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PubMed2005

A human- and male-specific protocadherin that acts through the wnt signaling pathway to induce neuroendocrine transdifferentiation of prostate cancer cells.

Protocadherin-PC (PCDH-PC) is a gene on the human Y chromosome that is selectively expressed in apoptosis- and hormone-resistant human prostate cancer cells. The protein encoded by PCDH-PC is cytoplasmically localized and has a small serine-rich domain in its COOH terminus that is homologous to the beta-catenin binding site of classical cadherins. Variants of prostate cancer cells that express PCDH-PC have high levels of nuclear beta-catenin protein and increased wnt-signaling. In this study, we show that transfection of human prostate cancer cells (LNCaP) with PCDH-PC or culture of these cells in androgen-free medium (a condition that up-regulates PCDH-PC expression) activates wnt signaling as assessed by nuclear accumulation of beta-catenin, increased expression of luciferase from a reporter vector promoted by Tcf binding elements and increased expression of wnt target genes. Moreover, LNCaP cells transfected with PCDH-PC or grown in androgen-free medium transdifferentiate to neuroendocrine-like cells marked by elevated expression of neuron-specific enolase and chromogranin-A. Neuroendocrine transdifferentiation was also observed when LNCaP cells were transfected by stabilized beta-catenin. Increased wnt signaling and neuroendocrine transdifferentiation of LNCaP cells induced by culture in androgen-free medium was suppressed by short interfering RNAs that target PCDH-PC as well as by dominant-negative Tcf or short interfering RNA against beta-catenin, supporting the hypothesis that increased expression of PCDH-PC is driving neuroendocrine transdifferentiation by activating wnt signaling. These findings have significant implications for the process through which prostate cancers progress to hormone resistance in humans.

Cadherins↗
PubMed2005

Interleukin-1beta-induced transdifferentiation of renal proximal tubular cells is mediated by activation of JNK and p38 MAPK.

Interleukin (IL)-1beta induces renal tubular epithelial cells to transdifferentiate to myofibroblasts, which express alpha-smooth muscle actin (alpha-SMA). To understand the signal transduction mechanisms involved in transdifferentiation, we examined the roles of mitogen-activated protein kinases (MAPKs) in IL-1beta-stimulated alpha-SMA expression and cell migration in the HK-2 human renal proximal tubular cell line. IL-1beta induced the transdifferentiation of renal proximal tubular cells, which was characterized by upregulated expression of alpha-SMA and increased cell migration. In addition, IL-1beta increased the activity of the three members of the MAPK family, ERK, JNK and p38 MAPK, in these cells. Both SP600125, a specific inhibitor of JNK, and SB203580, a specific inhibitor of p38 MAPK, suppressed the IL-1beta-induced expression of alpha-SMA and cell migration, but these effects were not observed with PD98059, a specific inhibitor of ERK. These results suggest that IL-1beta-induced HK-2 cell transdifferentiation is mediated, at least in part, through the activation of the JNK and p38 MAPK signaling pathways.

Actins↗
PubMed2006

p38 inhibitors prevent TGF-beta-induced myofibroblast transdifferentiation in human tenon fibroblasts.

PURPOSE: The role of mitogen-activated protein kinase (MAPK) pathways in TGF-beta-induced myofibroblast transdifferentiation of human tenon fibroblasts (HTFs) was investigated to identify potential pharmacologic targets for the inhibition of scarring after glaucoma surgery. METHODS: TGF-beta-dependent activation of Smad2, p38, and Erk-1/2 was examined by Western blot analysis. TGF-beta-induced mRNA expression of collagen Ialpha1, fibronectin, and the myofibroblast transdifferentiation marker alpha smooth muscle actin (alpha-SMA) was analyzed by real-time RT-PCR. alpha-SMA protein expression and subcellular distribution were determined by Western blot analysis and immunofluorescence cytochemistry. Fibroblast contractility was assessed in three-dimensional collagen gel contraction assays, stress fiber assembly with rhodamine-phalloidin stains, and confocal microscopy. Cell proliferation was measured with an MTT assay. Specific pharmacologic kinase inhibitors were used to characterize the involvement of MAPK-dependent pathways. RESULTS: TGF-beta stimulation of HTF induced a rapid and transient activation of Smad2 and Erk, whereas p38 activation was biphasic and sustained. After 24 hours of TGF-beta stimulation, increased levels of collagen Ialpha1, fibronectin, and alpha-SMA transcripts were detected. After 3 days of stimulation, HTF displayed increased alpha-SMA protein levels, enhanced contractility, and assembly of actin stress fibers. TGF-beta also induced HTF proliferation. Specific p38 inhibitors prevented all these aspects of TGF-beta-induced myofibroblastic transdifferentiation. CONCLUSIONS: Pharmacologic inhibition of p38 abrogates TGF-beta-induced myofibroblast transdifferentiation, reduces extracellular matrix protein expression and HTF proliferation, and may therefore serve to inhibit scarring after glaucoma surgery.

Actins↗
PubMed2006

Exploring RPE as a source of photoreceptors: differentiation and integration of transdifferentiating cells grafted into embryonic chick eyes.

PURPOSE: To study the possibility of generating photoreceptors through programming RPE transdifferentiation by examining cell differentiation after transplantation into the developing chick eye. METHODS: RPE was isolated, and the cells were dissociated, cultured, and guided to transdifferentiate by infection with retrovirus expressing neuroD (RCAS-neuroD), using RCAS-green fluorescence protein (GFP) as a control. The cells were then harvested and microinjected into the developing eyes of day 5 to day 7 chick embryos, and their development and integration were analyzed. RESULTS: Cells from the control culture integrated into the host RPE. When grafted cells were present in large number, multilayered RPE-like tissues were formed, and the extra tissues consisted of grafted cells and host cells. None of the cells from the control culture expressed photoreceptor-specific genes. In contrast, most cells from RCAS-neuroD-infected culture remained depigmented. A large number of them expressed photoreceptor-specific genes, such as visinin and opsins. Antibodies against red opsin decorated the apical tips and the cell bodies of the grafted, transdifferentiating cells. In the subretinal space, visinin(+) cells aligned along the RPE or an RPE-like structure. When integrated into the host outer nuclear layer, grafted cells emanated elaborate, axonal arborization into the outer plexiform layer of the host retina. CONCLUSIONS: Cultured RPE cells retained their remarkable regenerative capabilities. Cells guided to transdifferentiate along the photoreceptor pathway by neuroD developed a highly ordered cellular structure and could integrate into the outer nuclear layer. These data suggest that, through genetic programming, RPE cells could be a potential source of photoreceptor cells.

Animals↗
PubMed2001

Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE).

Tubulointerstitial disease, a prominent phenomenon in diabetic nephropathy, correlates with decline in renal function. The underlying pathogenic link between chronic hyperglycemia and the development of tubulointerstitial injury has not been fully elucidated, but myofibroblast formation represents a key step in the development of tubulointerstitial fibrosis. RAGE, the receptor for advanced glycation end products (AGEs), induces the expression of TGF-beta and other cytokines that are proposed to mediate the transdifferentiation of epithelial cells to form myofibroblasts. Here we report specific binding of (125)I-AGE-BSA to cell membranes prepared from a rat proximal tubule cell line and show that the binding site was RAGE. AGE exposure induced dose-dependent epithelial-myofibroblast transdifferentiation determined by morphological changes, de novo alpha smooth-muscle actin expression, and loss of epithelial E-cadherin staining. These effects could be blocked with neutralizing Ab's to RAGE or to TGF-beta. Transdifferentiation was also apparent in the proximal tubules of diabetic rats and in a renal biopsy from a patient with type 1 diabetes. The AGE cross-link breaker, phenyl-4,5-dimethylthiazolium bromide (ALT 711) reduced transdifferentiation in diabetic rats in association with reduced tubular AGE and TGF-beta expression. This study provides a novel mechanism to explain the development of tubulointerstitial disease in diabetic nephropathy and provides a new treatment target.

Actins↗
PubMed1987

pp60c-src expression in transdifferentiating cultures of embryonic chick neural retina cells.

Chick embryo neural retinal cells transdifferentiate extensively into lens cells when cultured in Eagle's MEM containing horse and fetal calf sera (FHMEM). Such cultures express elevated levels of pp60c-src-associated tyrosine kinase activity relative to parallel cultures prevented from transdifferentiating by the addition of supplementary glucose (FHGMEM) or replacement of MEM by medium 199 (F199). Northern blotting and in vitro translation studies suggest that c-src mRNA levels are only slightly higher in late transdifferentiating (FHMEM) cultures as compared to parallel blocked (FHGMEM or F199) cultures. By immunocytochemical staining, we show that pp60c-src protein is largely localized in cell groups undergoing conversion into lens (i.e. expressing delta crystallin) in late FHMEM cultures. Initial studies of pp60c-src in chick lens tissues during development indicate that higher kinase activity is found in the epithelial cells relative to mature lens fibres. Thus pp60c-src may be expressed both during the differentiation of lens cells in vivo and during the transdifferentiation of neural retina cells into lens in vitro.

Animals↗
PubMed2006

Transforming growth factor-beta signaling enhances transdifferentiation of macrophages into smooth muscle-like cells.

Hemopoietic cells or bone marrow-derived cells contribute to tissue formation, possibly by transdifferentiation into smooth muscle cells (SMCs) or myofibroblasts. In this study our goal is to examine the effects of transforming growth factor-beta1 (TGF-beta1) on the transdifferentiation of the monocyte/macrophage lineage into SMC-like cells. Using rat peritoneal exudate macrophages, we investigated the expression of smooth muscle-specific differentiation markers, such as alpha-smooth muscle actin, embryonic smooth muscle myosin heavy chain, and calponin. The treatment of macrophages with TGF-beta1 enhanced the expression of SMC-specific markers at day 4; after 7 days in culture, a higher level of expression (approximately 3- to 5-fold) was detected on Western blots. In contrast, TGF-beta1 decreased the expression of CD11b, which is a macrophage marker. Furthermore, we examined the effect of the TGF-beta type 1 receptor inhibitor SB-431542 and a replication-defective adenovirus construct expressing Smad7 (Adeno-Smad7), which inhibits TGF-beta signaling by interfering with the activation of other Smad proteins. Both SB-431542 and Adeno-Smad7 suppressed the expression of SMC-specific markers. These results indicated that TGF-beta signaling is essential for the transdifferentiation of macrophages into SMC-like cells. Elucidating the mechanism by which macrophages transdifferentiate into SMC-like cells may reveal new therapeutic targets for preventing vascular diseases.

Adenoviridae↗
PubMed2001

Transdifferentiation in neoplastic development and its pathological implication.

Transdifferentiation is a process in which a cell committed to a particular specialization changes to another quite distinct type. It occurs during embryological development and some pathological processes, and causes the tumor cells to express a phenotype different from that of their normal progenitors. Neoplastic transdifferentiation involves pathogenesis of cancer subtype, transition between neoplastic epithelia and neuroendocrine cell, transition between neoplastic epithelia and mesenchyme, as well as transition between non-neuroectodermal and neuroectodermal cells. We propose that differentiation disturbance of cancer cells should include not only lower-, un-, or de-differentiation, but also transdifferentiation. Tumor cell transdifferentiation results from genetic instabilities. In some type of neoplastic transition, the initiation may be induced by extracellular matrix and growth factors.

Animals↗
PubMed2004

Transdifferentiation of cultured bovine lens epithelial cells into myofibroblast-like cells by serum modulation.

An after-cataract is caused by the proliferation of residual cells over the equator of the lens. These cells subsequently migrate to the posterior lens capsule, where they undergo aberrant differentiation into fiber-like cells or transdifferentiation into fibroblast-like cells. To study the precise molecular mechanisms of transdifferentiation, an attempt was made to establish an in vitro system, in which the lens epithelial cells (LECs) of the pre-equatorial zone could be transdifferentiated into fibroblast-like cells. The required conditions for culturing the LECs were identified as consisting of four phases; intact bovine explants, explant-cultured, serum-modulated and additionally modulated LECs. The LECs of each phase were compared by examining changes in the expression of the epithelial-mesenchymal transition (EMT)-related genes and changes in cellular morphology and adhesion. The explants that were cultured in a medium containing 10% fetal bovine serum (FBS) for 2 weeks, showed changes in the expression of the EMT-related genes, although the other explant-cultured cells maintained an epithelial morphology. To introduce a transition into mesenchymal cells, the explant cultures were subcultured in a medium containing 20% FBS for six passages. These cells displayed an elongated morphology and were able to grow and migrate in a similar way to fibroblast cells. The expression of the EMT-related genes, such as, extracellular matrix proteins and integrins, was altered. This was similar to the alteration of the 3-dimensional collagen gels model previously reported. During a further process of EMT by additional serum modulation, the inhibitory effect of disintegrin on cell adhesion was gradually decreased, integrin expression was differentially regulated and alpha-smooth muscle actin was post-translationally modified from the point of passage number six. Overall, it can be concluded that terminal transdifferentiation accompanies changes in the cytoskeletal proteins and cell surface molecules. These are modulated in systematic patterns of post-transcriptional and post-translational regulation and patterns of gene regulation, by the synergic effects of several transforming factors contained in serum. Therefore, posterior capsular opacification may also be accompanied by this molecular mechanism.

Animals↗
PubMed2000

[Synergistic effect of monocyte chemotactic protein-1 and aristolochic acid I on transdifferentiation of human tubular epithelial cells in vitro].

OBJECTIVE: To test the possible role of monocyte chemotactic protein-1 (MCP-1) and its synergistic effect with aristolochic acid I (AAI) on tubular epithelial-myofibroblast transdifferentiation (TEMT) of human renal tubular epithelial cells (HKC) in vitro. METHODS: The cultured HKC cells were divided into four groups: (1) negative control (serum-free); (2) MCP-1 group; (3) AAI group; (4) AAI + MCP-1 group. The expression of alpha-smooth muscle actin (alpha-SMA), vimentin and cytocreatin was assessed by indirect enzyme immunohistochemistry and the percentages of alpha-SMA((+)) HKC cells were assessed by flow cytometry. RESULTS: The expression of cytocreatin of HKC cells decreased, while the expression of alpha-SMA, vimentin increased when treated with MCP-1 or with AAI and MCP-I concomitantly. Alpha-SMA((+)) HKC cells cultured in serum-free medium was 3.1% by flow cytometry. The percentages of alpha-SMA((+)) HKC cells were 8.6%, 9.6%, 13.4% (P < 0.05 vs control) when treated with 20, 40, 80 microg/L of AAI. The percentages of alpha-SMA((+)) HKC cells were 0.5% and 1.4% (P > 0.05 vs control) when treated with 5, 10 microg/L. The percentages of alpha-SMA((+)) HKC cells were 20%, 26.2%, 20.3%, 23.2% (P < 0.05 vs control) when treated with 0.001, 0.01, 0.05, 0.1 microg/L of MCP-1. When the HKC cells were treated with MCP-1 (0.1 microg/L) and AAI (5, 10, 20, 40 microg/L), the percentage of alpha-SMA((+)) cells increased markedly to 23.2%, 98.7%, 81.5%, 65.1% (P < 0. 01 vs group 1, 2, 3, respectively). CONCLUSIONS: These findings suggest that: (1) MCP-1 may induce the transdifferentiation of HKC cells into myofibroblasts in vitro; (2) AAI at some doses may partially induce HKC cells transdifferentiation. (3) MCP-1 and AAI may have a synergistic effect on transdifferentiation of HKC cells in vitro.

Actins↗
PubMed2005

[Altered expression of vascular endothelial growth factor and its receptors in transdifferentiated human proximal tubular epithelial cells induced by transforming growth factor beta1].

OBJECTIVE: To examine the expression of vascular endothelial growth factor (VEGF) and its receptors (VEGFR1, VEGFR2) in transdifferentiated human proximal tubular epithelial (HK-2) cell induced by transforming growth factor beta1 (TGFbeta1). METHODS: The transdifferentiation of HK-2 cells was detected by evaluation of expression of alpha-SMA by cytoimmunochemistry and RT-PCR. The VEGF mRNA was evaluated with RT-PCR. The secreted VEGF in the culture media was measured with ELISA. The cellular VEGF, VEGFR1, and VEGFR2 were measured with Western blot. RESULTS: The immunostain of alpha-SMA were positive in HK-2 cell induced by TGFbeta1 at the concentration of 5 and 8 ng/ml for 72 h. The expression of alpha-SMA mRNA was induced by TGFbeta1 in concentration- and time-dependent manners. The expressions of mRNA and protein of VEGF were upregulated by TGFbeta1 at the concentration of 0.1 and 1 ng/ml for 72 h and at the concentration of 8 ng/ml for 12 h and 24 h when compared with the control. But expressions of mRNA and protein of VEGF were downregulated by TGFbeta1 at the concentration of 3, 5, and 8 ng/ml for 72 h and at the concentration of 8 ng/ml for 36, 48, and 72 h, respectively. Meanwhile, Protein levels of VEGFR1 and VEGFR2 were upregulated by TGFbeta1 in concentration- and time- dependent manners. CONCLUSIONS: Increased expression of VEGFR1 and VEGFR2 and two-phase change in VEGF expression occurred in the process of tubular epithelial transdifferentiation induced by TGFbeta1. Reduced expression of VEGF may contribute to tubular epithelial transdifferentiation in a vicious circle.

Cell Differentiation↗
PubMed2006

[The role of myocardin in hypoxia-induced transdifferentiation of pulmonary artery endothelial cells into smooth muscle-like cells].

OBJECTIVE: To investigate the transdifferentiation of pulmonary artery endothelial cells (PAECs) into smooth muscle-like cells under hypoxia and the role of myocardin therein. METHODS: Recombinant plasmid psimyocardin (pSi), capable of silencing the expression of myocardin gene, was constructed by RNAi to be used to transfect the PAECs. Endothelial cells of adult pig pulmonary small arteries were purified by immunomagnetic purification technique, and divided into 4 groups: normoxia group (to be cultured in normoxic cell culture box containing 21% O(2), 5% CO2, and 74% N(2)), normoxia + pSi group, hypoxia group (to be cultured in cell box containing 1% O(2), 5% CO2, and 74% N(2)), and hypoxia + pSi group to be cultured for 1, 4, and 7 days respectively. Indirect fluorescence technique and morphological examination were used to identify the smooth muscle (SM) -like cells and the alpha-SM-actin positive cell ratio. RT-PCR was used to detect the mRNA expression of myocardin. RESULTS: Alpha-SM-actin positive cell could not be seen in the normoxia group and hypoxia 1 d group. The alpha-SM-actin positive cell rate of the hypoxia 7 days group was 2.07% +/- 0.06%, significantly higher than that of the hypoxia 4 d group (0.96% +/- 0.08%, P < 0.01). mRNA expression of myocardin gene could not be seen in the normoxia, normoxia + pSi, hypoxia 1 days, and hypoxia + pSi 1 days groups. The mRNA expression of myocardin gene of the hypoxia 7 days group was 0.23 +/- 0.03, significantly higher than that of the hypoxia 4 days group (0.14 +/- 0.01, P < 0.01). The mRNA expression levels of myocardin gene of the hypoxia + pSi 4 days and 7 days groups 0.03 +/- 0.02 and 0.05 +/- 0.01, both significantly lower than those of the hypoxia 4 days and 7 days groups respectively (0.14 +/- 0.01 and 0.23 +/- 0.03, both P < 0.01). The SM-like cell transdifferentiation rates of the hypoxia + pSi 4 days and 7 days groups were 0.19% +/- 0.07% and 0.21% +/- 0.04% respectively, both significantly lower than those of the corresponding hypoxia groups (0.96% +/- 0.08 and 2.07% +/- 0.06% respectively, both P < 0.01). CONCLUSION: Some PAECs have the potential to transdifferentiate into SM-like cells and may be one of the resources of muscularization of peripheral small vessels. Hypoxia remarkably promotes this transdifferentiation and myocardin may play an important role in this process.

Animals↗
PubMed1987

Conjunctival transdifferentiation induced by systemic vitamin A deficiency in vascularized rabbit corneas.

Conjunctival transdifferentiation, the process in which conjunctival epithelium transforms into a cornea-like epithelium with the loss of goblet cells during the healing of a total corneal epithelial defect, can be retarded or reversed by corneal neovascularization. We have previously shown that this process normally occurring on non-vascularized corneas can be retarded or reversed by topical retinoids, suggesting that vitamin A may be one of the factors from blood circulation which is responsible for modulating transdifferentiation. Herein, we have examined the effect of systemic vitamin A deficiency on vascularized corneas starting 4 months after epithelial denudation, and compared this deficient group with their vascularized and non-vascularized controls. Mean serum retinol level (microgram/dl) (n = 4) measured by HPLC was gradually reduced from 83 of the controls to 20 in a 10 month follow-up. Topographical analysis disclosed a centrifugal loss of goblet cell density with time. Histology showed complete transdifferentiation in vascularized areas at 9 months, initiated by the loss of mucin contents from receding zones first noted at 2 months. Using impression cytology, all corneas were not keratinized and all conjunctivas maintained a normal goblet cell density at 10 months. These results indicate that conjunctival epithelium on corneal surface is more sensitive to the decrease of serum vitamin A levels than that on conjunctiva, and support the hypothesis that the relative vitamin A deficiency on vascularized corneas can also result in the conjunctival transdifferentiation.

Animals↗
PubMed1982

Regeneration of the lens as a phenomenon of cellular transdifferentiation: regulability of the differentiated state of the vertebrate pigment epithelial cell.

The transdifferentiation of pigment epithelial cells in vitro was reviewed on the basis of results in the classic studies of lens regeneration in the newt. It is now known that pigment epithelial cells of avian embryos and human foetuses as well as of the newt can readily transdifferentiate into lens cells, when dissociated and cultured in vitro. The evidence now permits us to postulate that the potential of the pigment epithelial cell population for transdifferentiation is strongly conserved in vertebrates in general. Several environmental conditions controlling the processes have been suggested, and we can now provide an in vitro experimental system which is particularly useful for analysis of the molecular basis of transdifferentiation of the pigment epithelial cell, and its role as the cellular basis of lens regeneration.

Animals↗
PubMed1978

Influence of embryonic stage on the transdifferentiation of chick neural retina cells in culture.

Neural retina cells from chick embryos up to 15 days of incubation can transdifferentiate in culture into both lentoids and pigment cells. Some transdifferentiation into pigment cells but none into lentoids was found in cultures of 17-day embryonic neural retina. No transdifferentiation occurred in cultures of neural retina from embryos immediately before hatching. In general, lentoids and pigment cells develop more rapidly and in greater numbers in cultures of neural retina from the earlier embryonic stages, and lens-specific crystallins also appear earlier and accumulate in greater amounts in these cultures. Delta crystallin accumulation is much greater in transdifferentiating cultures of early embryonic neural retina, wheras alpha and beta crystallins become proportionately more prominent in cultures of late embryonic neural retina. Traces of alpha and beta but not delta crystallin are detectable in 60-day cultures of 17-day embryonic neural retina. Analogies between these results and the ontogeny of crystallin polypeptides in lens cells in vivo are discussed.

Animals↗
PubMed1995

Transdifferentiation of retinal pigment epithelial cells from epithelial to mesenchymal phenotype.

PURPOSE: To describe and evaluate retinal pigment epithelial (RPE) cell transdifferentiation in vitro and to determine its importance to the development of proliferative vitreoretinal disorders. METHODS: Porcine RPE cells from single animals were examined at different passages in culture. The authors examined cellular morphology, contraction of a collagenous matrix, and adhesion to fibronectin and type I collagen-coated substrata. These activities were correlated with loss of epithelial characteristics, redistribution of the actin cytoskeleton, and expression of alpha-smooth muscle actin (alpha-SMA), a marker of myoid differentiation. RESULTS: During routine culture on tissue culture plastic, porcine RPE cells lose epithelial characteristics and acquire a mesenchymal cell-like phenotype. The ability of cultured porcine RPE cells to adhere to and exert tractional forces on an extracellular matrix increases with continued passage in vitro and transdifferentiation. This correlates with the loss of the differentiated epithelial morphology, decreased expression of the epithelial marker cytokeratin 18, redistribution of the actin cytoskeleton, and de novo expression of alpha-SMA. CONCLUSION: Results indicate that RPE transdifferentiate in culture and that this transition is accompanied by a shift in biologic activities. Therefore, morphologic and behavioral transdifferentiation of these cells in culture are influencing factors in experimental pathology. The potential relevance of these extensive changes to the biology of proliferative vitreoretinal disorders is discussed.

Actins↗
PubMed2004

Evidence for the involvement of neurotrophins in muscle transdifferentiation and acetylcholine receptor transformation in the esophagus of Myf5(-/-):MyoD(-/-) and NT-3(-/-) embryos.

The primary aim of our study was to determine whether the esophageal innervation (i.e., vagal and enteric) and the skeletal muscle-secreted neurotrophins have a role in smooth-to-skeletal muscle transdifferentiation and in the muscarinic-to-nicotinic acetylcholine receptor type transition. To that end, we used genetically engineered embryos and immunohistochemistry. We found that, in the absence of Myf5 and MyoD, the esophageal muscle cells failed to develop the striated phenotype of acetylcholine receptors. In addition, the development of vagal and enteric innervation was delayed in Myf5(-/-):MyoD(-/-) and NT-3(-/-) mutants, but it was reestablished 2 days before the end of gestation. The smooth muscle cells in the esophagus appeared to be a distinct subpopulation of cells and their ability to transdifferentiate was based on their competence to express neurotrophins and their receptors. Finally, our data suggest a role for NT-3 in the esophageal muscle transdifferentiation.

Animals↗
PubMed2004

Induction of bone marrow stromal cells to neurons: differentiation, transdifferentiation, or artifact?

Differentiation of stem cells toward a neuronal lineage normally involves a gradually progressive restriction in developmental potential and is regulated by a diverse set of specific and temporally precise genetic events. However, recent studies have indicated that both rodent and human bone marrow stromal cells (MSCs) can be rapidly (within minutes to hours) induced to differentiate into neurons in vitro by relatively simple chemical means (using beta-mercaptoethanol [BME] or dimethylsulfoxide [DMSO] and butylated hydroxyanisol [BHA]; Woodbury et al. [ 2000] J. Neurosci. Res. 61:364-370). The ability to transdifferentiate an easily accessible cell source into neurons could have substantial potential for promoting neural repair. We therefore explored the potential of simple chemical methods to transdifferentiate other cell types, including primary rat fibroblasts, primary human keratinocytes, HEK293 cells, rat PC-12 cells, and as positive control rat bone marrow stromal (BMS) cells. Surprisingly, all cells except for keratinocytes adopted at least partial "neuron-like" pyramidal cell morphology with fine-cellular extensions resembling neurites upon stimulation with BME or DMSO/BHA. However, time-lapse microscopy indicated that the chemical exposure of MSCs did not result in new neurite growth but rather cellular shrinkage, with retraction of the majority of existing cell extensions, leaving only few, fine neurite-like processes. To determine whether the chemically induced transdifferentiation resulted from simple cellular toxicity, MSCs were exposed to various stressors, including detergents, high-molarity sodium chloride, and extremes of pH. In all cases, cellular shrinkage and adoption of pseudoneuronal morphology were observed. Concomitantly with cellular shrinkage, apparent increases in immunolabeling for the neuronal markers NSE and NeuN were detected in the cell soma that could not be confirmed by RT-PCR. Furthermore, blockade of protein synthesis with cycloheximide did not prevent cells from adopting "neuron-like" morphology after chemical induction. Thus, morphological changes and increases in immunolabeling for certain cellular markers upon "chemical induction" of MSCs are likely the result of cellular toxicity, cell shrinkage, and changes in the cytoskeleton and do not represent regulated steps in a complicated cellular differentiation process.

Animals↗