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PubMed2005

Inhibition of transdifferentiation into tracheary elements by polar auxin transport inhibitors through intracellular auxin depletion.

Polar auxin transport is essential for the formation of continuous vascular strands in the plant body. To understand its mechanism, polar auxin transport inhibitors have often been used. However, the role of auxin in vascular differentiation at the unicellular level has remained elusive. Using a Zinnia elegans cell culture system, in which single mesophyll cells transdifferentiate into tracheary elements (TEs), we demonstrated that auxin transport inhibitors prevented TE differentiation and that high concentrations of 1-naphthaleneacetic acid (NAA) and IAA overcame the repression of TE differentiation. Measurements of NAA accumulation with 3H-labeled NAA in the presence or absence of 1-N-naphthylphthalamic acid (NPA) revealed enhanced NAA accumulation within the cell. In the NPA-treated cells, intracellular free NAA decreased, while its metabolites increased. Therefore, the polar auxin transport inhibitors may prevent auxin efflux and consequently promote NAA accumulation in Zinnia cells. The excess intracellular NAA may also activate NAA metabolism, resulting in a decrease in free NAA levels. This depletion of free NAA may prevent TE differentiation. The decreased auxin activity in NPA-treated cells was confirmed by the fact that the DR5 (a synthetic auxin-inducible promoter)-mediated expression of a reporter protein was suppressed in such cells. Gene expression analysis indicated that NPA suppressed TE differentiation at an early process of transdifferentiation into TEs. Based on these results, the inter-relationship between auxin and vascular cell development at a cellular level is discussed.

Asteraceae↗
PubMed2004

Oncostatin M, a cytokine released by activated mononuclear cells, induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathway activation.

Interactions between inflammatory infiltrates and resident tubular epithelial cells may play important roles in the development of tubulointerstitial fibrosis, by promoting epithelial cell-myofibroblast transdifferentiation (EMT). Human proximal tubular epithelial cells transdifferentiated to myofibroblasts after treatment with activated PBMC conditioned medium. mRNA and protein levels for alpha-smooth muscle actin, collagen I, and fibronectin EDA(+) (markers for the myofibroblastic phenotype) were increased, whereas those for E-cadherin and cytokeratin 19 (markers for the epithelial phenotype) were decreased. cDNA microarray analysis was used to identify other changes in gene expression that might point to novel molecular mechanisms driving EMT. Of 1176 array genes, 61 demonstrated at least a twofold change at at least two consecutive time points, of the five time points examined (0.5, 4, 8, 16, and 48 h). Of these genes, 59% were upregulated and 41% were downregulated. The array indicated upregulation of expression of the oncostatin M (OSM)-specific receptor beta subunit from 4 to 48 h after exposure of kidney epithelial cells to activated PBMC conditioned medium, which contained high levels of OSM. In additional experiments, it was demonstrated that OSM induced EMT. OSM activated the Jak/Stat signaling pathway in epithelial cells, and a specific inhibitor of Jak2 blocked both its phosphorylation after exposure to OSM and the induction of alpha-actin and loss of cytokeratin 19 expression. Therefore, OSM is a novel inducer of EMT and is likely to be one of several cytokines produced by inflammatory infiltrates that contribute to this and subsequent tubulointerstitial fibrosis.

Cell Differentiation↗
PubMed2004

The ATE genes are responsible for repression of transdifferentiation into xylem cells in Arabidopsis.

We isolated three recessive mutants of Arabidopsis (Arabidopsis thaliana) showing ectopic expression of the xylem-specific marker, pAtxyn3::YFP. Genetic analysis indicated that the phenotypes were caused by mutations in three different genes, designated Abnormal Tracheary Element formation-related gene expression (ate1-3). The ate1 mutants showed a normal DR5::GUS gene expression pattern, and the ate1 mutation did not affect the abnormal vascular pattern formation in the van3 and pin1 mutants, indicating that the ate1 mutation does not affect the vascular pattern organization governed by auxin. The ate mutants showed ectopic lignin deposition, patterned secondary wall thickenings, and cell death, which are characteristic of mature tracheary elements (TEs) in cells ectopically expressing the pAtxyn3::YFP gene. Ectopic TE formation was rapidly induced in parenchymal tissue of the ate mutants in a TE-inducible system with excised hypocotyl. Furthermore, reverse transcription-polymerase chain reaction experiments showed that the expression of TE formation-related genes is up-regulated in the ate mutants. The ate1 mutation also caused ectopic expression of another xylem-specific marker gene, pAt3g62160::YFP. Overall, our results suggest that the ATE genes are responsible for the in situ repression of transdifferentiation into TEs in Arabidopsis and could be participants in the transdifferentiation-masking system.

Arabidopsis↗
PubMed1990

The proportion altering factor (PAF) and the in vitro transdifferentiation of isolated striated muscle of jellyfish into nerve cells.

The effect of proportion altering factor (PAF) on the transdifferentiation of isolated striated muscle into RFamide-positive nerve cells was investigated. The factor reduces incorporation of 3H-thymidine into replicating DNA; the effect is concentration-dependent and reversible. Transdifferentiation to nerve cells increases by up to 60% if PAF is applied shortly before or at the time of initiation of DNA synthesis. When treatment was terminated 4 h before the start of S-phase or when PAF was applied at the peak of S-phase no increase in nerve cell formation was observed.

Animals↗
PubMed1991

Microvessel endothelial cell transdifferentiation: phenotypic characterization.

Human dermal microvessel endothelial cells (MEC) have two basic functions: maintenance of tissue homeostasis and facilitation of inflammatory responses. The former requires that the endothelium expresses traits of an epithelium, while inflammatory reactions are associated with intimal disruption. Acute inflammation transiently alters endothelium, whereas chronic inflammation may result in vessel reorganization and MEC mesenchymalization. Foreskin MEC in vitro undergo a similar epithelial-mesenchymal modulation. In the presence of cAMP, cultivated dermal MEC exhibit the structural and functional characteristics of an epithelium. MEC grown in cAMP-deficient medium initially have a "transitional" configuration and are subsequently transformed into mesenchymal cells. If cAMP is replaced by histamine, MEC maintain a stable intermediate transitional configuration. Transitional MEC refed cAMP-supplemented medium revert to an epithelial phenotype, whereas parallel cultures fed cAMP-deficient medium are transformed into mesenchymal cells. Phenotypic modulation can be induced without cell division and thus provides a unique example of direct transdifferentiation. Our data furthermore suggest that this transdifferentiation results in the acquisition of properties usually attributed to cells of the reticuloendothelial system.

Cell Differentiation↗
PubMedDate not supplied

The molecular basis of transdifferentiation.

There is now excellent experimental evidence demonstrating the remarkable ability of some differentiated cells to convert to a completely different phenotype. The conversion of one cellular phenotype to another is referred to as 'transdifferentiation' and belongs to a wider class of cell-type switches termed 'metaplasias'. Defining the molecular steps in transdifferentiation will help us to understand the developmental biology of the cells that interconvert, as well as help identify key regulatory transcription factors that may be important for the reprogramming of stem cells. Ultimately, being able to produce cells at will offers a compelling new approach to therapeutic transplantation and therefore the treatment and cure of diseases such as diabetes.

Adipocytes↗
PubMed2005

Effect of daidzin, genistin, and glycitin on osteogenic and adipogenic differentiation of bone marrow stromal cells and adipocytic transdifferentiation of osteoblasts.

AIM: To examine the effect of daidzin, genistin, and glycitin on the osteogenic and adipogenic differentiation of bone marrow stromal cells (MSC) and the adipogenic transdifferentiation of osteoblasts. METHODS: MTT test, alkaline phosphatase (ALP) activity measurement, Oil Red O stain and measurement were employed. RESULTS: Daidzin, genistin, and glycitin 1*10(-8), 5*10(-7), 1*10(-6), 5*10(-6), and 1*10(-5) mol/L all promoted the proliferation of primary mouse bone MSC and osteoblasts. Daidzin 5*10(-7) mol/L and genistin 1*10(-6) mol/L promoted the osteogenesis of MSC. Genistin 1*10(-8), 5*10(-7), 1*10(-6), 5*10(-6), and 1*10(-5) mol/L and glycitin 1*10(-8), 1*10(-6), and 1*10(-5) mol/L inhibited the adipogenesis of MSC. Daidzin, genistin, and glycitin 1*10(-8), 5*10(-7), 1*10(-6), 5*10(-6), and 1*10(-5) mol/L all inhibited the adipocytic transdifferentiation of osteoblasts. CONCLUSIONS: Daidzin, genistin, and glycitin may modulate differentiation of MSC to cause a lineage shift toward the osteoblast and away from the adipocytes, and could inhibit adipocytic transdifferen-tiation of osteoblasts. They could also be helpful in preventing the development of osteonecrosis.

Adipocytes↗
PubMed2006

Transforming growth factor-beta1 induces transdifferentiation of fibroblasts into myofibroblasts in hypoxic pulmonary vascular remodeling.

The muscularization of non-muscular pulmonary arterioles is an important pathological feature of hypoxic pulmonary vascular remodeling. However, the origin of the cells involved in this process is still not well understood. The present study was undertaken to test the hypothesis that transforming growth factor-beta1 (TGF-beta1) can induce transdifferentiation of fibroblasts into myofibroblasts, which might play a key role in the muscularization of non-muscular pulmonary arterioles. It was found that mean pulmonary arterial pressure increased significantly after 7 d of hypoxia. Pulmonary artery remodeling index and right ventricular hypertrophy became evident after 14 d of hypoxia. The distribution of nonmuscular, partially muscular, and muscular vessels was significantly different after 7 d of hypoxia. Immunocytochemistry results demonstrated that the expression of a-smooth muscle actin was increased in intra-acinar pulmonary arteries with increasing hypoxic time. TGF-beta1 mRNA expression in pulmonary arterial walls was increased significantly after 14 d of hypoxia, but showed no obvious changes after 3 or 7 d of hypoxia. In pulmonary tunica adventitia and tunica media, TGF-beta1 protein staining was poorly positive in control rats, but was markedly enhanced after 3 d of hypoxia, reaching its peak after 7 d of hypoxia. The myofibroblast phenotype was confirmed by electron microscopy, which revealed microfilaments and a well-developed rough endoplasmic reticulum. Taken together, our results suggested that TGF-beta1 induces transdifferentiation of fibroblasts into myofibroblasts, which is important in hypoxic pulmonary vascular remodeling.

Animals↗
PubMed1995

Evidence for developmentally programmed transdifferentiation in mouse esophageal muscle.

Transdifferentiation is a relatively rare phenomenon in which cells of one differentiated type and function switch to a second discrete identity. In vertebrate embryos, smooth muscle and skeletal muscle are distinct tissues that arise from separate compartments of the mesoderm. The musculature of the mouse esophagus was found to undergo a conversion from smooth muscle in the fetus to skeletal muscle during early postnatal development. The switch from smooth to skeletal muscle features the transitory appearance of individual cells expressing a mixed phenotype, which suggests that this conversion is a result of programmed transdifferentiation.

Actinin↗
PubMedDate not supplied

Cell shape, intracellular pH, and fibroblast growth factor responsiveness during transdifferentiation of retinal pigment epithelium into neuroepithelium in vitro.

In this report we show that some retinal pigment epithelial (RPE) cells, with no expression of neural cell adhesion molecule (N-CAM) (RPEN-CAM-), spontaneously lose pigment and start to express N-CAM in culture. Chick RPE cells normally do not express N-CAM, while the protein is present in chick neural retina. Thus some of the RPE cells in culture started to transdifferentiate into a neuroepithelium (NEN-CAM+). We have measured intracellular pH (pHi) in the RPE cultures and followed its changes in response to basic fibroblast growth factor (bFGF). The depigmented cells protrude above the RPE cell sheet and have a lower resting pHi (approximately 7.05) than the pigmented RPE cells (approximately 7.15). The majority of cells with low resting pHi express N-CAM. The difference in the resting pHi between RPEN-CAM- and NEN-CAM+ cells is not due to the N-CAM expression by NEN-CAM+ cells, as their pHi is the same as the pHi of freshly plated single "round" RPEN-CAM- cells that have not spread yet. NEN-CAM+ cells respond to bFGF with a quick and sustained pHi rise. In contrast, neither the cuboidal RPEN-CAM- cells in a colony centre nor single round RPEN-CAM- cells respond to bFGF with cytoplasmic alkalinization. RPE cells do not proliferate in response to bFGF, while NE cells respond to bFGF with a stimulation of growth. We conclude that bFGF acts not on the fully differentiated RPEN-CAM-, but only on those cells which have already started to transdifferentiate and changed their shape and (or) adhesive status.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Differential expression of cell-cell adhesion proteins and cyclin D in MEK1-transdifferentiated MDCK cells.

Overexpression of a constitutively active mutant of the mitogen-activated protein kinase kinase MEK1 (caMEK1) in epithelial Madin-Darby canine kidney (MDCK)-C7 cells disrupts morphogenesis, induces an invasive phenotype, and is associated with a reduced rate of cell proliferation. The role of cell-cell adhesion molecules and cell cycle proteins in these processes, however, has not been investigated. We now report loss of E-cadherin expression as well as a marked reduction of beta- and alpha-catenin expression in transdifferentiated MDCK-C7 cells stably expressing caMEK1 (C7caMEK1) compared with epithelial mock-transfected MDCK-C7 (C7Mock1) cells. At least part of the remaining alpha-catenin was coimmunoprecipitated with beta-catenin, whereas no E-cadherin was detected in beta-catenin immunoprecipitates. In both cell types, the proteasome-specific protease inhibitors N-acetyl-Leu-Leu-norleucinal (ALLN) and lactacystin led to a time-dependent accumulation of beta-catenin, including the appearance of high-molecular-weight beta-catenin species. Quiescent as well as serum-stimulated C7caMEK1 cells showed a higher cyclin D expression than epithelial C7Mock1 cells. The MEK inhibitor U-0126 inhibited extracellular signal-regulated kinase phosphorylation and cyclin D expression in C7caMEK1 cells and almost abolished their already reduced cell proliferation rate. We conclude that the transdifferentiated and invasive phenotype of C7caMEK1 cells is associated with a diminished expression of proteins involved in cell-cell adhesion. Although beta-catenin expression is reduced, C7caMEK1 cells show a higher expression of U-0126-sensitive cyclin D protein.

Animals↗
PubMed2004

Effects of transdifferentiation and EGF on claudin isoform expression in alveolar epithelial cells.

Rat alveolar epithelial type II cells grown on polycarbonate filters form high-resistance monolayers and concurrently acquire many phenotypic properties of type I cells. Treatment with EGF has previously been shown to increase transepithelial resistance across alveolar epithelial cell (AEC) monolayers. We investigated changes in claudin expression in primary cultured AEC during transdifferentiation to the type I cell-like phenotype (days 0, 1, and 8), and on day 5 in culture +/- EGF (10 ng/ml) from day 0 or day 4. Claudins 4 and 7 were increased, whereas claudins 3 and 5 were decreased, on later compared with earlier days in culture. Exposure to EGF led to increases in claudins 4 and 7 and decreases in claudins 3 and 5. Claudin 1 was only faintly detectable in freshly isolated type II cells and remained unchanged over time in culture and after exposure to EGF. These results suggest that increases in transepithelial resistance accompanying AEC transdifferentiation and/or EGF exposure are mediated, at least in part, by changes in the pattern of expression of specific claudin isoforms.

Animals↗
PubMed2002

Mechanisms and kinetics of Bowman's epithelial-myofibroblast transdifferentiation in the formation of glomerular crescents.

BACKGROUND: We investigated the mechanisms and kinetics of Bowman's epithelial-myofibroblast transdifferentiation in the formation of glomerular crescents. METHODS: Crescentic glomerulonephritis was induced by i.v. injection of rabbit anti-rat glomerular basement membrane antiserum in WKY rats. RESULTS: Cellular crescents (83.5% of glomeruli) were first observed at day 7 after disease induction. Immunostaining of alpha-smooth muscle actin (alpha-SMA), as a marker for the myofibroblast phenotype, was found in some periglomerular regions as early as day 3, when it was also seen in parietal epithelial cells (PEC) of Bowman's capsule at day 5 and in crescent formation at day 7. Proliferation marker Ki67-positive PEC was found at day 3, and double Ki67- and alpha-SMA-positive PEC could be seen at day 5. The migratory figure of PEC with the expression of alpha-SMA was found by immunoelectron microscopy. At day 7, some crescent cells were stained positive for PEC marker, protein gene product 9.5, in association with alpha-SMA or Ki67. Expression of transforming growth factor (TGF)-beta receptor types I and II, as well as platelet-derived growth factor (PDGF) receptor beta and PDGF-B increased in PEC as early as day 3. At day 5 marked deposition of cellular and common fibronectin, but not other extracellular matrix components examined was found in Bowman's spaces where ED 1-positive macrophages infiltrated. CONCLUSIONS: PEC may be stimulated to proliferate and/or transdifferentiate into myofibroblast phenotype possibly by action of TGF-beta and PDGF and/or binding of fibronectin to PEC, then migrate and/or proliferate, participating in glomerular crescents.

Activin Receptors, Type I↗
PubMed1996

Light and electron microscopy of stage-specific features of the transdifferentiation of mouse Meckel's cartilage chondrocytes in vitro.

The changes in the morphological characteristics of Meckel's cartilage cells in culture can be divided into five stages during their transdifferentiation to cells with an osteocyte-like phenotype, as demonstrated in this study by light and electron microscopy. Chondrocytes were isolated from day-17 embryonic mice by enzymatic digestion and inoculated at a density of 1 x 10(4) cells. The cultures were incubated at 37 degrees C and cells were harvested every week for 4 weeks and processed for light and electron microscopy, as well as an immunohistochemical analysis of type I and II collagens. The primary cultures were characterized by fibroblastic cells (stage 1) around days 2-4. Polygonal cells (stage 2) expanded on a poorly formed extracellular matrix on day 7, and then they differentiated into large, round cells (stage 3) which began to form cellular nodules. The large, round cells contained many vacuoles, which were rapidly released into the pericellular space with a significant resultant decrease in cell size. Immunostaining showed that the extracellular matrix was occupied predominantly by type II collagen after 2 weeks in culture. However, the type II collagen was gradually replaced by type 1 collagen. Cells that formed multiple layers gradually changed into small, round cells (stage 4) at the tops of nodules and ultimately expressed an osteocytic phenotype (stage 5) after further transdifferentiation.

Animals↗
PubMed1991

Molecules specific to pigment epithelial cells: expression during in situ development and in vitro lens transdifferentiation of chick embryo pigment epithelium.

The retinal pigment epithelium (PE) is a monolayer of cells and plays a vital role in the regulation of the neural retina. We prepared monoclonal antibodies directed against retinal PE cells to analyze the specificity and differentiation of these cells. Spleen cells from BALB/c mice immunized with chick embryo retinal PE cells were fused with myeloma cells. Seven independent monoclonal antibodies were obtained which specifically recognized PE cells but did not react with any other tissues examined. None of the monoclonal antibodies reacted with the choroid and skin of pigmented chicks, suggesting that these antigens were unrelated to melanogenesis. Two of the 7 antibodies reacted with the PE cells in the retina, ciliary body and iris; the remaining 5 antibodies were specific to the PE cells in the retina. In the process of in vitro lens transdifferentiation from PE cells, the distribution of an antigen detected by one monoclonal antibody changed from the cytoplasmic granules to the actin fibers and then its immunoreactivity declined. The other monoclonal antibodies did not react with the differentiated PE cells and transdifferentiated lens cells, suggesting that the antibodies might be specific to the PE cells in the differentiated state, both in vivo and in vitro. During the in situ developmental process, each monoclonal antibody began to be immunoreactive to future PE cells in the optic eye cup at various stages from 72 to 120 h. The molecules common to all types of PE cells were expressed earlier than those specific to PE cells of the retina. Future ciliary and iridial PE cells appeared to transiently express the molecules specific to the retinal PE cells before the tip of eye cup contacted the lens vesicle. These data suggest that the monoclonal antibodies established in this study are powerful probes for exploring the functions and differentiation of PE cells.

Actins↗
PubMed2004

Both cell fusion and transdifferentiation account for the transformation of human peripheral blood CD34-positive cells into cardiomyocytes in vivo.

BACKGROUND: Adult human peripheral blood CD34-positive (CD34+) cells appear to transform into cardiomyocytes in the injured hearts of severe combined immunodeficient mice. It remains unclear, however, whether the apparent transformation is the result of transdifferentiation of the donor stem cells or of fusion of the donor cell with the cardiomyocyte of the recipients. METHODS AND RESULTS: We performed flow cytometry analyses of cells isolated from the hearts of mice that received human CD34+ cells. Human HLA-ABC antigen and cardiac troponin T or Nkx2.5 were used as markers for cardiomyocytes derived from human CD34+ cells, and HLA-ABC and VE-cadherin were used to identify the transformed endothelial cells. The double-positive cells were collected and interphase fluorescence in situ hybridization was used to detect the expression of human and mouse X chromosomes in these cells. We found that 73.3% of nuclei derived from HLA+ and troponin T+ or Nkx2.5+ cardiomyocytes contain both human and mouse X chromosomes and 23.7% contain only human X chromosome. In contrast, the nuclei of HLA-, troponin T+ cells contain only mouse X chromosomes. Furthermore, 97.3% of endothelial cells derived from CD34+ cells contained human X chromosome only. CONCLUSIONS: Thus, both cell fusion and transdifferentiation may account for the transformation of peripheral blood CD34+ cells into cardiomyocytes in vivo.

Animals↗
PubMed2005

Mobilization of bone marrow-derived cells enhances the angiogenic response to hypoxia without transdifferentiation into endothelial cells.

Bone marrow-derived cells (BMCs) have been implicated as a modifiers of vascular growth either directly by transdifferentiation into endothelial cells (ECs) or indirectly through growth factor release. To examine these possibilities under physiological conditions, we developed a model of hypoxia-mediated angiogenesis in the mouse spinotrapezius muscle. This allows whole-mount analysis; therefore, the morphology and location of BMCs within the vascular network may be observed along with differentiation markers. We exposed bone marrow transplant chimeric mice to hypoxia and treated a subset with granulocyte macrophage colony-stimulating factor. Exposure to hypoxia caused an 13% increase in capillary density relative to control. Hypoxia did not increase the overall number of muscle-resident BMCs, but did increase the number of rounded BMCs by 25%. There was no discernable BMC contribution to the endothelium, although some BMCs assumed a pericyte morphology around capillaries. Granulocyte macrophage colony-stimulating factor treatment further increased the number of round BMCs within the muscle and caused a 23% increase in angiogenesis. The results of this study suggest a potentially beneficial action of BMCs during hypoxia through paracrine release of growth factors but not transdifferentiation into ECs.

Animals↗
PubMed1997

Embryonic endothelial cells transdifferentiate into mesenchymal cells expressing smooth muscle actins in vivo and in vitro.

All blood vessels are lined by endothelium and, except for the capillaries, surrounded by one or more layers of smooth muscle cells. The origin of the embryonic vascular smooth muscle cell has until now been described from neural crest and locally differentiating mesenchyme. In this study, we have substantial evidence that quail embryonic endothelial cells are competent in the dorsal aorta of the embryo to transdifferentiate into subendothelial mesenchymal cells expressing smooth muscle actins in vivo. At the onset of smooth muscle cell differentiation, QH1-positive endothelial cells were experimentally labeled with a wheat germ agglutinin-colloidal gold marker (WGA-Au). No labeled subendothelial cells were observed at this time. However, 19 hours after the endothelial cells had endocytosed, the WGA-Au-labeled subendothelial mesenchymal cells were observed in the aortic wall. Similarly, during the same time period, subendothelial cells that coexpressed the QH1 endothelial marker and a mesenchymal marker, alpha-smooth muscle actin, were present. In such cells, QH1 expression was reduced to a cell membrane localization. A similar antigen switch was also observed during endocardial-mesenchymal transformation in vitro. Our results are the first direct in vivo evidence that embryonic endothelial cells may transdifferentiate into candidate vascular smooth muscle cells. These data arouse new interpretations of the origin and differentiation of the cells of the vascular wall in normal and diseased vessels.

Actins↗