this study, we systematically evaluated the expression pattern, prognostic significance, genomic associations, biological function, and therapeutic relevance of RAPGEF2 in KIRC through integrated multi-omics analyses and experimental validation. Pan-cancer single-cell and Spatial transcriptomic analysis revealed heterogeneous RAPGEF2 expression across tumor types, with a relatively prominent signal in KIRC, where RAPGEF2 was mainly enriched in endothelial cells. Survival analyses in the TCGA-KIRC showed that high RAPGEF2 expression was significantly associated with favorable overall survival, disease-specific survival, and progression-free interval, and these findings were validated in independent ICGC_RECA-EU and E-MTAB-1980 cohorts. Multivariate Cox regression further confirmed RAPGEF2 as an independent protective prognostic factor. Immunohistochemistry in a tissue microarray cohort demonstrated that higher RAPGEF2 protein expression was associated with improved overall survival. Genomic analyses showed that low RAPGEF2 expression was related to higher mutational burden. Functional assays demonstrated that RAPGEF2 knockdown promoted KIRC progression. Enrichment analyses indicated that RAPGEF2 may be associated with metabolic pathway remodeling, while immunotherapy cohort analyses suggested its potential association with therapeutic benefit. Collectively, RAPGEF2 is identified as a protective prognostic biomarker and potential functional regulator in KIRC.

Biomarker↗
PubMed2026

Epigenetic alterations induced by ionizing radiation: pathways to cancer and prognostic strategies.

PURPOSE: Ionizing radiation (IR) is widely used not only in cancer diagnosis and therapy, but its biological effects also extend beyond radiation-induced lethal lesions, e.g., specifically DNA double-strand breaks (DNA-DSBs). This review aims to summarize current evidence on IR-induced epigenetic alterations and to integrate mechanistic insights from radiation chemistry and radiation biology that link DNA damage to long-term epigenetic dysregulation. RESULTS: Experimental and clinical studies collectively show that IR induces persistent epigenetic reprogramming, including global and gene-specific DNA methylation changes, radiation-responsive histone modifications, chromatin remodeling, and dysregulation of non-coding RNAs. Aberrant RNA methylation, including modifications like N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanine (m7G), and N3-methylcytosine (m3C), is closely linked to tumorigenesis and progression. Due to its tumor-specific properties, RNA methylation markers, specifically m6A, m5C, m1A, m7G, and m3C, emerge as valuable markers in liquid biopsy. Radiation chemistry studies indicate that epigenetically modified bases, for example, m5C, are preferential targets of radiation-induced oxidative damage, thereby promoting mutational hotspots and genomic instability. By altering DNA repair, apoptosis, immune responses, and cellular differentiation, these epigenetic changes promote carcinogenesis, radioresistance, and tissue toxicity. CONCLUSION: IR-induced epigenetic alterations represent a critical interface between initial DNA damage and long-term biological outcomes. Improved understanding of radiation-associated epigenetic signatures may enhance risk assessment, inform prognostic stratification, and support the development of epigenetic-targeted strategies to optimize radiotherapy and reduce adverse effects.

Ionizing radiation↗
PubMed2026

Multi-Omics Landscape of Paraspinal Muscles in Spinal Muscular Atrophy With Scoliosis.

Most spinal muscular atrophy (SMA) patients develop severe scoliosis by late adolescence. Given that the paraspinal muscles-particularly the multifidus-are indispensable for maintaining spinal stability, their site-specific multi-omics characteristics in SMA remain insufficiently defined. Herein, integrated multi-omics sequencing was performed on bilateral multifidus samples from SMA patients and surgical controls. We identified 5219 differentially expressed genes, 1063 differentially expressed proteins and 370 differential metabolites between the control and SMA, showing significant enrichment in glucose and amino acid metabolism pathways, specifically key steps of glycolysis/gluconeogenesis. Key enzymes in the glycolytic process such as PFKM, ENO3 and PKM1 were markedly downregulated. Notably, a comparative analysis of the bilateral paraspinal muscles in SMA revealed asymmetrical metabolic signatures in carbohydrate and amino acid processing between the concave and convex sides. Key regulatory enzymes exhibited significant differential expression: PYGL, a central driver of starch and sucrose metabolism; creatine kinase, involved in arginine and proline metabolism; and PGAM2, a key mediator of glycine, serine, and threonine metabolism. These metabolic signatures indicate a complex metabolic reprogramming in the multifidus, where asymmetric disparities point to the influence of mechanical loading, while systemic dysregulation aligns with the effects of SMN depletion.

Humans↗
PubMed2026

Loss of maternal PADI6 disrupts DNA methylation and genomic imprinting maintenance in late preimplantation mouse embryos.

BACKGROUND: The maternal-effect protein PADI6, which is part of the subcortical maternal complex, is involved in proper spindle assembly, organelle distribution, ribosome storage, and cytoplasmic lattice organization in mouse oocytes. In humans, variants of PADI6 are associated with female infertility and multilocus imprinting disturbance in offspring. Recently, it was demonstrated that PADI6 plays a role in the storage and cytoplasmic localization of epigenetic factors, including UHRF1 and DNMT1. Moreover, maternal PADI6 depletion leads to defective epigenetic reprogramming and zygotic genome activation but not to an imprinting defect in two-cell mouse embryos. These findings raise the possibility that imprinting disturbances arise later in development. RESULTS: By employing combined single-blastocyst RNA-seq/BS-seq and immunostaining validation in the embryos derived from Padi6P620A-mutant oocytes, we investigated the role of Padi6 in late preimplantation development. We demonstrated that embryos that overcame the two-cell stage block had a dramatic reduction in UHRF1 and DNMT1 protein levels, a decrease in H3K9me3, and whole-genome hypomethylation, including most imprinted loci and repetitive elements, at the blastocyst stage. Furthermore, these maternal mutant embryos showed deregulation of inner cell mass markers and defective blastocyst implantation, but no effect on trophoblast differentiation. CONCLUSION: Our results demonstrate that maternal PADI6 is a key regulator of the stability of epigenetic factors required to maintain repressive marks in late preimplantation mouse embryos. Its deficiency results in genomic imprinting defects that closely resemble those found in human patients and provide a mechanistic explanation for MLID caused by maternal PADI6 variants. Furthermore, the impairment of blastocyst implantation capacity, likely due to dysregulation of inner cell mass differentiation, provides new mechanistic insights into the control of female fertility and embryo development exerted by PADI6.

DNA Methylation↗
PubMed2025

Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.

"Trained immunity" of innate immune cells occurs through a sequential two-step process where an initial pathogenic or sterile inflammatory trigger is followed by an amplified response to a later un-related secondary pathogen challenge. The memory effect is mediated at least in part through epigenetic modifications of the chromatin landscape. Here, we investigated the role of the epigenetic modifier Setdb2 in microbial (β-glucan) or sterile trigger (Western-diet-WD/oxidized-LDL-oxLDL)-induced trained immunity of macrophages. Using genetic mouse models and genomic analysis, we uncovered a critical role of Setdb2 in regulating proinflammatory and metabolic pathway reprogramming. We further show that Setdb2 regulates trained immunity through two different complementary mechanisms: one where it positively regulates glycolytic and inflammatory pathway genes via enhancer-promoter looping, and is independent of its enzymatic activity; while the second mechanism is associated with both increased promoter associated H3K9 methylation and repression of interferon response pathway genes. Interestingly, while both mechanisms occur in response to pathogenic training, only the chromatin-looping mechanism operates in response to the sterile inflammatory stimulus. These results reveal a previously unknown bifurcation in the downstream pathways that distinguishes between pathogenic and sterile inflammatory signaling responses associated with the innate immune memory response and may provide potential therapeutic opportunities to target cytokine vs. interferon pathways to limit complications of chronic inflammation.

Setdb2↗
PubMed2026

Integrated multi-omics analysis of metabolomics and proteomics uncovers dysregulated amino acid metabolism in HCC metastasis.

BACKGROUND: Metastasis is the primary cause of treatment failure and adverse prognosis in hepatocellular carcinoma (HCC), and the molecular basis of HCC metastasis remains poorly defined. This work investigated the potential mechanisms underlying HCC metastasis through integrated multi-omics analysis of metabolomics and proteomics. METHOD: This retrospective study included 105 individuals with HCC, with comparative analysis between metastatic and non-metastatic cases. We further evaluated the effects of metastasis on serum metabolomics and proteomics in HCC patients. RESULT: Widespread disturbances in amino acid metabolism were identified via untargeted metabolomics in HCC patients with metastasis, closely governing inflammation-related metabolic remodeling and oxidative stress responses. Specifically, we identified 91 and 59 distinct differential metabolites capable of indicating HCC metastasis, with the screening criteria set as log2 fold change > 1.5, adjusted P value < 0.05, and VIP > 1.5 in positive and negative modes, respectively. The alanine, aspartate and glutamate metabolism pathway correlated with HCC-associated lung metastasis, while the gluconeogenesis pathway was linked to HCC-associated bone metastasis. Compared with HCC (non-metastatic hepatocellular carcinoma), the key molecular alterations in the multi-omics network of HCC_M (HCC with metastasis) are implicated in inflammatory metabolic reprogramming, oxidative stress response, gluconeogenesis, glycolysis, and the tricarboxylic acid (TCA) cycle. Twenty-five proteins, including PKM2, PERCK, ALDH2, CPS1, GLS1, GLUD1, GOT1, and SLC38A2, were identified as potential biomarkers for HCC metastasis. CONCLUSION: By integrating untargeted metabolomic and proteomic profiling, we identified distinct metabolic and proteomic changes linked to HCC metastasis. This work also characterized the pathological characteristics and core pathways underlying HCC metastasis, while identifying potential therapeutic candidates.

Humans↗
PubMed2018

Signaling Pathways Regulating Redox Balance in Cancer Metabolism.

The interplay between rewiring tumor metabolism and oncogenic driver mutations is only beginning to be appreciated. Metabolic deregulation has been described for decades as a bystander effect of genomic aberrations. However, for the biology of malignant cells, metabolic reprogramming is essential to tackle a harsh environment, including nutrient deprivation, reactive oxygen species production, and oxygen withdrawal. Besides the well-investigated glycolytic metabolism, it is emerging that several other metabolic fluxes are relevant for tumorigenesis in supporting redox balance, most notably pentose phosphate pathway, folate, and mitochondrial metabolism. The relationship between metabolic rewiring and mutant genes is still unclear and, therefore, we will discuss how metabolic needs and oncogene mutations influence each other to satisfy cancer cells' demands. Mutations in oncogenes, i.e., PI3K/AKT/mTOR, RAS pathway, and MYC, and tumor suppressors, i.e., p53 and liver kinase B1, result in metabolic flexibility and may influence response to therapy. Since metabolic rewiring is shaped by oncogenic driver mutations, understanding how specific alterations in signaling pathways affect different metabolic fluxes will be instrumental for the development of novel targeted therapies. In the era of personalized medicine, the combination of driver mutations, metabolite levels, and tissue of origins will pave the way to innovative therapeutic interventions.

OXPHOS↗
PubMed1996

Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer.

Cells possess within their epigenetic repertoire the ability to undergo an active process of cellular suicide termed programmed (or apoptotic) cell death. This programmed cell death process involves an epigenetic reprogramming of the cell that results in an energy-dependent cascade of biochemical and morphologic changes (also termed apoptosis) within the cell, resulting in its death and elimination. Although the final steps (i.e., DNA and cellular fragmentation) are common to cells undergoing programmed cell death, the activation of this death process is initiated either by sufficient injury to the cell induced by various exogenous damaging agents (e.g., radiation, chemicals, viruses) or by changes in the levels of a series of endogenous signals (e.g., hormones and growth/survival factors). Within the prostate, androgens are capable of both stimulating proliferation as well as inhibiting the rate of the glandular epithelial cell death. Androgen withdrawal triggers the programmed cell death pathway in both normal prostate glandular epithelia and androgen-dependent prostate cancer cells. Androgen-independent prostate cancer cells do not initiate the programmed cell death pathway upon androgen ablation; however, they do retain the cellular machinery necessary to activate the programmed cell death cascade when sufficiently damaged by exogenous agents. In the normal prostate epithelium, cell proliferation is balanced by a equal rate of programmed cell death, such that neither involution nor overgrowth normal occurs. In prostatic cancer, however, this balance is lost, such that there is greater proliferation than death producing continuous net growth. Thus, an imbalance in programmed cell death must occur during prostatic cancer progression. The goal of effective therapy for prostatic cancer, therefore, is to correct this imbalance. Unfortunately, this has not been achieved and metastatic prostatic cancer is still a lethal disease for which no curative therapy is currently available. In order to develop such effective therapy, an understanding of the programmed death pathway, and what controls it, is critical. Thus, a review of the present state of knowledge concerning programmed cell death of normal and malignant prostatic cells will be presented.

Androgens↗
PubMed1998

Mesenchyme specifies epithelial differentiation in reciprocal recombinants of embryonic lung and trachea.

Normal lung morphogenesis and cytodifferentiation require interactions between epithelium and mesenchyme. We have previously shown that distal lung mesenchyme (LgM) is capable of reprogramming tracheal epithelium (TrE) from day 13-14 rat fetuses to branch in a lung-like pattern and express a distal lung epithelial phenotype. In the present study, we have assessed the effects of tracheal mesenchyme (TrM) on branching and cytodifferentiation of distal lung epithelium (LgE). Tracheae and distal lung tips from day 13 rat fetuses were separated into purified epithelial and mesenchymal components, then recombined as homotypic (LgM + LgE or TrM + TrE) or heterotypic (LgM + TrE or TrM + LgE) recombinants and cultured for 5 days; unseparated lung tips and tracheae served as controls. Control lung tips, LgM + LgE, and LgM + TrE recombinants all branched in an identical pattern. Epithelial cells, including those from the induced TrE, contained abundant glycogen deposits and lamellar bodies, and expressed surfactant protein C (SP-C) mRNA. Trachea controls, and both TrM + TrE, and TrM + LgE recombinants did not branch, but instead formed cysts. The epithelium contained ciliated and mucous secretory cells; importantly, no cells containing lamellar bodies were observed, nor was SP-C mRNA detected. Mucin immunostaining showed copious production of mucous in both LgE and TrE when recombined with TrM. These results demonstrate that epithelial differentiation in the recombinants appears to be wholly dependent on the type of mesenchyme used, and that the entire respiratory epithelium has significant plasticity in eventual phenotype at this stage in development.

Animals↗
PubMed1997

Polycystic ovarian condition in the dehydroepiandrosterone-treated rat model: hyperandrogenism and the resumption of meiosis are major initial events associated with cystogenesis of antral follicles.

BACKGROUND: The purpose of this study was to elucidate the early effects of dehydroepiandrosterone (DHEA) in the polycystic rat model by charting cytological changes in the early antral follicle of the ovary and constructing a serum hormonal profile. Histological examinations of ovaries from DHEA-treated rats for ten consecutive days revealed that the oocyte of antral follicles, ranging from 1.5 mm to 3.4 mm in diameter, had become activated, i.e., had resumed meiosis. Tabulation and statistical analysis revealed a highly significant difference in the percentage of oocyte activation between the ovaries of DHEA-treated and control rats. Granulosa cells associated with those antral follicles included in our statistical analysis showed no evidence of atresia. A few follicles not included in our analysis contained oocytes that had resumed meiosis and whose associated granulosa cells were atretic. The observed resumption of meiosis occurred in the absence of surges of follicle stimulating hormone (FSH) and luteinizing hormone (LH). During meiosis, a period when many oocytes become activated, levels of serum androgens (DHEA, testosterone, and androstenedione) were high, while FSH, LH, and prolactin (PRL) levels did not differ significantly from those in the controls. Follicles that resume meiosis may be members of a group of follicles that produces a signal(s) when the oocyte becomes uncoupled from the granulosa cell. This signal(s) permit(s) a reprogramming of the accompanying granulosa cells of the follicle to engage in certain developmental processes of cystogenesis. Just what cascade of signals is necessary to achieve this selection remains elusive at this time and is the subject of our continuing investigations.

Androstenedione↗
PubMed1997

FGF-2 converts mature oligodendrocytes to a novel phenotype.

Fibroblast growth factor (FGF)-2 differentially regulates oligodendrocyte progenitor proliferation and differentiation in culture, and modulates gene expression of its own receptors, in a developmental and receptor type-specific manner (Bansal et al., 1996a,b). Three FGF receptors (types 1, 2, 3) are expressed in postmitotic, terminally differentiating oligodendrocytes. Exposure of such cells to FGF-2 results in: (a) the down-regulation of myelin-specific gene expression (e.g., ceramide galactosyltransferase, 2',3'-cyclic nucleotide 3'-phosphohydrolase, myelin basic protein, proteolipid protein), (b) dramatic increases in the length of cellular processes in a time- and dose-dependent manner, (c) re-entrance into the cell cycle without accompanying mitosis, and (d) the alteration of the expression of both low- and high-affinity FGF receptors. Compared to oligodendrocyte progenitors, the differentiated oligodendrocytes treated with FGF-2 incorporate BrdU at a slower rates, exhibit different patterns of both FGF high- and low-affinity (syndecans) receptors, and are morphologically very different. In addition, they do not re-express the progenitor markers A2B5, NG2 or PDGFalpha receptor. Therefore, although the FGF-treated cells lose their differentiated OL/myelin markers, they do not revert to progenitors and clearly represent a different, apparently novel, phenotype both morphologically and biochemically, which we have termed NOLs. These data indicate that terminally differentiated oligodendrocytes retain the plasticity to reprogram their differentiation fate under the influence of environmental factors. The possible significance of this response to FGF relative to normal and pathological physiology is discussed. In particular, on the basis of these data we predict the appearance of cells in and around multiple sclerosis plaques with the phenotype O4+, NG2-, A2B5-, O1-, MBP-.

Animals↗
PubMed1998

Hypergravity exposure decreases gamma-aminobutyric acid immunoreactivity in axon terminals contacting pyramidal cells in the rat somatosensory cortex: a quantitative immunocytochemical image analysis.

Quantitative evaluation of gamma-aminobutyric acid immunoreactivity (GABA-IR) in the hindlimb representation of the rat somatosensory cortex after 14 days of exposure to hypergravity (hyper-G) was conducted by using computer-assisted image processing. The area of GABA-IR axosomatic terminals apposed to pyramidal cells of cortical layer V was reduced in rats exposed to hyper-G compared with control rats, which were exposed either to rotation alone or to vivarium conditions. Based on previous immunocytochemical and behavioral studies, we suggest that this reduction is due to changes in sensory feedback information from muscle receptors. Consequently, priorities for muscle recruitment are altered at the cortical level, and a new pattern of muscle activity is thus generated. It is proposed that the reduction observed in GABA-IR of the terminal area around pyramidal neurons is the immunocytochemical expression of changes in the activity of GABAergic cells that participate in reprogramming motor outputs to achieve effective movement control in response to alterations in the afferent information.

Animals↗
PubMed1998

Increased transcription and modified growth state-dependent expression of the plasminogen activator inhibitor type-1 gene characterize the senescent phenotype in human diploid fibroblasts.

The type-1 inhibitor of plasminogen activator (PAI-1) is a major physiologic regulator of pericellular proteolytic activity and, as such, influences matrix integrity, cell-to-substrate adhesion, and cellular proliferation. Excessive accumulation of both PAI-1 mRNA and protein correlates with the progressive acquisition of morphological and growth traits characteristic of the senescent phenotype (Mu and Higgins, 1995, J. Cell. Physiol., 165:647-657). Compared to early-passage IMR-90 human diploid fibroblasts, a late-passage senescence-associated 11-fold elevation in steady-state PAI-1 mRNA content reflected a 15-fold increase in constitutive PAI-1 gene transcription. Differential mRNA stability was not a factor in age-associated PAI-1 overexpression in IMR-90 cells. Upon removal of serum, early-passage human fibroblasts enter into a state of growth arrest with marked down-regulation of PAI-1 synthesis. Rapid induction of both the 3.0- and 2.2-kb PAI-1 mRNA species was evident upon serum-induced "activation" of quiescent early-passage fibroblasts; induced PAI-1 transcripts were maximal at 2 hr post-serum stimulation and declined in late G1 prior to entry into S phase. In contrast, late-passage (p32) fibroblasts maintained a significant level of PAI-1 expression under serum-free culture conditions. Although the PAI-1 gene was further responsive to serum in senescent cells, transcript abundance remained elevated and actually increased over the 12 to 16 hr post-serum addition period (a time when early-passage fibroblasts down-regulate PAI-1 mRNA content). Development of the senescent phenotype in human fibroblasts is associated, therefore, with significant changes in PAI-1 gene regulation. Such reprogramming involves predominantly transcriptional events and results in a marked increase in steady-state PAI-1 transcript abundance involving both the 3.0- and 2.2-kb mRNA species.

Cell Division↗