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At least 1,387 records · Page 77Linked to original sources
PubMed1999

Induction of alveolar type II cell differentiation in embryonic tracheal epithelium in mesenchyme-free culture.

We have previously shown that fetal lung mesenchyme can reprogram embryonic rat tracheal epithelium to express a distal lung phenotype. We have also demonstrated that embryonic rat lung epithelium can be induced to proliferate and differentiate in the absence of lung mesenchyme. In the present study we used a complex growth medium to induce proliferation and distal lung epithelial differentiation in embryonic tracheal epithelium. Day-13 embryonic rat tracheal epithelium was separated from its mesenchyme, enrobed in growth factor-reduced Matrigel, and cultured for up to 7 days in medium containing charcoal-stripped serum, insulin, epidermal growth factor, hepatocyte growth factor, cholera toxin, fibroblast growth factor 1 (FGF1), and keratinocyte growth factor (FGF7). The tracheal epithelial cells proliferated extensively in this medium, forming lobulated structures within the extracellular matrix. Many of the cells differentiated to express a type II epithelial cell phenotype, as evidenced by expression of SP-C and osmiophilic lamellar bodies. Deletion studies showed that serum, insulin, cholera toxin, and FGF7 were necessary for maximum growth. While no single deletion abrogated expression of SP-C, deleting both FGF7 and FGF1 inhibited growth and prevented SP-C expression. FGF7 or FGF1 as single additions to the medium, however, were unable to induce SP-C expression, which required the additional presence of serum or cholera toxin. FGF10, which binds the same receptor as FGF7, did not support transdifferentiation when used in place of FGF7. These data indicate that FGF7 is necessary, but not sufficient by itself, to induce the distal rat lung epithelial phenotype, and that FGF7 and FGF10 play distinct roles in lung development.

Animals↗
PubMed2000

Signaling and transcriptional regulation in early mammalian eye development: a link between FGF and MITF.

During vertebrate eye development, the optic vesicle is partitioned into a domain at its distal tip that will give rise to the neuroretina, and another at its proximal base that will give rise to the pigmented epithelium. Both domains are initially bipotential, each capable of giving rise to either neuroretina or pigmented epithelium. The partitioning depends on extrinsic signals, notably fibroblast growth factors, which emanate from the overlying surface ectoderm and induce the adjacent neuroepithelium to assume the neuroretinal fate. Using explant cultures of mouse optic vesicles, we demonstrate that bipotentiality of the optic neuroepithelium is associated with the initial coexpression of the basic-helix-loop-helix-zipper transcription factor MITF, which is later needed solely in the pigmented epithelium, and a set of distinct transcription factors that become restricted to the neuroretina. Implantation of fibroblast growth factor-coated beads close to the base of the optic vesicle leads to a rapid downregulation of MITF and the development of an epithelium that, by morphology, gene expression, and lack of pigmentation, resembles the future neuroretina. Conversely, the removal of the surface ectoderm results in the maintenance of MITF in the distal optic epithelium, lack of expression of the neuroretinal-specific CHX10 transcription factor, and conversion of this epithelium into a pigmented monolayer. This phenomenon can be prevented by the application of fibroblast growth factor alone. In Mitf mutant embryos, parts of the future pigment epithelium become thickened, lose expression of a number of pigment epithelium transcription factors, gain expression of neuroretinal transcription factors, and eventually transdifferentiate into a laminated second retina. The results support the view that the bipotential optic neuroepithelium is characterized by overlapping gene expression patterns and that selective gene repression, brought about by local extrinsic signals, leads to the separation into discrete expression domains and, hence, to domain specification.

Animals↗
PubMed2001

Expression of activated Ras during Dictyostelium development alters cell localization and changes cell fate.

There is now a body of evidence to indicate that Ras proteins play important roles in development. Dictyostelium expresses several ras genes and each appears to perform a distinct function. Previous data had indicated that the overexpression of an activated form of the major developmentally regulated gene, rasD, caused a major aberration in morphogenesis and cell type determination. We now show that the developmental expression of an activated rasG gene under the control of the rasD promoter causes a similar defect. Our results indicate that the expression of activated rasG in prespore cells results in their transdifferentiation into prestalk cells, whereas activated rasG expression in prestalk causes gross mislocalization of the prestalk cell populations.

Animals↗
PubMed2003

Chronic acid exposure leads to activation of the cdx2 intestinal homeobox gene in a long-term culture of mouse esophageal keratinocytes.

To explore mechanisms whereby Malpighian keratinocytes can transdifferentiate into an intestinal-like epithelium, as observed in the early steps of Barrett's esophagus (BE) development, long-standing cultures of esophageal keratinocytes derived from normal mouse esophageal explants were developed. These cells were able to form multilayers and to differentiate on filter support by the formation of differentiated layers of basal cells (cytokeratine 14 positive) on which secondary suprabasal cell layers (cytokeratine 4 positive) spontaneously developed. Thus, these cultured cells, referred to as P3E6, reproduced, at least in part, the proliferation and stratification pattern existing in the normal esophagus. Because chronic exposure to acid pH is known to be a critical factor for BE development, culture medium at pH 3.5 was added into the apical chamber of cell cultures. This led to a decrease in the overall number of cells but it did not affect cell proliferation. Furthermore, external acid environment triggered expression of the GFP reporter gene fused downstream of the cdx2 intestinal homeogene regulatory sequences in P3E6 transfected cells. Expression of the endogenous CDX2 protein, detected by western blot and immunocytochemical analysis, correlated with promoter activation. These findings demonstrate that chronic exposure of esophageal keratinocytes to acid pH induces transcription of cdx2, an intestinal specific homeobox gene known to play a critical role in the differentiation and maintenance of intestinal epithelial functions. The results suggest that chronic acid exposure can modify the fate of P3E6 esophageal keratinocytes towards an intestinal program. This can be a key step in the development of intestinal metaplasia often observed in esophagus-cardia junction.

Adult↗
PubMed2006

The role of MAP65-1 in microtubule bundling during Zinnia tracheary element formation.

The MAP65 family of microtubule-associated proteins performs various functions at different stages of the cell cycle and differentiation. In this study, we have investigated the synchronous transdifferentiation of Zinnia mesophyll cells into tracheary elements in vitro. This allowed us to examine the role of the microtubule-associated protein MAP65 during the characteristic bunching of cortical microtubules that underlie the developing ribs of secondarily thickened cell wall. Immunofluorescence confirmed the microtubule bundles to be decorated with anti-MAP65 antibodies. Three Zinnia MAP65 genes were examined; the expression of ZeMAP65-1 was found to match that of the differentiation marker TED2 and both were found to be upregulated upon addition of inductive hormones. We cloned the full-length sequence of ZeMAP65-1 and found it to be most similar to other MAP65 isoforms known to bundle microtubules in other plant species. However, not all MAP65 proteins crosslink cortical microtubules and so, to confirm its potential bundling capacity, ZeMAP65-1 was transiently overexpressed in Arabidopsis suspension cells. This resulted in the super-bundling of microtubules in patterns resembling those in differentiating xylem cells. These findings establish that the MAP65-1 group of proteins is responsible for the bundling of cortical microtubules during secondary cell wall formation of xylogenesis as well as during the expansion of primary cell walls.

Arabidopsis↗
PubMed2006

Acquisition and extinction of gene expression programs are separable events in heterokaryon reprogramming.

Although differentiated cells normally retain cell-type-specific gene expression patterns throughout their lifetime, cell identity can sometimes be modified or reversed in vivo by transdifferentiation, or experimentally through cell fusion or by nuclear transfer. To examine the epigenetic changes that are required for the dominant conversion of lymphocytes to muscle, we generated heterokaryons between human B lymphocytes and mouse C2C12 myotubes. We show that within 2 days of heterokaryon formation lymphocyte nuclei adopt an architecture resembling that of muscle and then initiate the expression of muscle-specific genes in the same temporal order as developing muscle. The establishment of this muscle-specific program is coordinated with the shutdown of several lymphocyte-associated genes. Interestingly, erasing lymphocyte identity in reprogrammed cells requires histone deacetylase (HDAC) activity. Inhibition of HDAC activity during reprogramming selectively blocks the silencing of lymphocyte-specific genes but does not prevent the establishment of muscle-specific gene expression. Successful reprogramming is therefore shown to be a multi-step process in which the acquisition and extinction of lineage-specific gene programs are separable events.

Animals↗
PubMed2003

Hepatic stellate cells: unique characteristics in cell biology and phenotype.

Hepatic stellate cells (HSCs), a mesenchymal cell type in hepatic parenchyma, have unique features with respect to their cellular origin, morphology, and function. Normal, quiescent HSCs function as major vitamin A-storing cells containing over 80% of total vitamin A in the body to maintain vitamin A homeostasis. HSCs are located between parenchymal cell plates and sinusoidal endothelial cells, and extend well-developed, long processes surrounding sinusoids in vivo as pericytes. However, HSCs are known to be 'activated' or 'transdifferentiated' to myofibroblast-like phenotype lacking cytoplasmic lipid droplets and long processes in pathological conditions such as liver fibrosis and cirrhosis, as well as merely during cell culture after isolation. HSCs are the predominant cell type producing extracellular matrix (ECM) components as well as ECM degrading metalloproteases in hepatic parenchyma, indicating that they play a pivotal role in ECM remodeling in both normal and pathological conditions. Recent findings have suggested that HSCs have a neural crest origin from their gene expression pattern similar to neural cell type and/or smooth muscle cells and myofibroblasts. The morphology and function of HSCs are regulated by ECM components as well as by cytokines and growth factors in vivo and in vitro. Liver regeneration after partial hepatectomy might be an invaluable model to clarify the HSC function in elaborate organization of liver tissue by cell-cell and cell-ECM interaction and by growth factor and cytokine regulation.

Animals↗
PubMed2004

Alveolar epithelial type I cells express beta2-adrenergic receptors and G-protein receptor kinase 2.

Beta2-Adrenergic agonists stimulate alveolar epithelial sodium (Na(+)) transport and lung fluid clearance. Alveolar type II (AT2) cells have been reported to express beta2-adrenergic receptors (beta2AR). Given the large surface area covered by alveolar type I (AT1) cells and their potential role in alveolar fluid removal, we were interested in learning if AT1 cells express beta2AR as well. Because beta2AR is potentially susceptible to desensitization by G-protein-coupled receptor kinase 2 (GRK2), we also undertook localization of GRK2. beta2AR and GRK2 expression was evaluated in whole lung, isolated alveolar epithelial cells (AECs), and AECs in primary culture, and was localized to specific AEC phenotypes by immunofluorescence techniques. beta2AR is highly expressed in AT1 cells. beta2AR mRNA increases with time in culture as AT2 cells transdifferentiate towards the AT1 cell phenotype. Immunoreactive GRK2 is seen in both AT1 and AT2 cells in similar amounts. These data suggest that both AT1 and AT2 cells may contribute to the increased alveolar Na(+) and water clearance observed after exposure to beta2 adrenergic agents. Both cell types also express GRK2, suggesting that both may undergo desensitization of beta2AR with subsequent decline in the stimulatory effects of beta2-adrenergic agonists over time.

Animals↗
PubMed2005

The pituitary in Turner syndrome.

Although Turner syndrome is not uncommon, studies of the pituitary in this condition are few. We undertook a histochemical and immunohistochemical study of four cases. As expected, "gonadal failure cells" were seen, but without recognizable gonadotroph hyperplasia. No gonadotroph adenomas were encountered. Instead, three silent corticotroph microadenomas were seen; their etiology remains unexplained. The question of whether the simultaneous occurrence of Turner syndrome and silent corticotroph adenoma is causal or incidental cannot be answered on the basis of the study of our material. Because these two diseases are rare, an etiologic association has to be considered. For example, it is possible that (a) protracted stimulation of gonadotrophs leads to transdifferentiation to corticotrophs, a hypothesis supported by the fact that normal and neoplastic gonadotrophs can contain ACTH and that some corticotroph adenomas produce LH and/or alpha subunit, (b) corticotrophs develop gonadotropin-releasing hormone (GnRH) receptors and undergo neoplastic transformation when exposed to continuous elevation of GnRH, FSH, and/or LH levels, and (c) the genetic defect in Turner syndrome promotes the formation of corticotroph adenomas.

Adenoma↗
PubMed2005

Plasticity and tissue regenerative potential of bone marrow-derived cells.

Diverse in vivo studies have suggested that adult stem cells might have the ability to differentiate into cell types other than those of the tissues in which they reside or derive during embryonic development. This idea of stem cell "plasticity" has led investigators to hypothesize that, similar to embryonic stem cells, adult stem cells might have unlimited tissue regenerative potential in vivo, and therefore, broad and novel therapeutic applications. Since the beginning of these observations, our group has critically examined these exciting possibilities for mouse bone marrow-derived cells by taking advantage of well-characterized models of tissue regeneration, Cre/lox technology, and novel stem cell isolation protocols. Our experimental evidence does not support plasticity of hematopoietic stem cells as a frequent physiological event, but rather indicates that cell fusion could account for reported cases of hematopoietic stem cell plasticity or "transdifferentiation" in vivo. Our studies highlight the need for meticulous technical controls during the isolation, transplantation, tracking, and analysis of bone marrow-derived cells during in vivo studies on plasticity. Further studies will be necessary to better define experimental conditions and criteria to unequivocally prove or reject plasticity in vivo. In this review, we focus on results from several studies from our laboratory, and discuss their conclusions and implications.

Animals↗
PubMed2004

Retinal stem cells and regeneration.

The optic vesicle gives rise to several very different epithelial tissues, including the neural retina, the pigmented epithelium, the iris, the ciliary epithelium of the ciliary body and the optic stalk. Retinal regeneration can arise from several different cellular sources; in some species, the process involves interconversion, or transdifferentiation, among cells of the different tissue types. Therefore, prior to a discussion of retinal regeneration, we will briefly discuss current knowledge about the influence of signaling molecules in cell fate determination in ocular tissues. Next, we will detail the evidence for neurogenesis in the mature retina. Lastly, we will describe various types of regenerative phenomena that occur in the retina, from complete regeneration of functional retina in fish and amphibians, to the more limited neuronal production that occurs in avian and mammalian retinas.

Animals↗
PubMed2004

From embryonic induction to cell lineages: revisiting old problems for modern study.

A history of embryological studies of lens development and regeneration is sketched, paying special attention to the contribution of these studies to the conceptual aspect of embryology and later developmental biology. Emphasis is made on the fact that the interaction of different tissues during development, namely embryonic induction, was first discovered during studies of the lens and that the degree of the dependence of lens development on the inductive effect of the eye-cup varies among different species. Studies along the line of comparative-experimental embryology at the species level should be informative, in particular in combination with the recent trend of evo-devo studies. The processes of lens regeneration and in vitro transdifferentiation indicate the existence of multiple cell lineages with the potential of lens development in one animal. The occurrence of Wolffian lens regeneration in nature can be reconsidered from the new "eco-devo" viewpoint.

Animals↗
PubMed2005

The instability of the neural crest phenotypes: Schwann cells can differentiate into myofibroblasts.

In the vertebrate embryo, the neural crest cells (NCCs) that migrate out from the neural primordium yield multiple phenotypes, including melanocytes, peripheral neurones and glia and, in the head, cartilage, bone, connective cells and myofibroblasts / vascular smooth muscle cells (SMCs). The differentiation of pluripotent NCCs is mainly directed by local growth factors. Even at postmigratory stages, NC-derived cells exhibit some fate plasticity. Thus, we reported earlier that pigment cells and Schwann cells are able in vitro to interconvert in the presence of endothelin 3 (ET3). Here, we further investigated the capacity of Schwann cells to reprogram their phenotype. We show that purified quail Schwann cells in dissociated cultures produce alpha smooth muscle actin ((alpha)SMA)-expressing myofibroblasts through the generation of a pluripotent progeny. This transdifferentiation took place independently of ET3, but was promoted by transforming growth factor beta1 (TGF(beta)1). Moreover, when implanted into chick embryos, the Schwann cells were found to contribute with host cephalic NCCs to perivascular SMCs. These data provided the first evidence for the acquisition of an NC-derived mesenchymal fate by Schwann cells and further demonstrate that the differentiation state of NC-derived cells is unstable and capable of reprogramming. The high plasticity of Schwann cells evidenced here also suggests that, as in the CNS, glial cells of the PNS may function as NC stem cells in particular circumstances such as repair.

Animals↗
PubMed2006

C/EBPalpha and C/EBPbeta are markers of early liver development.

Pancreatic cells can be converted to hepatocytes by overexpression of C/EBPbeta (Shen, C-N, Slack, J.M.W. and Tosh, D., 2000. Molecular basis of transdifferentiation of pancreas to liver. Nature Cell Biology 2: 879-887). This suggested that expression of one or more C/EBP factors may distinguish liver and pancreas in early development. We have now studied the early expression of C/EBPalpha and C/EBPbeta in the mouse embryo and show that both are expressed exclusively in the early liver bud and not in the pancreatic buds. Their expression is identical to that of hepatocyte nuclear factor 4 (HNF4), another key hepatic transcription factor and alpha-fetoprotein (AFP), a differentiation product characteristic of immature hepatocytes. Both are complementary to the early expression of Pdx1, a key pancreatic transcription factor. These results are consistent with the idea that C/EBP factors are master regulators for liver development.

Animals↗
PubMed2005

Photopigment coexpression in mammals: comparative and developmental aspects.

In mammals, each cone had been thought to contain only one single type of photopigment. It was not until the early 1990s that photopigment coexpression was reported. In the house mouse, the distribution of color cones shows a characteristic division. Whereas in the upper retinal field the ratio of short wave to middle-to-long wave cones falls in the usual range (1:10), in the ventral retinal field M/L-pigment expression is completely missing. In the transitional zone, numerous dual cones are detectable (spatial coexpression). In other species without retinal division, dual cones appear during development, suggesting that M/L-cones develop from S-cones. Dual elements represent a transitory stage in M/L-cone differentiation that disappear with maturation (transitory coexpression). These two phenomena seem to be mutually exclusive in the species studied so far. In the comparative part of this report the retinal cone distribution of eight rodent species is reported. In two species dual cones appear in adult specimens without retinal division, and dual elements either occupy the dorsal peripheral retina, or make up the entire cone population. This is the first observation proving that all cones of a retina are of dual nature. These species are good models for the study of molecular control of opsin expression and renders them suitable sources of dual cones for investigations on the role and neural connections of this peculiar cone type. In the developmental part, the retinal maturation of other species is examined to test the hypothesis of transitory coexpression. In these species S-pigment expression precedes that of the M/L-pigment, but dual cones are either identified in a small number or they are completely missing from the developing retina. These results exclude a common mechanism for M/L-cone maturation: they either transdifferentiate from S-cones or develop independently.

Animals↗
PubMed2005

Labeling of adult stem cells for in vivo-application in the human heart.

Tissue regeneration with human hematopoietic or mesenchymal stem cells has become a fashionable research topic. In cardiology, intracoronary injection of adult stem cells has already been used for the treatment of human myocardial infarction and ischemic cardiomyopathy. The experimental background of such therapies, however, i.e. the potential of adult stem cells to regenerate myocardium through "transdifferentiation" of hematopoietic or mesenchymal stem cells into cardiomyocytes described in animal models, has recently been challenged by other experimental data. Nonetheless, clinical trials are continuing. This may be due to the fact that, in open-labeled pilot trials, a benefit of intracoronary injection of adult stem cells for the treatment of myocardial infarction has been described. As pilot trials may overemphasize the beneficial effects of intracoronary injection of bone marrow stem cells, controlled double-blinded randomised multicenter studies are warranted. Furthermore, a careful characterization of the cells involved in the proposed cardiac repair as well as in vivo-monitoring of such cells following intracoronary injection in humans might help to answer many essential questions linked to this important research topic. The latter requires biocompatible labeling. This review focuses on the technologies available for stem cell labeling and summarizes the arguments and contra-arguments to use these labeling technologies for application in humans.

Adult↗
PubMed2005

Nuclear reprogramming and adult stem cell potential.

Cell-based therapy may represent a new strategy to treat a vast array of clinical disorders including neurodegenerative diseases. Recent observations indicate that adult somatic stem cells have the capacity to contribute to the regeneration of different tissues, suggesting that differentiative restrictions are not completely irreversible and can be reprogrammed. Cell fusion might account for some changed phenotype of adult cells but it seems to be biologically irrelevant for its extreme rarity. Other experimental evidences are compatible with the hypothesis of wide multipotency of well-defined stem cell populations, but also with transdifferentiation and/or dedifferentiation. Further studies on nuclear reprogramming mechanisms are necessary to fulfil the promise for developing autologous cellular therapies.

Adult↗
PubMed2006

Adult stem and transit-amplifying cell location.

Adult stem cells (ASC)--able to self renew and to intervene in maintaining the structural and functional integrity of their original tissue--can express greater plasticity than traditionally attributed to them, adopting functional phenotypes and expression profiles of cells from other tissues. Therefore, they could be useful to regenerative medicine and tissue engineering. Transit-amplifying cells (TAC) are committed progenitors among the ASC and their terminally differentiated daughter cells. The ASC reside in a specialized physical location named niche, which constitutes a three-dimensional microenviroment where ASC and TAC are protected and controlled in their self-renewing capacity and differentiation. The niche can be located near or far from the recruitment point, requiring a short or long-distance cellular migration, respectively. This paper briefly reviews the current status of research about ASC plasticity, transdifferentiation, fusion and functional adaptation mechanisms. Subsequently, ASC and TAC occurrence, characteristics and location have been considered in the skin, cornea, respiratory tract, teeth, gastrointestinal tract, liver, pancreas, salivary glands, kidney, breast, prostate, endometrium, mesenchyma, bone marrow, skeletal and cardiac muscle, nervous system and pituitary gland. Moreover, the role of cancer ASC has also been revised.

Animals↗