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Results for “Transdifferentiation”

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At least 451 records · Page 25Linked to original sources
PubMed2001

Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism.

Transforming growth factor-beta1 (TGF-beta) can be tumor suppressive, but it can also enhance tumor progression by stimulating the complex process of epithelial-to-mesenchymal transdifferentiaion (EMT). The signaling pathway(s) that regulate EMT in response to TGF-beta are not well understood. We demonstrate the acquisition of a fibroblastoid morphology, increased N-cadherin expression, loss of junctional E-cadherin localization, and increased cellular motility as markers for TGF-beta-induced EMT. The expression of a dominant-negative Smad3 or the expression of Smad7 to levels that block growth inhibition and transcriptional responses to TGF-beta do not inhibit mesenchymal differentiation of mammary epithelial cells. In contrast, we show that TGF-beta rapidly activates RhoA in epithelial cells, and that blocking RhoA or its downstream target p160(ROCK), by the expression of dominant-negative mutants, inhibited TGF-beta-mediated EMT. The data suggest that TGF-beta rapidly activates RhoA-dependent signaling pathways to induce stress fiber formation and mesenchymal characteristics.

Animals↗
PubMed2004

Spontaneous fusion of cells between species yields transdifferentiation and retroviral transfer in vivo.

Human cells can fuse with damaged or diseased somatic cells in vivo. Whether human cells fuse in vivo in the absence of disease and with cells of disparate species is unknown. Such a question is of current interest because blood exchanges between species through direct physical contact, via insect vectors or parasitism, are thought to underlie the transmission of zoonotic agents. In a model of human-pig chimerism, we show that some human hematopoietic stem cells engrafted in pigs contain both human and porcine chromosomal DNA. These hybrid cells divide, express human and porcine proteins, and contribute to porcine nonhematopoietic tissues. In addition, the hybrid cells contain porcine endogenous retroviral DNA sequences and are able to transmit this virus to uninfected human cells in vitro. Thus, spontaneous fusion can occur in vivo between the cells of disparate species and in the absence of disease. The ability of these cell hybrids to acquire and transmit retroviral elements together with their ability to integrate into tissues could explain genetic recombination and generation of novel pathogens. * differentiation * fusion * retrovirus

Animals↗
PubMed2005

Improved retention of zymogen granules in cultured murine pancreatic acinar cells and induction of acinar-ductal transdifferentiation in vitro.

OBJECTIVES: To establish a primary culture model for murine pancreatic acinar cells and to investigate the effects of different culture conditions on the phenotype and plasticity of these cells in extended culture. METHODS: Acinar cells, cultured in Chee (CME) or Waymouth/Ham F-12 (WHME) media, exhibited 2 markedly dissimilar phenotypes. We employed 5'-bromo-2'-deoxyuridine (BrdU) incorporation, immunocytochemistry, and electron microscopy to investigate differences in cell cycle status and phenotype. RESULTS: CME-cultured cells grew as discrete epithelial islands and retained zymogen granules and endoplasmic reticulum stacks, yet expressed cytokeratin 7, suggesting that they comprise an intermediate between the acinar and ductal cell types. Observed by time-lapse videomicroscopy, cells transferred to WHME formed a confluent monolayer, flattened and dedifferentiated to a duct-like phenotype typified by loss of secretory apparatus, variable beta-catenin expression, an elongated teardrop shape, increased cell size, and nuclear pleomorphism. Transition between phenotypes did not involve apoptosis as assessed by morphologic criteria in Feulgen-stained cultures. The flattened cells exhibited increased BrdU incorporation and mitotic index, suggesting that dedifferentiation precedes the capacity for increased cell cycle entry, while the appearance of meganuclei is consistent with amplified DNA content. We also demonstrate greatly improved gene delivery to cultured acinar cells by adenovirus-mediated transduction compared with lipid-mediated transfection. CONCLUSIONS: This in vitro model confirms the plasticity of acinar cells and may serve to delineate the changes underlying acinar cell dedifferentiation and acquisition of a duct-like pluripotent phenotype.

Adenoviridae↗
PubMed2005

Altered melanocyte differentiation and retinal pigmented epithelium transdifferentiation induced by Mash1 expression in pigment cell precursors.

Transcription factor genes governing pigment cell development that are associated with spotting mutations in mice include members of several structural transcription factor classes but not members of the basic helix-loop-helix (bHLH) class, important for neurogenesis and myogenesis. To determine the effects of bHLH factor expression on pigment cell development, the neurogenic bHLH factor Mash1 was expressed early in pigment cell development in transgenic mice from the dopachrome tautomerase (Dct) promoter. Dct:Mash1 transgenic founders exhibit variable microphthalmia and patchy coat color hypopigmentation. Transgenic F1 mice exhibit microphthalmia with complete coat color dilution. Marker analysis demonstrates that Mash1 expression in the retinal pigmented epithelium (RPE) initiates neurogenesis in this cell layer, whereas expression in remaining neural crest-derived melanocytes alters their differentiation, in part by profoundly downregulating expression of the p (pink-eyed dilution) gene, while maintaining their cell fate. The effects of transcriptional perturbation of pigment cell precursors by Mash1 further highlight differences between pigment cells of distinct developmental origins, and suggest a mechanism for the alteration of melanogenesis to result in marked coat color dilution.

Animals↗
PubMed2004

Stem cell plasticity: from transdifferentiation to macrophage fusion.

The past 5 years have witnessed an explosion of interest in using adult-derived stem cells for cell and gene therapy. This has been driven by a number of findings, in particular, the possibility that some adult stem cells can differentiate into non-autologous cell types, and also the discovery of multipotential stem cells in adult bone marrow. These discoveries suggested a quasi-alchemical nature of cells derived from adult organs, thus raising new and exciting therapeutic possibilities. Recent data, however, argue against the whole idea of stem cell 'plasticity', and bring into question the therapeutic strategies based upon this concept. Here, we will review the current state of knowledge in the field and discuss some of the clinical implications.

Adult↗
PubMed2006

TGFbeta1 induces epithelial-mesenchymal transition, but not myofibroblast transdifferentiation of human kidney tubular epithelial cells in primary culture.

The origin and fate of renal interstitial myofibroblasts (MFs), the effector cells of renal fibrosis, are still debated. Experimental evidence suggests that renal MFs derive from tubular epithelial cells throughout the epithelial-mesenchymal transition (EMT) process. Primary human tubular epithelial cells (HUTECs) were cultured for 4 and 6 days on plastic or type I collagen-coated plates with 1, 5, 10 and 50 ng/ml of transforming growth factor beta1 (TGFbeta1). The EMT process was monitored by morphology and immunophenotyping for alphaSMA, cytokeratin 8-18, E-cadherin, vimentin and collagen III. Quantitative comparative RT/PCR and real-time PCR were used to evaluate the expression of collagen III and IV, fibronectin, tenascin, MMP-2, CTGF, E-cadherin and cadherin 11 genes, as well as those of the Smad signalling pathway. TGFbeta1 was found capable of reactivating the mesenchymal programme switched off during tubulogenesis, but it induced no de novo expression of alphaSMA gene or myofibroblast phenotype. We demonstrate that the EMT process is conditioned by the extracellular matrix and characterized by TGFbeta1-driven Smad3 downregulation. Our study results suggest that TGFbeta1 could function as a classic embryonal inducer, initiating a cascade of de-differentiating events that might be further controlled by other factors in the cellular environment.

Actins↗
PubMed1991

Evidence for the extralenticular expression of members of the beta-crystallin gene family in the chick and a comparison with delta-crystallin during differentiation and transdifferentiation.

The beta-crystallins are major water soluble proteins of vertebrate lens fibre cells and have previously been regarded as lens-specific proteins: however beta B2-and beta A3/A1-crystallin RNAs are transcribed and beta-crystallin polypeptides are detectable in the developing chick retina. The beta-crystallin RNA is transcribed in a subpopulation of retina cells and the number of transcribing cells and the level of beta-crystallin polypeptides increase during the differentiation of the retina. Several tissues express beta-crystallin polypeptides, but individual tissues are characterised by qualitative and quantitative differences in the beta- and delta-crystallin polypeptides expressed. The expression of beta-crystallins appears to be non-random as defined by tissue distribution, cellular localisation and ontogeny, implying a function for extralenticular beta-crystallins and a complex mechanism for the regulation of their expression.

Animals↗
PubMed2001

Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations.

Multipotent stem cells are clonal cells that self-renew as well as differentiate to regenerate adult tissues. Whereas stem cells and their fates are known by unique genetic marker studies, the fate and function of these cells are best studied by their prospective isolation. This review is about the properties of various highly purified tissue-specific multipotent stem cells and purified oligolineage progenitors. We contend that unless the stem or progenitor cells in question have been purified to near homogeneity, one cannot know whether their generation of expected (or unexpected) progeny is a property of a known cell type. It is interesting that in the hematopoietic system the only long-term self-renewing cells in the stem and progenitors pool are the hematopoietic stem cells. This fact is discussed in the context of normal and leukemic hematopoiesis.

Animals↗
PubMed2002

Neural stem cells: plasticity and their transdifferentiation potential.

The presence of resident stem cells in adult tissues is of fundamental importance for the maintenance of their structural and functional integrity. In fact, throughout life, somatic stem cells attend to the critical function of substituting terminally differentiated cells lost to physiological turnover, injury or disease. Thence, one of the basic dogmata in tissue biology holds that the differentiation potential of an adult stem cell is restricted to the generation of the mature cell lineages found in the tissue to which the stem cell belongs. A plethora of recent evidences from many groups, including ours, is now providing evidence that adult stem cells may possess a broader differentiation repertoire than expected and that their fate potential may not be as tissue specific as once thought. The initial example of an unforeseen, trans-germ layer plasticity - that seems now to emerge as a prototypic functional trait of various somatic stem cells of different origin - has come from the reported awakening of a latent hemopoietic developmental capacity in stem cells isolated from the adult mammalian brain following their transplantation into sub-lethally irradiated mice. More recently, it has been shown that adult neural stem cells can differentiate into a wide array of bodily cells of different origin when injected into the blastocyst and into myogenic cells when transplanted into the adult regenerating skeletal muscle. Moreover, bone marrow stem cells can now give rise to skeletal muscle, hepatic and brain cells, whereas muscle precursors can generate blood cells. In this article, we review some of the basic notions regarding the functional properties of the adult neural stem cells and discuss findings in the expanding area of trans-germ layer conversion, with emphasis on the neural stem cell.

Animals↗
PubMed1999

Soluble transforming growth factor-beta type II receptor inhibits negative remodeling, fibroblast transdifferentiation, and intimal lesion formation but not endothelial growth.

Using the rat balloon catheter denudation model, we examined the role of transforming growth factor-beta (TGF-beta) isoforms in vascular repair processes. By en face in situ hybridization, proliferating and quiescent smooth muscle cells in denuded vessels expressed high levels of mRNA for TGF-beta1, TGF-beta2, TGF-beta3, and lower levels of TGF-beta receptor II (TGF-betaRII) mRNA. Compared with normal endothelium, TGF-beta1 and TGF-beta2, as well as TGF-betaRII, mRNA were upregulated in endothelium at the wound edge. Injected recombinant soluble TGF-betaRII (TGF-betaR:Fc) localized preferentially to the adventitia and developing neointima in the injured carotid artery, causing a reduction in intimal lesion formation (up to 65%) and an increase in lumen area (up to 88%). The gain in lumen area was largely due to inhibition of negative remodeling, which coincided with reduced adventitial fibrosis and collagen deposition. Four days after injury, TGF-betaR:Fc treatment almost completely inhibited the induction of smooth muscle alpha-actin expression in adventitial cells. In the vessel wall, TGF-betaR:Fc caused a marked reduction in mRNA levels for collagens type I and III. TGF-betaR:Fc had no effect on endothelial proliferation as determined by reendothelialization of the denuded rat aorta. Together, these findings identify the TGF-beta isoforms as major factors mediating adventitial fibrosis and negative remodeling after vascular injury, a major cause of restenosis after angioplasty.

Actins↗