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PubMedDate not supplied

Effects of collagen concentration on epithelial differentiation: in vitro analysis with a mucosal tissue model.

Using collagen, epithelial cells, and fibroblasts isolated from the rabbit oral mucosa, a mucosal tissue model was prepared in vitro. Using this model, the effects of the collagen concentration on growth and differentiation of epithelial cells were studied. A positive correlation was found to exist between the collagen concentration and growth as well as the differentiation of epithelial cells. Further, above a 8.6% concentration of collagen, formation of the epithelial process and the basement membrane at the border between the epithelial layer and the connective tissue was noted. A conclusion was drawn that the collagen concentration in the extracellular matrix is deeply related to the growth and differentiation of mucosal epithelial cells. At the same time, it can be said that the successful completion of this research project endorsed the reliability of our methodology for the study of mucosa.

Animals↗

PubMed1999

Mesenchymal reprogramming of adult human epithelial differentiation.

The objective of this study was to determine whether neonatal rat seminal vesicle mesenchyme (rSVM) can reprogram epithelial differentiation in a fully differentiated adult human bladder epithelium. For this purpose neonatal rSVM was isolated from newborn (0-day) Sprague-Dawley rats, and normal adult human bladder epithelium (hBLE) was isolated from radical cystoprostatectomy specimens to prepare rSVM+hBLE tissue recombinants in vitro. After overnight culture the tissue recombinants were grafted beneath the renal capsule of male athymic rodent hosts and allowed to grow in vivo for 6 months. As controls, rSVM and hBLE were grafted separately and allowed to grow for the same period. Tissue recombinants and control tissue grafts were harvested, and secretions were collected for biochemical studies. Tissues were fixed both for histologic as well as immunohistochemical staining. Neonatal rSVM induced normal adult human bladder urothelium to form glandular structures resembling prostate. The induced prostatic acini were filled with secretions that expressed human prostate-specific secretory proteins. These findings demonstrate that adult human urothelial cells retain a responsiveness to neonatal prostatic mesenchymal inductors. Change in urothelial histodifferentiation was associated with change in functional activity. The ability of the neonatal rat mesenchymal tissues to induce morphologic as well as biochemical changes in normal adult human urothelium provides a basis for human tissue engineering and organ reconstruction.

Adult↗

PubMed1996

The Dri 42 gene, whose expression is up-regulated during epithelial differentiation, encodes a novel endoplasmic reticulum resident transmembrane protein.

A search for novel genes that are up-regulated during development and differentiation of the epithelial cells of the intestinal mucosa led us to the isolation of the Dri 42 cDNA clone (Dri, differentially expressed in rat intestine). The nucleotide sequence of the full-length cDNA has shown that it encodes a 35.5-kDa protein with one consensus sequence for N-linked glycosylation and alternating hydrophilic and hydrophobic domains. To determine the intracellular localization of Dri 42 we have raised polyclonal antibodies in hens against a bacterially produced Dri 42-glutathione S-transferase fusion protein. Immunofluorescence detection with these antibodies has shown specific staining of the endoplasmic reticulum (ER) in the relatively undifferentiated fetal rat intestinal cell line FRIC B and in sections of rat small intestine. ER membrane localization of Dri 42 was confirmed by laser confocal microscopy of polarized Madin-Darby canine kidney cells overexpressing a Dri 42-chloramphenicol acetyltransferase (CAT) fusion protein by transfection. Pulse labeling experiments on transiently transfected cells demonstrated that the protein does not acquire Golgi modifications up to 4 h after synthesis, thus indicating that Dri 42 is an ER resident protein. The transmembrane disposition of Dri 42 was studied using in vitro insertion of Dri 42-CAT fusion proteins into microsomal membranes. The fusion proteins consisted of several different lengths of truncated Dri 42 and a reporter protein, CAT, that was linked in-frame after each hydrophobic segment. We found that hydrophobic segments H1, H3, and H5 had a signal/anchor function, and that membrane insertion of Dri 42 was achieved co-translationally by the action of a series of alternating insertion signals and halt transfer signals, resulting in the exposure of both termini of the protein to the cytosolic side. The functional implications of the structure and localization of Dri 42, whose primary sequence does not share significant homology to any previously described protein, are discussed.

Amino Acid Sequence↗

PubMed2003

Sonic hedgehog regulates prostatic growth and epithelial differentiation.

The Sonic hedgehog (SHH)-signalling pathway mediates epithelial-mesenchymal interactions in several tissues during development and disease, and we have investigated its role in rat ventral prostate (VP) development. We have demonstrated that Shh and Ptc expression correlates with growth and development of the prostate and that their expression is not regulated by androgens in the VP. Prostatic budding was induced in response to testosterone in Shh null mouse urogenital sinus (UGS) explants grown in vitro and in rat UGS explants cultured with cyclopamine, suggesting that SHH-signalling is not critical for prostatic induction. SHH-signalling was disrupted at later stages of VP development (in vitro), resulting in a reduction in organ size, an increase in ductal tip number, and reduced proliferation of ductal tip epithelia. The addition of recombinant SHH to VPs grown in vitro caused a decrease in ductal tip number and expansion of the mesenchyme. In the presence of testosterone, inhibition of SHH-signalling accelerated the canalisation of prostatic epithelial ducts and resulted in ducts that showed morphological similarities to cribiform prostatic intraepithelial neoplasia (PIN). The epithelia of these ducts also demonstrated precocious and aberrant differentiation, when examined by immunohistochemistry for p63 and cytokeratin 14. In conclusion, we show that SHH-signalling is not essential for prostatic induction, but is important for prostatic growth, branching, and proliferation, and that androgen-stimulated growth in the absence of signalling from the SHH pathway results in aberrant epithelial differentiation.

Androgens↗

PubMed1988

Epithelial-mesenchymal interactions in intestinal epithelial differentiation.

The complex morphogenetic events and the concomitant structural and functional differentiation of intestinal progenitor cells are dependent on tissue interactions. Several experimental models of hetero-species or -topic recombinants between epithelial and mesenchymal anlagen are described. They enabled us to elucidate the respective roles of these tissue components in morphogenesis, epithelial differentiation, and hormone-elicited responses. Among the mechanisms of tissue interactions, the possible mediation of permissive and instructive information via the extracellular matrix is postulated. Arguments in favor of this are provided by the observation of compositional changes in matrix molecules during intestinal development and differentiation. On the other hand, in vitro experimental data emphasize the role of actual contacts between epithelial and mesenchymal cell populations and the importance of the mesenchyme for basement membrane formation.

Animals↗

PubMed1986

Langerhans cell density in epithelial skin tumors correlates with epithelial differentiation but not with the peritumoral infiltrate.

We investigated the intraepithelial density of Langerhans cells in 17 epithelial skin tumors by immunohistologic and morphometric methods. There was a significant difference between seborrheic keratosis (Langerhans cell density 431 +/- 31/mm2; normal epidermis: 378 +/- 20/mm2), basal cell carcinoma (28 +/- 6/mm2), and squamous cell carcinoma (100 +/- 21/mm2). No correlation was found between the Langerhans cell density and the number of intraepithelial T lymphocytes or the extent of the peritumoral inflammatory infiltrate. A significant inverse correlation was demonstrated between mean nuclear area of the epithelial tissue and the Langerhans cell density (r = -0.7; p less than 0.05). These data indicate that the number of Langerhans cells does not influence the extent of the antitumoral immune response. The correlation with the level of epithelial differentiation may be due to different homing conditions.

Antibodies, Monoclonal↗

PubMed1992

Cytokeratins as epithelial differentiation markers in premalignant and malignant oral lesions.

The keratin expression pattern in oral stratified epithelium is related to the cellular differentiation level. The normal pattern shows the keratin pair K5 and K14 in the stratum basale whereas K1 and K10, or K4 and K13, are the two pairs associated with differentiating suprabasal cells. Monoclonal and polyclonal antibodies to individual keratins (K10, K13 and K14) were used in a two-color immunofluorescence staining method to study their coexpression in single cells. Altered keratin expression in premalignant and malignant lesions indicated abnormal differentiation. Monospecific keratin antibodies were suggested to be useful for evaluation of epithelial differentiation changes in oral dysplasias and oral squamous cell carcinomas.

Biomarkers, Tumor↗

PubMed1989

Epithelial differentiation in meningiomas. An immunohistochemical, histochemical, and ultrastructural study--with review of the literature.

Meningiomas possess features indicative of epithelial differentiation. The present study further documents this finding by a multimodality approach on serial sections from 25 meningiomas of all histologic and clinical categories. Standard light microscopic examination, immunohistochemical staining with a variety of epithelial and nonepithelial markers, and histochemical staining for mucin were performed on each case. Directed electron microscopic examination was performed on selected examples of epithelial feature-positive and -negative cases. All cases were immunoreactive for vimentin and epithelial membrane antigen. Thirty-two percent were reactive for cytokeratin and 39% for S-100. Twenty percent showed mucin positivity by histochemistry. Electron microscopic examination of cytokeratin-positive cases showed either intracellular lumina (secretory areas) or cytoplasmic tonofibrils, whereas cytokeratin-negative tumors lacked lumina and tonofibrils. Previous studies showing epithelial features in meningiomas are reviewed with emphasis on the studies using immunohistochemistry. These histochemical, immunohistochemical, and ultrastructural characteristics are of utility in the examination of tumors of suspected meningeal origin, particularly when dealing with atypical presentations or histomorphologic features.

Antigens, Neoplasm↗

PubMed2000

CLED: a calcium-linked protein associated with early epithelial differentiation.

Although it has been well established that Ca(2+) plays a key role in triggering keratinocyte differentiation, relatively little is known about the molecules that mediate this signaling process. By analyzing a bovine corneal epithelial subtraction cDNA library, we have identified a novel gene that we named CLED (calcium-linked epithelial differentiation), which encodes a messenger RNA present in all stratified squamous epithelia, hair follicle, the bladder transitional epithelium, and small intestinal epithelium. The deduced amino acid sequence of CLED, based on a bovine partial cDNA and its full-length, human and mouse homologues that have been described only as ESTs, contains 2 EF-hand Ca(2+)-binding domains, a myristoylation motif, and several potential protein kinase phosphorylation sites; the CLED protein is therefore related to the S100 protein family. In all stratified squamous epithelia, the CLED message is associated with the intermediate cell layers. Similar CLED association with cells that are above the proliferative compartment but below the terminally differentiated compartment is seen in hair follicle, bladder, and small intestinal epithelia. The only exception is corneal epithelium, where CLED is expressed in both basal and intermediate cells. The presence of CLED in corneal epithelial basal cells, but not in the adjacent limbal basal (stem) cells, provides additional, strong evidence for the unique lateral heterogeneity of the limbal/corneal epithelium. These results suggest that CLED, via Ca(2+)-related mechanisms, may play a role in the epithelial cell's commitment to undergo early differentiation, and that its down-regulation is required before the cells can undergo the final stages of terminal differentiation.

Animals↗

PubMed2000

Upregulation of 9 genes, including that for thioredoxin, during epithelial differentiation of mesothelioma cells.

Malignant mesothelioma is a tumour originating from mesothelial cells, and it exhibits epithelial, fibrous, or biphasic differentiation. This tumour is highly resistant to therapy, and presence of a sarcomatous growth pattern has been associated with worse prognosis. A mesothelioma cell line with retained ability to differentiate into either epithelial or fibroblast-like phenotype was subjected to subtractive hybridisation in order to identify the genes coupled to tumour cell differentiation. Nine genes were found to be selectively overexpressed in the epithelial sub-line, compared to only two genes in the fibroblast-like phenotype. This may support the idea that the sarcomatous phenotype represents a less differentiated tumour. One of the genes that is differentially expressed by the epithelial cells was thioredoxin, a small redox-active protein associated with cell-growth and differentiation. This overexpression was accompanied by increased protein levels both intracellularly and in the medium. Thioredoxin is reduced by the selenoprotein thioredoxin reductase and NADPH. The activity of this enzyme was high in both cell sub-lines but induced 2-fold in the epithelially-differentiated cells. Overexpression of thioredoxin might be a factor behind the poor prognosis and reduced responsiveness to therapy of mesotheliomas. Epithelial differentiation in this cell line has previously been linked to increased synthesis of heparan sulphate proteoglycans. The possible formation of complexes including thioredoxin, thioredoxin reductase, and heparan sulphate proteoglycans might play a role in the local control of cell growth and differentiation.

Blotting, Western↗

PubMed2002

Expression profiling of synovial sarcoma by cDNA microarrays: association of ERBB2, IGFBP2, and ELF3 with epithelial differentiation.

Synovial sarcoma is an aggressive spindle cell sarcoma with two major histological subtypes, biphasic and monophasic, defined respectively by the presence or absence of areas of glandular epithelial differentiation. It is characterized by a specific chromosomal translocation, t(X;18)(p11.2;q11.2), which juxtaposes the SYT gene on chromosome 18 to either the SSX1 or the SSX2 gene on chromosome X. The chimeric SYT-SSX products are thought to function as transcriptional proteins that deregulate gene expression, thereby providing a putative oncogenic stimulus. We investigated the pattern of gene expression in synovial sarcoma using cDNA microarrays containing 6548 sequence-verified human cDNAs. A tissue microarray containing 37 synovial sarcoma samples verified to bear the SYT-SSX fusion was constructed for complementary analyses. Gene expression analyses were performed on individual tumor samples; 14 synovial sarcomas, 4 malignant fibrous histiocytomas, and 1 fibrosarcoma. Statistical analysis showed a distinct expression profile for the group of synovial sarcomas as compared to the other soft tissue sarcomas, which included variably high expression of ERBB2, IGFBP2, and IGF2 in the synovial sarcomas. Immunohistochemical analysis of protein expression in tissue microarrays of 37 synovial sarcomas demonstrated strong expression of ERBB2 and IGFBP2 in the glandular epithelial component of biphasic tumors and in solid epithelioid areas of some monophasic tumors. Fluorescence in situ hybridization analysis indicated that the ERBB2 overexpression was not because of gene amplification. Differentially expressed genes were also found in a comparison of the expression profiles of the biphasic and monophasic histological subgroups of synovial sarcoma, notably several keratin genes, and ELF3, an epithelial-specific transcription factor gene. Finally, we also noted differential overexpression of several neural- or neuroectodermal-associated genes in synovial sarcomas relative to the comparison sarcoma group, including OLFM1, TLE2, CNTNAP1, and DRPLA. Our high-throughput studies of gene expression patterns, complemented by tissue microarray studies, confirm the distinctive expression profile of synovial sarcoma, provide leads for the study of glandular morphogenesis in this tumor, and identify a new potential therapeutic target, ERBB2, in a subset of cases.

Cell Differentiation↗

PubMed1991

Amplification of human papillomavirus genomes in vitro is dependent on epithelial differentiation.

Human papillomaviruses (HPVs) infect squamous epithelium and establish their genomes as episomes in proliferating basal cells. As infected cells differentiate, the viral DNA is amplified to high copy number and infectious virus is produced. Viral production has not yet been observed in vitro due to the inability of standard culture methods to duplicate most stages of epithelial differentiation. In this study, we have examined a cell line derived from a low-grade cervical lesion and found that it contained episomal copies of an HPV-31 subtype, HPV-31b, at approximately 50 copies per cell. When allowed to stratify at the air-liquid interface of in vitro raft cultures, this cell line differentiates in a manner which histologically resembles a low-grade cervical lesion in vivo. We have observed the amplification of HPV-31b genomes in distinct foci in the upper portion of the in vitro-stratified epithelium similar to that found in productive HPV infections in vivo. Although transcripts from the late region of HPV-31b were also detected specifically in stratified raft cultures, no capsid protein was found. These studies duplicate one important aspect of a productive HPV infection in vitro, the differentiation-dependent amplification of papillomavirus genomes.

Blotting, Northern↗

PubMed1998

Integration of growth factor, extracellular matrix, and retinoid signals during bronchial epithelial cell differentiation.

Epithelial cell differentiation is regulated by specific combinations of growth factors, hormones, and extracellular matrix (ECM). How these divergent signals are integrated is largely unknown. We used primary cultures of normal human bronchial epithelial cells (NHBEs) to investigate mechanisms of signal integration. In defined, serum-free media, NHBEs undergo mucosecretory differentiation only when grown in the presence of retinoids and on the appropriate substratum (collagen gels). We identified the retinoic acid receptor beta (RARbeta) gene as an early marker of NHBE differentiation. In contrast to immortalized cell lines, in NHBEs strong retinoid-induced RARbeta transcription occurs only when cells are grown on collagen gels, and it requires new protein synthesis and a cis-acting element that maps outside the known RARbeta promoter elements. NHBEs grown on collagen gels exhibit reduced epidermal growth factor (EGF)-induced Raf, MEK, and mitogen-activated protein kinase (MAPK) activity. This correlates with a specific inability to achieve high levels of p66(SHC) tyrosyl phosphorylation and association of p66(SHC) with GRB2, despite high levels of EGF receptor (EGFR) autophosphorylation. Notably, inhibition of EGFR or MEK/MAPK activation replaces the ECM requirement for RARbeta induction. Our results strongly suggest that a key mechanism by which specific ECMs facilitate retinoid-induced mucosecretory differentiation of NHBEs is by restricting the level of EGFR-dependent MEK/MAPK activation evoked by autocrine and/or paracrine EGFR ligands.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Mesenchyme specifies epithelial differentiation in reciprocal recombinants of embryonic lung and trachea.

Normal lung morphogenesis and cytodifferentiation require interactions between epithelium and mesenchyme. We have previously shown that distal lung mesenchyme (LgM) is capable of reprogramming tracheal epithelium (TrE) from day 13-14 rat fetuses to branch in a lung-like pattern and express a distal lung epithelial phenotype. In the present study, we have assessed the effects of tracheal mesenchyme (TrM) on branching and cytodifferentiation of distal lung epithelium (LgE). Tracheae and distal lung tips from day 13 rat fetuses were separated into purified epithelial and mesenchymal components, then recombined as homotypic (LgM + LgE or TrM + TrE) or heterotypic (LgM + TrE or TrM + LgE) recombinants and cultured for 5 days; unseparated lung tips and tracheae served as controls. Control lung tips, LgM + LgE, and LgM + TrE recombinants all branched in an identical pattern. Epithelial cells, including those from the induced TrE, contained abundant glycogen deposits and lamellar bodies, and expressed surfactant protein C (SP-C) mRNA. Trachea controls, and both TrM + TrE, and TrM + LgE recombinants did not branch, but instead formed cysts. The epithelium contained ciliated and mucous secretory cells; importantly, no cells containing lamellar bodies were observed, nor was SP-C mRNA detected. Mucin immunostaining showed copious production of mucous in both LgE and TrE when recombined with TrM. These results demonstrate that epithelial differentiation in the recombinants appears to be wholly dependent on the type of mesenchyme used, and that the entire respiratory epithelium has significant plasticity in eventual phenotype at this stage in development.

Animals↗

PubMed1998

Constitutive expression of interferon beta in differentiated epithelial cells exposed to environmental stimuli.

The body's first line of defense against external challenge are the epithelial cells that line the skin and the respiratory, digestive, and genitourinary tracts. Inasmuch as interferon-beta (IFN-beta) participates in host defense against viral, bacterial, and parasitic infections and tumors, we hypothesized that this secreted protein is expressed in various murine epithelial cell types that line portals of entry to the body. We used immunohistochemistry and in situ hybridization techniques to measure IFN-beta expression in the various epithelial cell types and in internal murine organs sheltered from environmental stimuli. The epithelial cell types lining the skin, digestive tract, urinary tract, reproductive tract, and upper respiratory tract constitutively expressed IFN-beta. Specifically, all differentiated epithelial cells at risk of environmental exposure expressed IFN-beta (protein and mRNA) with the exception of the ciliated epithelial cells lining the lower respiratory tract. Epithelial cells of internal organs that are not directly exposed to external pathogens did not express IFN-beta.

Animals↗

PubMed1993

Transforming growth factor beta 2 in epithelial differentiation of developing teeth and odontogenic tumors.

Dysregulation of TGF beta 2, a modulator of cell growth and differentiation, can result in uncontrolled growth and tumor formation. Our comparative studies on the expression of TGF beta 2 mRNA and protein indicate that TGF beta 2 may primarily be a regulator of epithelial differentiation during tooth development (between 13 and 20 gestational wk) and tumorigenesis of odontogenic neoplasms. A paracrine mode of action for TGF beta 2 in early human tooth germ (cap/early bell stage) is suggested by location of mRNA in the mesenchyme surrounding the tooth germ, whereas protein is found in the epithelial dental lamina and enamel organ. During the late bell stage, TGF beta 2 gene expression shifted from the mesenchyme to the odontogenic epithelium and was colocalized with protein, suggesting an autocrine role for the terminal differentiation of ameloblasts. In odontogenic tumors of epithelial origin (ameloblastomas) and epithelial-ectomesencymal origin (ameloblastic fibromas), TGF beta 2 mRNA was mostly located in the mesenchymal tumor component and protein in the epithelial tumor component. Odontogenic ectomesenchymal tumors (myxomas) were not associated with TGF beta 2 mRNA and protein expression. The results imply that TGF beta 2 may play an important role in epithelial-mesenchymal interactions in human tooth morphogenesis and development of odontogenic tumors.

Adolescent↗

PubMed1995

Retinoic acid regulates oral epithelial differentiation by two mechanisms.

The effect of retinoic acid (RA) concentration on differentiation of oral keratinocytes and the influence of fibroblasts on RA-dependent regulation were investigated in a lifted culture system. Keratinocyte differentiation was assessed by morphology, immunohistochemistry and immunoblotting. Filaggrin/profilaggrin and keratin 1 were used as biochemical markers for cornified epithelium and keratins 13 and 19 as markers for noncornified epithelium. Cultured oral keratinocytes in RA-free conditions differentiated in a manner that closely resembled the differentiation pattern of gingival epithelia in vivo. Increasing RA concentrations altered the in vivo-like terminal differentiation of oral keratinocytes by disruption of organized stratification, inhibition of filaggrin/profilaggrin and K1 expression, and stimulation of K13 and K19 expression. Differentiation of keratinocytes from both cornified and noncornified regions of the oral cavity varied in a similar manner in response to added RA, with the exception of K19 expression. K19 was consistently expressed at higher levels in keratinocytes originating from noncornified epithelial as compared to those from cornified epithelia. The level of RA regulation was ultimately dependent on the type of fibroblasts underlying the epithelial cells. Homologous fibroblasts rendered the oral keratinocytes less sensitive to the effects of RA than skin fibroblasts. In addition, at a given RA concentration, fibroblasts from cornified oral mucosa potentiated keratinocyte expression of RA sensitive markers of keratinization as compared to the influence exerted by fibroblasts originating from noncornified oral mucosa. These results indicate that the RA regulation of oral epithelial differentiation is mediated by two separate mechanisms: a direct, RA concentration-dependent effect, and an indirect, fibroblast-mediated effect.

Cell Differentiation↗

PubMed1996

Ontogeny of the rat bladder: smooth muscle and epithelial differentiation.

The sequential expression of smooth muscle and epithelial markers in the rat bladder has been defined. Smooth muscle differentiation, based on cell morphology and immunohistochemical localization of smooth muscle alpha-actin, myosin, vinculin, desmin, vimentin and laminin, begins at 16 days of gestation (birth = 22 days) in the rat bladder. Smooth muscle cell differentiation begins in the periphery of the bladder mesenchyme immediately subadjacent to the serosa and continues toward the urothelium. The cytokeratins 5, 7, 8, 14, 18, and 19 are expressed in the bladder epithelium as a function of developmental age with cytokeratin 7, 8, 18, and 19 being coexpressed at 15 days' gestation followed by cytokeratin 5 at 17 days' gestation and cytokeratin 14 in the newborn bladder. An understanding of the ontogeny of both smooth muscle and epithelial differentiation markers in the normal bladder will allow us to study events that occur in the diseased bladder.

Animals↗