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At least 19 recordsLinked to original sources
PubMed1986

Amplification of nuclear DNA sequences during induced plant cell dedifferentiation.

Cell dedifferentiation has been induced in Vicia faba roots by removing the whole meristem (decapitation). When centrifuged to equilibrium in CsCl density gradient, the DNA from dedifferentiating tissues forms a heavier satellite, not occurring in the DNA from differentiated tissues. Most of the radioactivity after [3H]thymidine feeding is found in the satellite DNA. Its sequences have a well defined nuclear localization, as shown by in situ hybridization experiments. These results indicate amplification of G + C-rich nuclear DNA sequences during cell dedifferentiation.

Cell Differentiation↗
PubMed2004

The Ras/Raf/ERK signalling pathway drives Schwann cell dedifferentiation.

Schwann cells are a regenerative cell type. Following nerve injury, a differentiated myelinating Schwann cell can dedifferentiate and regain the potential to proliferate. These cells then redifferentiate during the repair process. This behaviour is important for successful axonal repair, but the signalling pathways mediating the switch between the two differentiation states remain unclear. Sustained activation of the Ras/Raf/ERK cascade in primary cells results in a cell cycle arrest and has been implicated in the differentiation of certain cell types, in many cases acting to promote differentiation. We therefore investigated its effects on the differentiation state of Schwann cells. Surprisingly, we found that Ras/Raf/ERK signalling drives the dedifferentiation of Schwann cells even in the presence of normal axonal signalling. Furthermore, nerve wounding in vivo results in sustained ERK signalling in associated Schwann cells. Elevated Ras signalling is thought to be important in the development of Schwann cell-derived tumours in neurofibromatosis type 1 patients. Our results suggest that the effects of Ras signalling on the differentiation state of Schwann cells may be important in the pathogenesis of these tumours.

Animals↗
PubMed1991

Conversion of a rabbit proximal convoluted tubule (PCT) into a cell monolayer: ultrastructural study of cell dedifferentiation and redifferentiation.

The evolution of a primary culture of kidney proximal convoluted tubule (PCT) cells was followed step by step from the plating time of an isolated tubule to the 39th day of culture. During the first 48 h, the structural remodeling of PCT, leading to the formation of a cell monolayer without cell division, is accompanied by intracytoplasmic changes indicating cell dedifferentiation. Numerous autophagic vacuoles are observed inside the cells, and the ultrastructural features characteristic of in situ PCT cells are progressively lost. Despite these drastic modifications, cell polarity, as observed by immunocytochemical detection of the leucine aminopeptidase, remains unaltered. Starting at 48 h, the peripheral cells divide, and the culture proliferates in a centrifugal direction while newly formed cells differentiate. From 6 days onwards, glycogen granules, never encountered in in situ PCT cells, appear in cultured cells and progressively accumulate. At the optimal stage of the culture (12-17 days old), cells somewhat resemble PCT cells, but their apical brush borders remain rudimentary, and basal cytoplasmic interdigitations surrounding densely packed mitochondria are poorly developed. Subsequently, the cells become overloaded with glycogen and lipid inclusions and resemble degenerating cells.

Animals↗
PubMed1999

Defective NF-kappaB signaling in dedifferentiated hepatoma cells.

Dedifferentiated rat hepatoma cells contain defects that result in the loss of hepatic gene expression, including the liver-enriched HNF4/HNF1alpha pathway. We examined induction of NF-kappaB, a key mediator of the inflammatory response, in hepatoma and dedifferentiated hepatoma cells. We show that exposure of dedifferentiated hepatoma cells, but not rat and human hepatoma cell lines, to proinflammatory cytokines or lipopolysaccharide resulted in rapid and sustained NF-kappaB induction. IkappaB-beta levels, but not NF-kappaB subunit p65 or IkappaB-alpha levels, were elevated compared with those for parental hepatoma cells. Interestingly, LPS-mediated activation of NF-kappaB was found to be independent of degradation of IkappaB-alpha or IkappaB-beta. Thus, these results suggest that loci responsible for maintaining hepatic gene expression also influence cellular responses to inflammatory agents.

Animals↗
PubMed2005

Mitochondria as a connected population: ensuring continuity of the mitochondrial genome during plant cell dedifferentiation through massive mitochondrial fusion.

Mitochondrial fusion in plants and its role in development are poorly understood. Cultured tobacco mesophyll protoplasts provide an excellent experimental system for visualizing mitochondrial dynamics. Before protoplasts first divide, mitochondria undergo a phase of extensive elongation before fission causes an increase in number, followed by actin filament (AF)-dependent dispersion that distributes mitochondria uniformly throughout the cytoplasm. Here, by fusing protoplasts containing either green fluorescent protein- or MitoTracker-labelled mitochondria, we show that elongation results from fusion during early (4-8 h) protoplast culture. This massive mitochondrial fusion (MMF) leads to near-complete mixing of the mitochondrial population within 24 h. Staining isolated mitochondria with 4',6-diamidino-2-phenylindole (DAPI) revealed that in freshly prepared protoplasts mitochondrial nucleoids were unequally distributed, with many mitochondria failing to stain with DAPI, suggesting the presence of an incomplete mitochondrial genome. Following MMF, nucleoids were distributed evenly throughout the population, thereby ensuring continuity of the mitochondrial genome in daughter cells. Massive mitochondrial fusion appears to be specific to dedifferentiation, since it also occurs in mesophyll protoplasts of Arabidopsis and Medicago but not in protoplasts from already dedifferentiated cells such as BY-2 or callus cultures. Efficient MMF requires an inner membrane electrical gradient, cytoplasmic protein synthesis, microtubules and functional kinesin but not ATP or AFs, indicating fundamental differences from mitochondrial fusion in non-plant systems. Our studies reveal that individual mitochondria are connected over time by fusion events, a finding that allows a clearer interpretation of how novel mitochondrial genotypes develop following cell fusion, and indicates that developmentally regulated fusion ensures continuity of the mitochondrial genome.

Arabidopsis↗
PubMed1995

Overexpression of cellular activity and protein level of protein kinase FA/GSK-3 alpha correlates with human thyroid tumor cell dedifferentiation.

Computer analysis of protein phosphorylation sites sequence revealed that transcriptional factors and viral oncoproteins are prime targets for regulation of proline-directed protein phosphorylation, suggesting an association of the proline-directed protein kinase (PDPK) family with neoplastic transformation and tumorigenesis. In this report, an immunoprecipitate activity assay of protein kinase FA/glycogen synthase kinase-3 alpha (kinase FA/GSK-3 alpha) (a member of the PDPK family) has been optimized for human thyroid tissue and used to demonstrate for the first time significantly increased (P < 0.001) activity in thyroid carcinoma (24.2 +/- 2.8 units/mg of protein) (n = 7), thyroid adenoma (14.5 +/- 2.2 units/mg of protein) (n = 6), and thyroid hyperplasia (8.0 +/- 2.4 units/mg of protein) (n = 5) when compared to five normal controls (4.1 +/- 1.8 units/mg of protein). Immunoblotting analysis further revealed that increased activity of kinase FA/GSK-3 alpha in thyroid tumor cells is due to overexpression of the protein synthesis of the enzyme. Taken together, the results provide initial evidence that overexpression of protein level and cellular activity of kinase FA/GSK-3 alpha is involved in human thyroid tumor cell dedifferentiation, supporting an association of PDPK with neoplastic transformation and tumorigenesis. Since kinase FA/GSK-3 alpha may function as a possible regulator of transcription factors/protooncogenes, kinase FA/GSK-3 alpha may therefore play an important role in thyroid cell carcinogenesis, especially in its differentiation.

Adenoma↗
PubMed2005

Follicular dendritic cell dedifferentiation reduces scrapie susceptibility following inoculation via the skin.

Transmissible spongiform encephalopathies (TSEs) are a group of subacute infectious neurodegenerative diseases that are characterized by the accumulation in affected tissues of PrP(Sc), an abnormal isoform of the host prion protein (PrPc). Following peripheral exposure, TSE infectivity and PrP(Sc) usually accumulate in lymphoid tissues prior to neuroinvasion. Studies in mice have shown that exposure through scarified skin is an effective means of TSE transmission. Following inoculation via the skin, a functional immune system is critical for the transmission of TSEs to the brain, but until now, it has not been known which components of the immune system are required for efficient neuroinvasion. Temporary dedifferentiation of follicular dendritic cells (FDCs) by treatment with an inhibitor of the lymphotoxin-beta receptor signalling pathway (LTbetaR-Ig) 3 days before or 14 days after inoculation via the skin, blocked the early accumulation of PrP(Sc) and TSE infectivity within the draining lymph node. Furthermore, in the temporary absence of FDCs before inoculation, disease susceptibility was reduced and survival time significantly extended. Treatment with LTbetaR-Ig 14 days after TSE inoculation also significantly extended the disease incubation period. However, treatment 42 days after inoculation did not affect disease susceptibility or survival time, suggesting that the infection may have already have spread to the nervous system. Together these data show that FDCs are essential for the accumulation of PrP(Sc) and infectivity within lymphoid tissues and subsequent neuroinvasion following TSE exposure via the skin.

Animals↗
PubMed2007

Tubular epithelial cell dedifferentiation is driven by the helix-loop-helix transcriptional inhibitor Id1.

In the fibrotic kidney, tubular cells undergo epithelial-to-mesenchymal transition (EMT), a phenotypic conversion that is characterized by sequential loss of epithelial markers and gain of mesenchymal features. For understanding of the molecular mechanism that governs this process, a high-throughput gene expression microarray analysis was used to identify the critical genes in the initial phase of the TGF-beta1-mediated EMT. Inhibitor of differentiation-1 (Id1), a dominant negative antagonist of the basic helix-loop-helix transcription factors, was found to be induced rapidly in human proximal tubular epithelial cells after TGF-beta1 treatment. This induction of Id1 depended on intracellular Smad signaling. Ectopic expression of Id1 suppressed epithelial E-cadherin and zonula occludens-1 expression. Id1 physically formed complex with basic helix-loop-helix transcription factor HEB (Hela E-box binding factor), sequestered its ability to bind to E-box, and repressed the trans-activation of E-cadherin promoter. However, overexpression of Id1 failed to induce alpha-smooth muscle actin, matrix metalloproteinase-2, fibronectin, and integrin-linked kinase (ILK), indicating its inability to confer a complete EMT. Overexpression of ILK or inhibition of ILK activity had no effect on Id1 induction by TGF-beta1, suggesting that Id1 and ILK have independent roles in epithelial dedifferentiation and EMT. In vivo, Id1 was induced exclusively in the degenerated, dilated renal tubular epithelium after unilateral ureteral obstruction. These studies identify Id1 transcriptional inhibitor as a crucial player in mediating cell dedifferentiation of renal tubular epithelium and suggest that EMT is a multistep process in which loss of epithelial adhesion does not necessarily lead to an autonomous mesenchymal transition.

Adult↗
PubMed2004

How cells dedifferentiate: a lesson from plants.

The remarkable regenerative capacity displayed by plants and various vertebrates, such as amphibians, is largely based on the capability of somatic cells to undergo dedifferentiation. In this process, mature cells reverse their state of differentiation and acquire pluripotentiality--a process preceding not only reentry into the cell cycle but also a commitment for cell death or trans- or redifferentiation. Recent studies provide a new perspective on cellular dedifferentiation, establishing chromatin reorganization as its fundamental theme.

Cell Differentiation↗
PubMed1979

Cytofluorometry of electromagnetically controlled cell dedifferentiation.

Cellular morphology changes, which appear related to dedifferentiation (despecialization), have been produced in vitro in the nucleated red blood cell of the frog. This has been achieved by controlled alterations in the electrochemical environment of these living cells, both by a selective modification of the ionic concentrations of an isotonic amphibian Ringer solution, and by the electromagnetic induction of pulsating current having specific waveform parameters. Laser flow microfluorometry shows that the modified Ringer solution is able, per se, to partially trigger the process in the same time interval that certain induced current waveforms can significantly affect the number of cells in the so-called dedifferentiated state. It has also been found that, for a given waveform, the repetition rate appears to have a significant effect on the rate of cell change. Preliminary automated image analysis of cell smears suggests that dedifferentiated and normal cells have the same integrated optical density but different nuclear areas. In conclusion, it appears that, after the initial electrochemical trigger, the early stage of the process, when the cells move from a state of specialized function to one of less specific activity, is the unfolding of their chromatin supercoil, not involving DNA synthesis. Then cytofluorometry allowed us to identify, for the first time, fundamental modifications which occur in the cell nucleus under electromagnetic exposure.

Acridine Orange↗
PubMed1997

Ochratoxin A-induced stimulation of extracellular signal-regulated kinases 1/2 is associated with Madin-Darby canine kidney-C7 cell dedifferentiation.

The kidneys represent one of the main targets of ochratoxin A (OTA), a secondary fungal metabolite that is produced by certain species of Aspergillus and Penicillium. OTA has the ability to disturb Madin-Darby canine kidney (MDCK) cell pH homeostasis, leading to intracellular alkalinization and morphological alterations resembling those that occur when MDCK cells are exposed to transient alkaline stress. Because alkali-induced epithelial dedifferentiation of MDCK-C7 cells is associated with an increase in the activity of extracellular signal-regulated kinases (ERK), we performed experiments that investigated a possible role for ERK1 and ERK2 as intracellular signaling molecules mediating some of the mycotoxin's effects on renal epithelia. We studied the effects of OTA on ERK1/2 phosphorylation and activation, as well as on cell morphology by using cloned MDCK-C7 and MDCK-C11 cells. In MDCK-C7 cells, but not in MDCK-C11 cells, OTA led to a time-dependent and concentration-dependent increase in ERK1/2 phosphorylation. OTA-induced ERK1/2 phosphorylation in MDCK-C7 cells occurred at concentrations of 500 nM, started after 2 hr and was maximal after 8 hr. Furthermore, after 8 hr of incubation, 500 nM and 1 microM OTA significantly increased ERK1/2 activity in MDCK-C7 but not in MDCK-C11 cells. This OTA-stimulated ERK1/2 phosphorylation and ERK1/2 activation in MDCK-C7 cells was partially inhibited by the synthetic mitogen-activated protein kinase kinase (MKK or MEK) inhibitor PD098059. Transepithelial resistance and lactate dehydrogenase release remained unaltered after incubation in the presence of 1 microM OTA for 8 hr or of 100 nM OTA for 24 hr, so it is unlikely that these OTA effects on ERK1/2 are due to secondary toxic effects of the mycotoxin. Interestingly, OTA-induced long-term activation of ERK1/2 in MDCK-C7 cells was associated with epithelial dedifferentiation, as assessed by analysis of vectorial solute and water transport as well as cell morphology. In contrast, MDCK-C11 cells, which do not show significant increases in ERK1/2 phosphorylation and ERK1/2 activity in response to OTA, retained their epithelial phenotype under identical experimental conditions. Taken together, our data demonstrate an epithelial dedifferentiation of MDCK-C7 cells, but not of MDCK-C11 cells, after long-term incubation in the presence of OTA, a result associated with the ability of this mycotoxin to stimulate ERK1/2 in MDCK-C7 cells but not in MDCK-C11 cells. We conclude that OTA-induced activation of ERK1/2 could be an important intracellular signaling pathway that mediates some of the mycotoxin's effects on renal epithelia.

Animals↗
PubMed2006

Neuroblastoma as an experimental model for neuronal differentiation and hypoxia-induced tumor cell dedifferentiation.

Neuroblastoma is a childhood tumor derived from precursor or immature cells of the sympathetic nervous system. Neuroblastomas show a tremendous clinical heterogeneity, encompassing truly benign as well as extremely aggressive forms. In vivo as well as in vitro data have shown that the degree of sympathetic neuronal tumor cell differentiation influences patient outcome. Unraveling mechanisms governing neuroblastoma cell differentiation is therefore a central issue in the neuroblastoma research field. In this communication, we discuss some of the in vitro models frequently used to study human neuroblastoma cell differentiation. We also review recent data demonstrating that oxygen shortage, hypoxia, shifts neuroblastoma cells toward an immature, stem cell-like phenotype and discuss the potential clinical impact of hypoxia on neuroblastoma behavior.

Cell Differentiation↗
PubMed1994

Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogenous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells.

The mechanisms leading to the recovery of the kidney after ischemic acute renal failure are poorly understood. To explore the role played by mitogenesis and dedifferentiation in this repair process and to identify whether the genetic response of the nephron segments reflects the level of susceptibility to injury, the temporal and nephron segment expressions of various proteins implicated in mitogenesis, differentiation, and injury were determined. Proliferating cell nuclear antigen (PCNA), a marker for the G1-S transition in the cell cycle and hence mitogenesis, was detected primarily in the S3 segment of the proximal tubule, with maximal expression at 2 d postischemia. Vimentin, normally present in mesenchymal cells but not epithelial cells, and hence a marker for the state of differentiation, was prominently expressed in the S3 segment 2-5 d postischemia. In the S3 segments in the outer stripe of the medulla cells that stained positively for PCNA also stained positively for vimentin. Clusterin, a marker for cell injury, was expressed primarily in the S3 segment and in the distal tubule with distinct staining patterns in each segment. None of the cells that stained with clusterin antibodies were positively stained with PCNA or vimentin antibodies. Likewise, none of the PCNA or vimentin-positive cells expressed clusterin at detectable levels. Thus, in the S3 segment, where there is significant ischemic injury, surviving cells express markers indicating that they undergo mitogenesis and dedifferentiate in the postischemic period. While there is some expression of c-Fos in the S3 segment, c-Fos was expressed predominantly, at 1 and 3 h postischemia, in the nuclei of the distal nephron, particularly in the thick ascending limb. The data support the view that the mature renal S3 segment epithelial cell can be a progenitor cell.

Animals↗
PubMed2005

Localization of calcitonin gene-related peptide in cardiomyocytes: comparison of neonatal and dedifferentiating cells to adult myocytes.

The purpose of this study was to localize sites of calcitonin gene-related peptide binding in neonatal, freshly isolated and dedifferentiated adult cardiac myocytes in order to help us elucidate the mechanisms of action of this neuropeptides. Previous work has shown that treatment with calcitonin gene-related peptide results in dramatic changes in calcium transients, so we carried out multi-channel acquisitions of fluorescently labeled images to reveal where calcitonin gene-related protein and the L-type calcium channel were localized. Calcitonin gene-related protein was sparse and randomly distributed in rod-like adult cardiomyocytes, found in abundance in areas of the cell where striations were apparent and not where adhesion proteins predominated in dedifferentiating adult myocytes, and in a large perinuclear concentration, with some spreading into the cytoplasm in neonatal cells. Subsequent modeling demonstrated that calcitonin gene-related peptide and the L-type calcium channel protein were closely associated in each of the three myocyte types, suggesting that while the peptide has dramatic and different effects on intracellular calcium levels of the various cardiomyocytes, the action is probably via diverse mechanisms as a result of effects on different channels or pump proteins due to alterations in intracellular calcium concentrations.

Actins↗
PubMed1990

In vitro development of hypertrophic chondrocytes starting from selected clones of dedifferentiated cells.

Single cells from enzymatically dissociated chick embryo tibiae have been cloned and expanded in fresh or conditioned culture media. A cloning efficiency of approximately 13% was obtained using medium conditioned by dedifferentiated chondrocytes. A cloning efficiency of only 1.4% was obtained when conditioned medium from hypertrophic chondrocytes was used, and efficiencies of essentially 0 were found with fresh medium or medium conditioned by J2-3T3 mouse fibroblasts. Cell clones were selected by morphological criteria and clones showing a dedifferentiated phenotype (fibroblast-like) were further characterized. Out of 38 clones analyzed, 17 were able to differentiate to the hypertrophic chondrocyte stage and reconstitute hypertrophic cartilage when placed in the appropriate culture conditions. Cells from these clones expressed the typical markers of chondrocyte differentiation, i.e., type II and type X collagens. Clones not undergoing differentiation continued to express only type I collagen. Hypertrophic chondrocytes from differentiating clones were analyzed at the single cell level by immunofluorescence; all the cells were positive for type X collagen, while approximately 50% of them showed positivity for type II collagen.

Animals↗
PubMed2000

Role of endothelial cell denudation and smooth muscle cell dedifferentiation in neointimal formation of human vein grafts after coronary artery bypass grafting: therapeutic implications.

OBJECTIVE: To provide better insights into the genesis of neointimal thickening in human vein grafts early after surgery. DESIGN: Retrospective study. SETTING: Tertiary referral centre. SUBJECTS: 18 distal anastomotic sites of patent grafts, obtained at necropsy from eight patients who died over differing periods (ranging from two days to nine months) after the procedure. MAIN OUTCOME MEASURES: Immunohistochemical evaluation of smooth muscle cell phenotype modulation in relation to proliferative activity. RESULTS: The earliest changes are characterised by loss of surface lining endothelial cells and insudation of blood corpuscular elements admixed with fibrin-platelet thrombus. At sites of injury vimentin positive and actin negative spindle shaped cells appear in the intima, while the related pre-existent media shows focal absence of actin positive smooth muscle cells. Proliferative activity colocalises at these sites. With time distinct neointimal thickening occurs, associated with disappearance of proliferative activity and a phenotypic shift of the smooth muscle cells. CONCLUSIONS: The observation that luminal endothelial cell denudation, with insudation of the intima with blood elements, occurs in the very early stages suggests that these phenomena are responsible for the observed dedifferentiation of pre-existent smooth muscle cells, known to be a prerequisite for cell proliferation and the evolution of intimal thickening. It is likely, therefore, that platelet released growth factors play a pivotal role, which thus may provide a target for preventive pharmacological intervention.

Aged↗
PubMed2003

Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility.

Transmissible spongiform encephalopathies (TSEs) may be acquired peripherally, in which case infectivity usually accumulates in lymphoid tissues before dissemination to the nervous system. Studies of mouse scrapie models have shown that mature follicular dendritic cells (FDCs), expressing the host prion protein (PrP(c)), are critical for replication of infection in lymphoid tissues and subsequent neuroinvasion. Since FDCs require lymphotoxin signals from B lymphocytes to maintain their differentiated state, blockade of this stimulation with a lymphotoxin beta receptor-immunoglobulin fusion protein (LT beta R-Ig) leads to their temporary dedifferentiation. Here, a single treatment with LT beta R-Ig before intraperitoneal scrapie inoculation blocked the early accumulation of infectivity and disease-specific PrP (PrP(Sc)) within the spleen and substantially reduced disease susceptibility. These effects coincided with an absence of FDCs in the spleen for ca. 28 days after treatment. Although the period of FDC dedifferentiation was extended to at least 49 days by consecutive LT beta R-Ig treatments, this had little added protective benefit after injection with a moderate dose of scrapie. We also demonstrate that mature FDCs are critical for the transmission of scrapie from the gastrointestinal tract. Treatment with LT beta R-Ig before oral scrapie inoculation blocked PrP(Sc) accumulation in Peyer's patches and mesenteric lymph nodes and prevented neuroinvasion. However, treatment 14 days after oral inoculation did not affect survival time or susceptibility, suggesting that infectivity may have already spread to the peripheral nervous system. Although manipulation of FDCs may offer a potential approach for early intervention in peripherally acquired TSEs, these data suggest that the duration of the treatment window may vary widely depending on the route of exposure.

Animals↗