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PubMed2006

Porcine peroxisome proliferator-activated receptor gamma induces transdifferentiation of myocytes into adipocytes.

Peroxisome proliferator-activated receptor gamma2 (PPARgamma) is a nuclear transcription factor that regulates adipocyte differentiation and lipogenic genes during adipogenesis. The activity of rodent PPARgamma is regulated by phosphorylation of serine 112. The current experiment was designed to study the ability of porcine PPARgamma to stimulate transdifferentiation of myoblasts to adipocytes by overexpressing wild-type PPARgamma or mutated PPARgamma (serine 112 was mutated to alanine) in mouse myoblast cells. The expression of adipogenic marker genes (adipocyte fatty acid binding protein, lipoprotein lipase, and glycerol-3 phosphate dehydrogenase) in cells stably expressing mutated porcine PPARgamma was greater than in cells with wild-type PPARgamma, indicating that the mutated PPARgamma has greater adipogenic capability than the wild-type PPARgamma. Under treatment with a ligand, both wild-type and mutant porcine PPARgamma-expressing C2C12 myoblasts differentiated into adipocytes in 10 d. The expression of myogenic marker genes (myogenin, myogenic regulatory factor-4) was suppressed in cells transfected with the mutated PPARgamma or wild-type PPARgamma. Moreover, wild-type and mutant PPARgamma were able to inhibit myogenesis without addition of a ligand. Our results suggest that porcine wild-type PPARgamma and mutated PPARgamma can both convert myoblast cells into adipocytes, and also that the ability to transdifferentiate was greater in cells containing the mutated PPARgamma than in cells containing the wild-type PPARgamma. Therefore, the existence of serine 112 in PPARgamma may have a role in regulating adipocyte differentiation.

Adipocytes↗
PubMed2005

[Effects of airway epithelium injury on the transdifferentiation of sub-epithelial fibroblasts and its role in the development of airway hyperresponsiveness in asthma].

OBJECTIVE: To address the possible role of injured airway epithelium in initiating transdifferentiation of sub-epithelial fibroblasts into myofibroblasts and accelerating cell proliferation in sub-epithelial fibroblasts, which may be involved in airway hyperresponsiveness in asthma. METHODS: Human primary cultured sub-epithelial fibroblasts were co-cultured with human bronchial epithelial cells (16HBE) which were treated with lipopolysaccharide (LPS) plus mechanical scratch prior to co-culture. The procedure was also performed in the presence or absence of endothelin (ET) receptor A inhibitor (BQ123), transforming growth factor-beta(1) (TGF-beta(1)) neutralized antibody, respectively or simultaneously, followed by immunostaining, Western blotting and bromodeoxyuridine (BrdU) incorporation respectively to detect alpha-SMA expression and cell proliferation in the co-cultured sub-epithelial fibroblasts. Using the inhibitors specific for mitogen-activated protein kinases (MAPKs) pathways, the role of MAPKs pathways in activating the expression of alpha-SMA was evaluated. In addition, the interaction between matrix metalloproteinases (MMPs) and ET-1 was investigated by cell transfection with anti-ET-1 converting enzyme (anti-ECE) mRNA expression plasmid followed by gelatin zymography analysis. RESULTS: 16HBE treated with LPS plus mechanical injury induced alpha-SMA expression in sub-epithelial fibroblasts and accelerated BrdU incorporation in the cells. BQ123, TGF-beta(1) neutralized antibody, specific inhibitors for p38 MAPK and extracellular signal-regulated kinase 1/2 (ERK1/2) were able to block the induction respectively to a certain extent. Phosphorylated p38 MAPK and ERK1/2 were detected in the sub-epithelial fibroblasts 10 min after being co-cultured with injured 16HBE. Compared to normal control (16HBE transfected with pEGFPN(2)) or those cells transfected with anti-ECE mRNA expression plasmids, ET-1 released from the 16HBE cells transfected with pEGFPN(2) into supernatants were increased significantly after the treatment described as above: 16HBE pre-transfected with pEGFP-N(2) expression plasmid before being treated with mechanical scrape plus LPS stimulation: (15.00 +/- 0.86) pg/ml; 16HBE pre-transfected with anti-ECE expression plasmid before being treated with mechanical scrape plus LPS stimulation: (7.57 +/- 0.94) pg/ml (all P < 0.01). At the same time, the activities of MMP-2 and MMP-9 were enhanced. CONCLUSIONS: Injured airway epithelial cells induced the transdifferentiation of sub-epithelial fibroblasts into myofibroblasts, which may be mediated by ET-1 and TGF-beta(1) through MARKs pathways such as p38 MAPK and ERK 1/2.

Actins↗
PubMed2005

[Tubular epithelial-myofibroblast transdifferentiation and expressions of hepatocyte growth factor and Smad7 in renal tissues of rat with experimental diabetes].

OBJECTIVE: To investigate the relationship of tubular epithelial-myofibroblast transdifferentiation and the expressions of hepatocyte growth factor (HGF) and Smad7, and to elucidate the role of HGF and Smad7 in diabetic nephropathy. METHODS: Diabetes was induced in male Wistar rats with right nephrectomy and streptozotocin (STZ) administration. The expressions of cytokeratin 18 (CK18), alpha-smooth muscle actin (alpha-SMA), HGF and Smad7 were assayed with immunohistochemistry. The expressions of alpha-SMA, HGF were assayed with flow cytometry. The expression of Smad7 was assessed by Western blot. RESULTS: Compared with those in kidneys of the control group, diabetic kidneys showed down-regulated expression of CK18 and up-regulated expression of alpha-SMA. The expressions of HGF and Smad7 were increased significantly in the kidneys of diabetic rats at first, then they decreased gradually, but were still higher than those of control. CONCLUSION: The tubular epithelial cells may undergo phenotypic alterations and change to myofibroblasts. The absence of up-regulation of HGF and Smad7 may be related with the transdifferentiation of tubular cells in this animal model.

Actins↗
PubMed2006

[The effect of hyperoxia on transdifferentiation of type II alveolar epithelial cells in premature delivery rat].

AIM: To investigate the effect of hyperoxia on the transdifferentiation of type II alveolar epithelial cells (AECII) in premature delivery rats. METHODS: AECII from fetal rat lung were cultured primarily to establish a model of cells damaged by hyperoxia. The morphological changes of the cells were observed by inverted phase contrast microscope and transmission electron microscope. AECII-specific surfactant protein C (SP-C) and AECI-specific aquaporin 5 (AQP5) were detected by immunocytochemical staining. The expression levels of SP-C, AQP5 mRNAs and their protein were detected by RT-PCR and flow cytometry. RESULTS: With the time of exposure to hyperoxia, primarily cultured AECII spread and flattened, losing lamellar bodies and microvilli. They rapidly lost their characteristics and gained some AECI appearance. With their morphological changes, AECII stopped expressing AECII-specific protein SP-C but began expressing AECI-associated protein AQP5. Compared with exposure to air at the same time in air group for 24, 48 and 72 hours, the expression rate of SP-C mRNA in positive cells and fluorescence index (FI) decreased markedly in 3 groups, but compared with exposure to air for 24 and 48 hours the expression of AQP5 increased significantly in 2 groups. The expression of AQP5 began decreasing and showed no marked difference compared with air group at the same time of for 72 hours. CONCLUSION: The transdifferentiation of AECII induced by hyperoxia may play a key role in the repair of alveolar epithelial cell injury in premature delivery rats.

Animals↗
PubMed1998

Transdifferentiation versus stem cell hypothesis for the regeneration of islet beta-cells in the pancreas.

The pancreas is composed of at least three types of differentiated tissue: the hormone-containing cells in islets (4 different cell types), the exocrine zymogen-containing acini, and the centroacinar cells, ductules and ducts (ductal tree). All of these cells appear to have a common origin during embryogenesis in the form of duct-like protodifferentiated cells. Later in life, the acinar and ductal cells retain a significant proliferative capacity that can ensure cell renewal and growth, whereas the islet cells become mitotically inactive. Interestingly, new islet cells, including the insulin-producing beta-cells, can regenerate after tissue injury by a process called neogenesis. The neogenetic process involves differentiation of duct-like (exocrine) epithelial cells to hormone-expressing cells. In this paper, we review the question whether islet beta-cell regeneration or neogenesis in the pancreas depends on "embryonic-like" stem cells or on transdifferentiation of "fully differentiated" cells. This issue is important to find the right model for in vitro research aiming at controlling the process of beta-cell neogenesis. The latter could lead to applications in the treatment of diabetes where functional beta-cells are deficient. We conclude from the available evidence that there is as yet no evidence for the existence of "dormant" stem cells in the adult pancreas. There is some evidence, however, that differentiated exocrine acinar and/or duct cells retain the capacity to transdifferentiate into insulin-expressing beta-cells.

Animals↗
PubMed2000

Radial glia phenotype: origin, regulation, and transdifferentiation.

Radial glial cells play a major guidance role for migrating neurons during central nervous system (CNS) histogenesis but also play many other crucial roles in early brain development. Being among the earliest cells to differentiate in the early CNS, they provide support for neuronal migration during embryonic brain development; provide instructive and neurotrophic signals required for the survival, proliferation, and differentiation of neurons; and may be multipotential progenitor cells that give rise to various cell types, including neurons. Radial glial cells constitute a major cell type of the developing brain in numerous nonmammalian and mammalian vertebrates, increasing in complexity in parallel with the organization of the nervous tissue they help to build. In mammalian species, these cells transdifferentiate into astrocytes when neuronal migration is completed, whereas, in nonmammalian species, they persist into adulthood as a radial component of astroglia. Thus, our perception of radial glia may have to change from that of path-defining cells to that of specialized precursor cells transiently fulfilling a guidance role during brain histogenesis. In that respect, their apparent change of phenotype from radial fiber to astrocyte probably constitutes one of the most common transdifferentiation events in mammalian development.

Animals↗
PubMed2003

CD40 and CD40L expression in the chicken embryo aorta: possible role in the endothelial-mesenchymal transdifferentiation process.

Endothelial-mesenchymal transdifferentiation (EMT) is believed to play a crucial role in embryonic vascular development and intimal thickening, which contributes to the pathogenesis of atherosclerotic lesions. However, the mechanisms by which it occurs, as well as the signals that control it, have not yet been elucidated. Given the important role played by the CD40-CD40 ligand (CD40L) system during the initiation and progress of atherosclerosis, we investigated whether both CD40 and CD40L were present in the aortic wall during EMT and the advanced stages of chicken embryo development. CD40-CD40L expression was found on endothelial cells (ECs), mesenchymal cells, and smooth muscle cells (SMCs) at all stages examined, and appeared to be distributed across the aortic wall. However, some notable differences between the expression patterns were observed. CD40 had a more restricted distribution compared to CD40L, and did not stain every cell type of the aortic wall. According to immunoblotting and enzyme-linked immunosorbent assay (ELISA) analyses, the CD40L content was highest at day 7 of development. An important and novel finding was the expression of CD40L in areas where ECs transdifferentiate into mesenchymal cells. Specifically, CD40L was associated to the surface of cells that were detaching and migrating from the monolayer of ECs, whereas for CD40 a very diffuse subcellular localization was seen at the monolayer and the detaching and migrating cells. These data suggest a possible role for CD40-CD40L interactions during EMT and the remodeling of the aorta.

Actins↗
PubMed2005

Transdifferentiation of smooth muscle cells into chondrocytes in atherosclerotic arteries in situ: implications for diffuse intimal calcification.

Several hypotheses have been offered to explain the occurrence of arteriosclerotic calcification but the mechanisms involved are still not well understood. Using a combination of electron microscopy and immunohistochemistry, atherosclerotic plaques from human arteries as well as atherosclerotic-like lesions from aortas of apo-E-deficient mice were examined to identify cell type(s) associated with calcification. Electron microscopic analysis showed that, in human atherosclerotic plaques, chondrocyte-like cells were present in areas surrounding the necrotic cores. In these areas, some smooth muscle cells displayed features of their transdifferentiation into chondrocyte-like cells. Immunohistochemical analysis confirmed that smooth muscle cells with a reduced content of alpha-smooth muscle actin expressed Sox-9. Destruction of chondrocytes resulted in the accumulation of numerous membrane-bound vesicles in the extracellular space. Membrane-bound vesicles originating from chondrocytes were found to undergo calcification. Similar processes were found to occur in atherosclerotic-like lesions in apo-E-deficient mice. These observations suggest that transdifferentiation of smooth muscle cells into chondrocytes contributes to atherosclerotic calcification.

Adult↗
PubMed1998

Transdifferentiation of rat hepatic stellate cells results in leptin expression.

Leptin is a peptide hormone that appears critical in regulating Fat metabolism. Recently, circulating leptin levels were reported higher in patients with alcoholic cirrhosis. In health, hepatic stellate cells store retinoids, but following liver injury they transdifferentiate into myofibroblast-like cells with loss of the retinoid stores. Leptin expression was demonstrated by detection of leptin mRNA by RT-PCR analysis and by immunohistochemistry viewed with confocal microscopy in transdifferentiated stellate cells after 14 days, or more, of culture. Leptin expression was not found in freshly isolated quiescent stellate cells. Leptin expression was not demonstrated in freshly isolated or cultured Kupffer cells. Treatment of activated stellate cells with either 1 microM retionic acid or 10 microM retinol acetate resulted in the inhibition of leptin mRNA expression. The observation that activated stellate cells in culture can express leptin has implications for understanding adipocyte biology in liver disease and treatment of malnutrition in cirrhotics.

Animals↗
PubMed2002

Activated MAPK/ERK kinase (MEK-1) induces transdifferentiation of pigmented epithelium into neural retina.

During vertebrate eye development, the optic vesicle originating from the neuroectoderm is partitioned into a domain that will give rise to the neural retina (NR) and another that will give rise to the retinal pigmented epithelium (RPE). Previous studies have shown that ectopic expression of FGFs in the RPE induces RPE-to-NR transdifferentiation. Similarly, a naturally occurring mutation of the transcription factor Mitf in mouse resulted in the formation of a second neural retina in place of the dorsal RPE, but the putative signaling pathway linking FGF to Mitf regulation is presently unknown. In cultures of neural crest-derived melanocytes, the MAPK pathway was recently shown to target the Mitf transcription factor for ubiquitin-dependent proteolysis, resulting in a rapid degradation and downregulation. In the present study, we show that ectopic expression of a constitutively activated allele of MEK-1, the immediate upstream activator of the MAPK ERK, in chicken embryonic retina in ovo, induces transdifferentiation of the RPE into a neural-like epithelium that is correlated with a downregulation of Mitf expression in the presumptive RPE.

Animals↗
PubMed1995

Transdifferentiation of isolated striated muscle of jellyfish in vitro: the initiation process.

Fragments of striated muscle tissue of Anthomedusae can be isolated and cultured. Without further treatment the isolated muscle fragments maintain the differentiated state. When treated with enzymes degrading the adhering extracellular matrix, drugs activating protein kinase C or substances destroying the actin cytoskeleton, dedifferentiation and DNA replication are initiated and transdifferentiation to several new cell types occurs. Initiation of DNA replication seems to be correlated with a disturbance of cell-ECM interactions. If muscle fragments are combined with isolated ECMs, cell migration onto the grafted ECMs occurs and DNA-replication and transdifferentiation are initiated in those cells which adhere to both, the native and the grafted ECM. If, however, the cells can stretch into a monolayer and adhere entirely to either the native or the grafted ECM, DNA-replication is inhibited. Carbohydrate moieties seem to be involved in mediating these cell-substrate interactions.

Animals↗
PubMed1995

Cellular and molecular characterization of transdifferentiation in the process of morphallaxis of budding tunicates.

In the budding tunicate, Polyandrocarpa misakiensis, a bud consists of two epithelial sheets, of which the inner, atrial epithelium shows developmental multipotency. It contains pigment granules in the cytoplasm and expresses a few differentiation markers on the cell surface. During bud development, these features are lost and new differentiation markers appear in organ rudiments that arise from the atrial epithelium. This transdifferentiation of the multipotent epithelium requires at least one cycle of cell division. It may be triggered by endogenous retinoids, probably retinoic acid (RA). RA acts on mesenchymal cells, which then secrete proteases that would serve as an actual transdifferentiation factor of the atrial epithelium.

Animals↗
PubMed1995

Hepatic transdifferentiation in the pancreas.

The differentiated state of specialized cells appears to be dependent on interactions between the extracellular microenvironment, cytoplasmic signals and DNA. Perturbations in these interactions lead to phenotypic alterations of the cell--referred to as transdifferentiation. Copper deficiency in rats leads to global acinar cell loss due to apoptosis possibly leading to perturbations in cell-cell interactions and the microenvironment. Acinar cell loss is associated with the proliferation of ductular epithelial and oval cells. Massive depletion of the acinar cell pool creates severe expansion pressure on oval and ductular cells to fill the vacuity. This probably causes a change in the commitment of these cells resulting in transdifferentiation into hepatocytes. Pancreatic hepatocytes exhibit all the morphological and functional properties of liver parenchymal cells.

Animals↗
PubMed1995

Transdifferentiation induced by gene transfer.

While for many tissues the differentiation process is well characterized, little is known about 'master switch' genes determining a specific differentiation pathway and having the potential to induce this process in a cell designed for a different differentiation pathway. Based on heterokaryon and 5-aza-cytidine-induced hypomethylation experiments, the muscle determination gene MyoD1 was identified and isolated, which was shown to induce myogenic differentiation even in cells of ectodermal lineage. Since transdifferentiation studies could also be performed in drosophila in vivo by 'false' expression of developmental genes, it is tempting to speculate that experimentally induced transdifferentiation mimics processes during embryonic development and tissue maturation.

Animals↗
PubMed2004

The effect of connective tissue growth factor on human renal tubular epithelial cell transdifferentiation.

To investigate the role of connective tissue growth factor (CTGF) in transdifferentiation of human renal tubular epithelial cell (HKC), in vitro cultured HKC cells were divided into 3 groups: negtive control, low dose CTGF-treated group (rh CTGF, 2.5 ng/ml) and high dose CTGF-treated (rhCTGF, 5.0 ng/ml). Then the expression of alpha-smooth muscle actin (alpha-SMA) were assessed by indirect immuno-fluorescence, and the percentage of alpha-SMA positive cells were assessed by flow cytometry. RT-PCR were also performed to examine the mRNA level of alpha-SMA. Upon the stimulation of different concentrations of rhCTGF, the expression of alpha-SMA were markedly stronger than that in negative controls. The percentages of alpha-SMA positive cells were significantly higher in the stimulated groups than that of negative controls (38.9%, 65.5% vs 2.4%, P<0.01). alpha-SMA mRNA levels were also up-regulated by the stimulation of rhCTGF (P<0.01). These results suggest that CTGF can promote the transdifferentiation of human renal tubular epithelial cells towards myofibroblast (Myo-F).

Actins↗
PubMed1993

Tumor necrosis factor alpha (TNF alpha) and transforming growth factor beta 1 (TGF beta 1) stimulate fibronectin synthesis and the transdifferentiation of fat-storing cells in the rat liver into myofibroblasts.

Transforming growth factor-beta (TGF beta 1) and tumor necrosis factor alpha (TNF alpha) stimulate the transdifferentiation of fat-storing cells (FSC) in the rat liver into highly active and "synthetic" myofibroblast-like cells (MFBIC). This activation has been documented by differential-interference contrast and light microscopy using morphologic criteria (a reduction in the number and size of fat droplets, cell flattening and the development of long cytoplasmic extensions), by the loss of retinyl-palmitate (measured by HPLC) and by the enhanced expression of iso-alpha smooth muscle actin (demonstrated by immunofluorescence microscopy). Furthermore, while cell growth measured by the cell count and DNA content is slightly inhibited by TGF beta 1 (0.81 of the control), the combination of TGF beta 1 with TNF alpha stimulates cell proliferation to 1.44 times of the control. In addition the combination of TGF beta and TNF alpha potentiated the stimulatory effect on fibronectin synthesis (TGF beta alone: 1.4 times control; TNF alpha alone: 2.2 times control; TGF beta plus TNF alpha: 4.7 times control). The total protein synthesis was not altered by TGF beta or TNF alpha. In summary the results obtained identify TGF beta and TNF alpha as mediators stimulating key events in liver fibrogenesis (i.e. FSC proliferation, FSC transdifferentiation into MFBIC, and fibronectin synthesis).

Adipose Tissue↗
PubMed1997

Lens fibre transdifferentiation in cultured larval Xenopus laevis outer cornea under the influence of neural retina-conditioned medium.

The outer cornea of larval Xenopus laevis can reprogram cell differentiation when cultured in medium conditioned by X. laevis neural retina (XRCM) or by Rana esculenta neural retina (RRCM). Under these experimental conditions corneal cells showed the same series of cytological changes of fibre cell differentiation observed during ontogenesis and in vivo lens regeneration: enlargement of nuclei and nucleoli, increase of ribosomal population (cytoplasm-basophilia), cell elongation gradual loss of basophilic properties and acquisition of acidophilic properties for crystallin synthesis and accumulation. These events were completely dependent on XRCM or RRCM, suggesting that the neural retina secretes a factor(s) which initiates and sustains lens fibre transdifferentiation of the corneal epithelial cells. This culture system appears to be a suitable one for investigating the control of lens fibre transdifferentiation in vitro.

Animals↗
PubMed2006

Adult rat liver cells transdifferentiated with lentiviral IPF1 vectors reverse diabetes in mice: an ex vivo gene therapy approach.

AIMS/HYPOTHESIS: We examined a clinical model of ex vivo transdifferentiation of primary adult hepatocytes to insulin-secreting cells for the treatment of type 1 diabetes. MATERIALS AND METHODS: Isolated rat hepatocytes were transduced in primary culture with a human lentivirus containing pancreatic duodenal homeobox 1 (PDX1, now known as insulin promoter factor 1, homeodomain transcription factor [IPF1]). Insulin expression and secretion of the newly engineered cells were assessed in vitro by RT-PCR, in situ hybridisation, immunostaining and radioimmunoassay. PDX1-transduced hepatocytes were further studied in vivo by injecting them under the renal capsule of diabetic SCID mice. RESULTS: Isolated rat hepatocytes were efficiently transduced with the lentiviral vector, as assessed by green fluorescent reporter gene expression. The transduced cells exhibited insulin at both mRNA (RT-PCR, in situ hybridisation) and protein levels (immunostaining and radioimmunoassay). Moreover, insulin secretion by the engineered cells was dependent on glucose and sulfonylurea. Other beta cell genes, including those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (Slc2a2), glucokinase (Gck), ATP-binding cassette, sub-family C (CFTR/MRP), member 8 (Abcc8), the potassium inwardly-rectifying channel, subfamily J, member 11 (Kcnj11) and proprotein convertase subtilisin/kexin type 1 (Pcsk1) were also expressed. The PDX1-transduced hepatocytes expressed several pancreatic transcription factors related to early pancreatic endocrine development (endogenous Pdx1, neurogenic differentiation factor 1 [Neurod1], and NK6 transcription factor related, locus 1 [Nkx6-1]) as well as the late-stage pancreatic transcription factors (paired box gene 4 [Pax4], paired box gene 6 [Pax6], and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A [Mafa]). Transplantation of 3 x 10(6) transdifferentiated liver cells under the renal capsule of seven streptozotocin-induced diabetic SCID mice resulted in significant reduction of non-fasting blood glucose levels from 30.7 +/- 1.3 to 8.7 +/- 3.7 mmol/l (mean +/- SEM, p = 0.01), in 6 to 8 weeks. Removal of the graft resulted in severe hyperglycaemia. CONCLUSIONS/INTERPRETATION: Ex vivo lentiviral-mediated PDX1 expression in isolated adult liver cells represents a potential model for type 1 diabetes mellitus therapy.

Animals↗