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San, Roman Adrianna Katrina. "Mechanisms of Stem Cell Maintenance and Cell Differentiation in the Intestinal Epithelium." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:14226057.
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Constant regeneration of the intestinal epithelium, a dynamic tissue with vital digestive and barrier functions, depends on proliferation of resident stem cells and their differentiation into mature cell types. This epithelium thus provides an ideal model to study stem cells and mechanisms of cell differentiation in an adult tissue.
The identification of a proliferative population of intestinal stem cells (ISCs) at the base of intestinal crypts presents the prospect of understanding their regulation by extrinsic and intrinsic factors. Although activation of Wnt signaling in ISCs is thought to be one crucial function of the ISC niche, the cellular source of Wnt ligands is uncertain. Chapter 2 addresses this question through genetic elimination of Wnt ligand secretion in candidate niche cell populations. The data reveal that Wnts originating in any of the sources considered in the literature – the epithelium (including Paneth cells) and sub-epithelial myofibroblasts – are not required for ISC function. These data support models of highly complex cell redundancy or alternative, non-Wnt ligands. Chapter 3 investigates the cell-intrinsic contributions of an intestine-restricted transcription factor (TF), CDX2, to important ISC behaviors. Cdx2 loss in vivo perturbs ISC proliferation and differentiation, distinct from its functions in mature enterocytes. Analysis of candidate direct CDX2 target genes in ISCs suggests that CDX2 modulates Fibroblast Growth Factor signaling, thus opening new avenues of investigation.
Although cells that differentiate from ISCs rely on gene expression changes mediated by TFs, loss of several individual TFs in vivo has modest effects on intestinal function. Chapter 4 characterizes the functional interactions of CDX2, which has many properties of a master regulator, with two other intestinal TFs: GATA4 and Hepatocyte Nuclear Factor 4 alpha (HNF4A). Analysis of compound mutant mouse intestines elucidated combinatorial roles for CDX2 with GATA4 in crypt cell proliferation and with HNF4A in enterocyte differentiation. Building on this foundation, Chapter 5 describes preliminary investigations into another TF, HNF1A, in intestinal gene regulation and its relationship with CDX2 in controlling cell differentiation and tissue architecture. These studies highlight the complexities of TF interactions and the functions of diverse TF complexes in controlling tissue-specific genes during cell differentiation.
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Shao, Xingguo. "Identification of a Tans-differentiation factor, Rad, a small Ras-like GTP-binding protein, in the regulation of epithelial cell differentiation in human airway epithelium /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2003. http://uclibs.org/PID/11984.
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Ruiz-Torres, Sonya Jomara. "Modeling Fanconi Anemia in Squamous Epithelium using Human Induced Pluripotent Stem Cell-Derived Organoids." University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573573103136768.
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De, las Heras Rachel, and n/a. "Neuronal Differentiation: A Study Into Differential Gene Expression." Griffith University. School of Biomolecular and Biomedical Science, 2003. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20040225.161725.
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Neuronal differentiation encompasses an elaborate developmental program which until recently was difficult to study in vitro. The advent of several cell lines able to differentiate in culture proved to be the turning point for gaining an understanding of molecular neuroscience. In particular the olfactory epithelium provides an attractive tool with which to investigate fundamental questions relating to neuronal differentiation, as it displays a unique capacity to regenerate and to retain a neurogenetic potential from its genesis and throughout adult life. The coordinated regulation of gene expression is fundamental to the control of neuronal differentiation. In order to reveal active processes at the molecular level and to dissect key components of molecular pathways, differential gene expression studies provide a foundation for the elucidation of dynamic molecular mechanisms. This thesis identified genes involved in neuronal differentiation by utilising a clonal olfactory receptor neuronal cell line (OLF442). Gene expression levels were identified using differential display and oligonucleotide array technology before and after serum deprivation. Differential display revealed two kinases whose expression levels were elevated during the differentiation of OLF442, identified as focal adhesion kinase (FAK) related non-kinase (FRNK) and mammalian ste20 like (MST)2 kinase. Furthermore, analysis of the oligonucleotide array data confirmed the expression of genes involved in altering presentation of extracellular matrix molecules, in mediating cytoskeletal rearrangements, and in ceasing the cell cycle, supporting the use of OLF442 as a model for studying differentiation. The differentiation of OLF442 results from the synchronisation of multiple transduction cascades and cellular responses as evidenced by the microarray data. A protein that can synchronise such signalling is the non-receptor protein tyrosine kinase, FAK. Thus the finding of the endogenous FAK inhibitor FRNK by differential display was intriguing as there was no difference in the expression level of FAK induced by differentiation, contrasting that of FRNK. This induced FRNK expression was derived autonomously as it was not responsive to the caspase-3 inhibitor, DEVD-CHO. This is particularly pertinent since the primary role of FRNK is to act as an inhibitor of FAK by competing with its substrates and reducing the phosphorylation of both FAK and its associated proteins. Differential display also revealed the upregulation of another kinase, which had 90% homology with rat MST2 kinase within the 3' UTR. Both mouse MST2 kinase (sequence submitted to GenBank, accession number AY058922) and the closely related family member MST1 kinase were sequenced and cloned. Moreover, evidence to support an autonomously expressed carboxyl-terminal domain of MST2 kinase is presented in Chapter 3 and provides a unique way in which MST2 may regulate its own activity. To further understand the role of MST in neuronal differentiation, a series of stable OLF442 transfections (with mutant and wild-type MST constructs) were carried out. MST was localised with cytoplasmic structures that may represent actin stress fibres, indicating a potential cytoskeletal role during neuronal differentiation. This indicated that MST1 may play a role in the morphological processes involved in neuronal differentiation. The identification of two kinases by differential display provided the motivation to understand the cellular context of OLF442 and to determine the phosphorylation status of the mitogen-activated protein kinase (MAPK) signalling cascades. Differentiation of OLF442 induced high-level phosphorylation of a putative B-Raf isoform, MEK2 and ERK1/2. Interestingly, there was a switch between preferential phosphorylation of MEK1 in undifferentiated OLF442 to preferential phosphorylation of MEK2 following differentiation. SAPK/JNK was also phosphorylated, as was the transcription factor c-Jun, which is a common substrate of both the ERK and SAPK/JNK signalling modules. The mapping of the cellular context of differentiating OLF442 has identified a promising model of a novel MAPK module. This consists of FAK signalling through Rap1 to ERK providing sustained activation, which is buffered or terminated by the expression of the endogenous FAK inhibitor FRNK. Furthermore, MST kinase could potentially play a role in regulating the cytoskeletal re-arrangements that are necessary for neuronal differentiation. MST kinase may signal transiently via the SAPK pathway to provide concomitant activation of c-Jun that is required for neuronal differentiation. An understanding of the gene expression pattern of the normal neuronal differentiation program allows a greater understanding of potential developmental aberrations. This could provide an opportunity for therapies to be conceived, while understanding the complexity of neuronal determination could also provide opportunities for stem cell transplantation.
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Alwosaibai, Kholoud. "Role of PAX2 in Maintaining the Differentiation of Oviductal Epithelium and Inhibiting the Transition to a Stem Cell State." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34450.
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Several studies have proposed the fallopian tube epithelium as a site of origin of ovarian cancer. The discovery of precursor lesions in the fallopian tube in patients at risk for ovarian cancer supports a probable origin for high-grade serous ovarian carcinoma in this tissue. While the fallopian tube epithelium consists of three distinct cell types, the paired box protein 2 (PAX2) positive cells and potentially the CD44 positive stem-like cells are most relevant to ovarian cancer. Loss of PAX2 expression in the fallopian tube cells is considered to be an early event in epithelial transformation, but the specific role of PAX2 in this transition is unknown.
The aim of this study was to define the role of PAX2 in oviductal epithelial cells (OVE) cells and in mouse ovarian surface epithelial cells (MOSE), and to understand its contribution to the formation of serous precursor lesions in the fallopian tubes. Herein, we studied the OVE response to transforming growth factor β (TGFβ, a cytokine found in follicular fluid) and provide evidence of its potential involvement in the regulation of stem cell-like behaviors that may contribute to formation of cancer-initiating cells. Treatment of primary cultures of OVE cells with TGFβ at concentrations found in ovulatory follicular fluid induced an epithelial-mesenchymal transition (EMT) with expected changes in proliferation, cell morphology and expression of SNAIL, Vimentin and E-cadherin. EMT was also associated with decreased expression of PAX2 and an increase in the fraction of cells expressing CD44. Pax2 knockdown in OVE cells and overexpression in ovarian epithelial cells confirmed that PAX2 inhibits CD44 expression and regulates the degree of epithelial differentiation of OVE cells. These results suggest that the loss of PAX2 seen in serous tubal intraepithelial carcinomas (STIC) leads to a shift to a more mesenchymal phenotype associated with stem-like features. Pax2 overexpression in MOSE cells also induced the formation of vascular channels both in vitro and in vivo, which indicate a possible contribution of PAX2 to ovarian cancer progression by increasing the vascular channels to supply nutrients to the tumor cells.
Furthermore, since loss of PAX2 in STIC was found associated with P53 and BRCA1 mutations, OVE cells with mutations of the tumor suppressor genes Trp53 and Brca1 were studied. We found that loss of Trp53 with or without loss of Brca1 increased cell proliferation and colony formation in vitro. In addition, loss of Trp53 induced OVE cells to undergo EMT and induced the expression of stem cell–associated genes. We therefore suggest a potential contribution of stem cells in initiating the precursor lesions in the fallopian tubes in combination with tumor suppressor gene mutation.
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Tanaka, Elly M., Yu Zhu, Madalena Carido, Andrea Meinhardt, Thomas Kurth, Mike O. Karl, and Marius Ader. "Three-Dimensional Neuroepithelial Culture from Human Embryonic Stem Cells and Its Use for Quantitative Conversion to Retinal Pigment Epithelium." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-191613.
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A goal in human embryonic stem cell (hESC) research is the faithful differentiation to given cell types such as neural lineages. During embryonic development, a basement membrane surrounds the neural plate that forms a tight, apico-basolaterally polarized epithelium before closing to form a neural tube with a single lumen. Here we show that the three-dimensional epithelial cyst culture of hESCs in Matrigel combined with neural induction results in a quantitative conversion into neuroepithelial cysts containing a single lumen. Cells attain a defined neuroepithelial identity by 5 days. The neuroepithelial cysts naturally generate retinal epithelium, in part due to IGF-1/insulin signaling. We demonstrate the utility of this epithelial culture approach by achieving a quantitative production of retinal pigment epithelial (RPE) cells from hESCs within 30 days. Direct transplantation of this RPE into a rat model of retinal degeneration without any selection or expansion of the cells results in the formation of a donor-derived RPE monolayer that rescues photoreceptor cells. The cyst method for neuroepithelial differentiation of pluripotent stem cells is not only of importance for RPE generation but will also be relevant to the production of other neuronal cell types and for reconstituting complex patterning events from three-dimensional neuroepithelia.
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Naillat, F. (Florence). "Roles of Wnt4/5a in germ cell differentiation and gonad development & ErbB4 in polarity of kidney epithelium." Doctoral thesis, Oulun yliopisto, 2011. http://urn.fi/urn:isbn:9789514295751.
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Abstract The embryonic urogenital system generates the metanephric kidneys, the gonads and the adrenal glands, and its development is based on sequential and reciprocal cell and tissue interactions. The mechanisms which regulate urogenital ontogeny are still poorly understood. In this thesis, the roles of Wnt-4 and ErbB4 functions in gonad and kidney development were analysed by using in vivo functional genomic technologies. Wnt-4 is crucial in female development since its absence leads to a partial female to male sex reversal. We found that Wnt-4 mediated the interactions between the somatic and the germ cells and played a role in meiosis which is regulated in part by the secreted signal retinoic acid (RA). Expression of certain meiosis-controlling genes (Stra8, Spo11) was inhibited in the Wnt-4 deficient germ cells, while certain pluripotency genes (Oct4, Fgf9, Sox2 and Dnmt3l) were activated similarly as in the wild-type male gonad. In addition to this, we noted that a gene encoding for a Cyp26b1 enzyme, which degrades RA in the embryonic testis, was ectopically expressed in the Wnt-4 deficient ovary. Microarray analysis was used to identify candidate Wnt-4 target genes by using the Wnt-4 knock-out mouse. Of these genes, Runx-1 may represent a novel signalling target to mediate Wnt-4 activity in the control female development The role of receptor-tyrosine kinase ErbB4 in kidney development was studied by using both in vivo gain and loss of function approaches. In the gain-of-function situation, we found that certain markers for the epithelial tubules and collecting ducts lost their polarized expression pattern. At the same time, the orientation of the cells in the kidney tubules was deregulated and an increase in cell proliferation was noticed. We suggest that the observed defects gave rise to an increase in the tubule diameter and to cyst formation in the kidney cortex. In the loss-of-function mouse, the lack of ErbB4 expression led to a similar phenotype as with the gain of function, and the renal functions of the mutant adult kidneys were compromised. In conclusion, the results point to specific roles for Wnt-4 and ErbB4 in the control of urogenital development. Wnt-4 appears to be crucial in sustaining proper female somatic cell and germ cell differentiation, and maintenance of gonad development during and after the sex determination event, while ErbB4 activity is critical for the regulation of tubular growth in embryonic kidney developmentTiivistelmä Sekä nisäkkään jälkimunuainen, lisämunuainen että sukurauhanen kehittyvät alkion urogenitaalialueen järjestelmästä ja solu- ja kudosvuorovaikutukset ohjaavat elinkehitysprosessia. Tapahtuman molekyylitason mekanismit ovat kuitenkin huonosti tunnettuja. Tässä väitöskirjatyössä tutkittiin Wnt-4 signaalin tehtäviä sukurauhasen ja ErbB4- proteiinin munuaisen kehityksessä. Wnt-4 signaali on keskeinen naisen sukupuolisuuden kehityksessä, koska signaalin puutos aiheuttaa alkion sukupuolen osittaisen kääntymisen naaraasta koiraaksi. Tarkastelimme aluksi sitä, välittääkö Wnt-4 itusolujen ja sukurauhasen somaattisten solujen vuorovaikutuksia ohjaten itusolujen meioosia, jota mm. A-vitamiini säätelee. Havaitsimme, että Wnt-4 geeni puuttuessa tietyt meioosia säätelevät geenit kuten Stra8 ja Spo11 olivat heikentyneet, kun taas solujen monikykyisyyteen liittyvät geenit kuten Oct4, Fgf9, Sox2 ja Dnmt3l aktivoituivat vastaavalla tavalla kuin havaitaan normaalisti koirasalkion kivesaiheessa. Tämän lisäksi havaitsimme, että Cyp26b1-geeni, joka johtaa A-vitamiinin hajoamiseen alkiossa ja estää normaalisti meioosin koirasalkion kivesaiheessa oli aktivoitunut munuaisrauhasaiheessa, jolta puuttuu Wnt-4 aktiivisuus. Tuloksemme osoittavat, että Wnt-4 säätelee osaltaan naarasalkion itusolujen meioosia. Tarkastelimme myös mikrosirututkimusten avulla niitä geenejä, joita Wnt-4 säätelee sukuelinaiheessa. Identifioimme useissa Wnt ja β-catenin signaalireittiin liittyvissä geeneissa muutoksia. Muuntuneet geenit voivat olla Wnt-4 signaalireitin kohdegeenejä. Näistä Runx-1 saattaa olla keskeinen Wnt signaalitien kohdegeeni, joka säätelee merkittävällä tavalla naaraan munarauhasen kehitystä. Väitöskirjan toisessa osassa tarkastelimme ErbB4-reseptorityrosiinikinaasin tehtäviä munuaisen kehityksen säätelyssä. ErbB4-geenin tehtäviä tutkittiin käyttäen hyväksi siirtogeenisiä malliorganismeja, joissa ErbB4-geenin määrä oli joko koholla tai ajastetusti inaktivoitu. ErbB4- geenin kokeellinen yliaktiivisuus muutti spesifisti tekijöitä, jotka säätelevät osaltaan jälkimunuaisen epiteeliputkien solujen orientaatiota ja solun jakautumista. Solujen orientaatiomuutoksen yhteydessä myös solujen jakautuminen häiriintyi. Oletuksemme on, että nämä epiteelikudoksessa tapahtuneet muutokset ovat syy, miksi kohotettu ErbB4-aktiviteetti muuttaa epiteeliputkien paksuutta ja pituutta erityisesti munuaisen pintakerroksissa. Havaitsimme myös, että ErbB4-geenin ajastettu poistaminen munuaisen epiteelikudoksessa johti hyvin samankaltaisiin, mutta vastakkaisiin muutoksiin kuin ErbB4-aktiviteetin kohottaminen. Muutokset johtivat myös muutoksiin munuaisen toiminnassa. Yhteenvetona toteamme, että näillä Wnt-4 ja ErbB4 solusignallointiin liittyvillä molekyyleillä on keskeinen tehtävä alkion munarauhasen ja munuaisen aiheen kehityksen säätelyssä. Wnt-4 ohjaa sekä itusolujen että somaattisten solujen erilaistumista ja samalla sukupuolen määräytymistä ja jatkokehitystä, kun taas ErbB4-signallointireseptorin tehtävä on avainasemassa munuaisen epiteeliputken kasvun säätelyssä
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Tanaka, Elly M., Yu Zhu, Madalena Carido, Andrea Meinhardt, Thomas Kurth, Mike O. Karl, and Marius Ader. "Three-Dimensional Neuroepithelial Culture from Human Embryonic Stem Cells and Its Use for Quantitative Conversion to Retinal Pigment Epithelium." Public Library of Science, 2013. https://tud.qucosa.de/id/qucosa%3A29136.
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A goal in human embryonic stem cell (hESC) research is the faithful differentiation to given cell types such as neural lineages. During embryonic development, a basement membrane surrounds the neural plate that forms a tight, apico-basolaterally polarized epithelium before closing to form a neural tube with a single lumen. Here we show that the three-dimensional epithelial cyst culture of hESCs in Matrigel combined with neural induction results in a quantitative conversion into neuroepithelial cysts containing a single lumen. Cells attain a defined neuroepithelial identity by 5 days. The neuroepithelial cysts naturally generate retinal epithelium, in part due to IGF-1/insulin signaling. We demonstrate the utility of this epithelial culture approach by achieving a quantitative production of retinal pigment epithelial (RPE) cells from hESCs within 30 days. Direct transplantation of this RPE into a rat model of retinal degeneration without any selection or expansion of the cells results in the formation of a donor-derived RPE monolayer that rescues photoreceptor cells. The cyst method for neuroepithelial differentiation of pluripotent stem cells is not only of importance for RPE generation but will also be relevant to the production of other neuronal cell types and for reconstituting complex patterning events from three-dimensional neuroepithelia.
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Vasconcelos, Michelle. "O papel da sinalização Notch na diferenciação do epitélio pulmonar." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/42/42134/tde-16052012-100050/.
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O epitélio pulmonar é formado por uma grande diversidade celular, que incluí: células secretoras, ciliadas, basais e neuroendócrinas (NE). A distribuição balanceada destes tipos celulares é crucial para a função pulmonar e pode ser dramaticamente alterada em doenças como a asma. Neste trabalho, estudamos o papel de Notch no pulmão em desenvolvimento ao inativar condicionalmente Rbpjk ou Pofut1, componentes críticos da sinalização Notch. Pulmões mutantes apresentaram-se superpopulados por células ciliadas e NE, além da ausência de células de Clara. Nossos dados sugeriram que Notch suprime os programas de diferenciação de células ciliadas e NE para permitir a diferenciação de células de Clara, através de um mecanismo de inibição lateral. Identificamos também genes associados com a diferenciação de células secretoras e ciliadas através de microarrays. A heterogeneidade no padrão de expressão gênica sugeriu que a via de sinalização Notch estabelece múltiplos subtipos de células ciliadas e secretoras no epitélio pulmonar em desenvolvimento.The airway epithelium comprises a diverse population of secretory, ciliated, basal and neuroendocrine cells (NE). The proper balance of these cell types is critical for normal lung function and can be altered dramatically in conditions, such as asthma. We studied the role of Notch in airway progenitor cell fate by conditionally inactivating Rbpjk or Pofut1, two critical Notch pathway components in mouse mutants. This resulted in airways overpopulated with ciliated and NE cells and absence of secretory Clara cells. We found that Notch suppresses the ciliated and the NE cell programs to allow secretory cell differentiation through a lateral inhibition mechanism. We also identified genes associated with the differentiation of secretory and ciliated cells through a microarray gene profiling experiment. The great heterogeneity of gene expression patterns suggested that Notch plays a role in establishing multiple subsets of secretory and ciliated cells in the developing lung.
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Zhao, Haotian. "Exploring the role of fibroblast growth factor (FGF) signaling in mouse lens fiber differentiation through tissue-specific disruption of FGF receptor gene family." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1072722841.
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Thesis (Ph. D.)--Ohio State University, 2004.Title from first page of PDF file. Document formatted into pages; contains xii, 203 p.; also includes graphics (some col.) Includes bibliographical references (p. 179-203). Available online via OhioLINK's ETD Center
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Deprez, Marie. "Étude de l’hétérogénéité cellulaire et des dynamiques de régénération de l’épithélium respiratoire sain par analyses des signatures transcriptionnelles sur cellules uniques." Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2019. http://www.theses.fr/2019AZUR6022.
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Les progrès technologiques en séquençage haut débit et en manipulation cellulaire permettent d'analyser simultanément et indépendamment le contenu de nombreuses cellules (ARN, ADN,...). Cette révolution "omique" offre un nouveau cadre pour revisiter la "Théorie Cellulaire", essentiellement basée sur des caractéristiques morphologiques et fonctionnelles. Les nombreuses modalités cellulaires désormais accessibles au niveau de la cellule unique, telles que leur transcriptome, leur localisation spatiale, leurs trajectoires développementales, enrichissent considérablement cette définition, et établissent un contexte totalement renouvelé pour réévaluer la définition de "types" ou d’"états" cellulaires ainsi que leurs interactions. \Mon travail de thèse a été de mettre en place des approches statistiques appropriées pour analyser ces données transcriptomiques sur cellule unique caractérisées par une forte variance, la présence d'un pourcentage élevé de valeurs nulles et un grand volume de données. Mon travail s’est focalisé sur le modèle expérimental central de mon laboratoire d’accueil, l'épithélium des voies respiratoires humaines. Les voies respiratoires humaines sont bordées d'un épithélium pseudo-stratifié composé principalement de cellules basales, sécrétrices, à gobelet et multiciliées. Les voies respiratoires constituent en outre un véritable écosystème cellulaire, dans lequel la couche épithéliale interagit étroitement avec les cellules immunitaires et mésenchymateuses. Cette coordination entre les cellules assure une bonne défense du système respiratoire et sa correcte régénération en cas d'agressions extérieures. Une meilleure compréhension des situations cellulaires normales et pathologiques peut améliorer les approches pour lutter contre des pathologies telles que la maladie pulmonaire obstructive chronique, l'asthme ou la mucoviscidose.J'ai d'abord pu caractériser au niveau de la cellule unique la séquence précise et spécifique des événements conduisant à la régénération fonctionnelle de l'épithélium, en utilisant un modèle 3D de cellules humaines. J'ai identifié des hiérarchies de lignées cellulaires et j'ai pu reconstruire les différentes trajectoires possibles de différentiation cellulaire. J'ai confirmé des trajectoires cellulaires décrites précédemment, mais j'ai aussi découvert une nouvelle trajectoire reliant les cellules à gobelet aux cellules multiciliées, identifiant de nouvelles populations cellulaires et de nouvelles interactions moléculaires impliquées dans le processus de régénération de l'épithélium sain des voies aériennes humaines. J'ai ensuite construit un atlas des différents types cellulaires qui tapissent les voies respiratoires humaines saines, du nez jusqu’à la 12ième génération de bronches. Le profilage de 10 volontaires sains a généré un ensemble de données de 77 969 cellules, provenant de 35 emplacements distincts, qui comprend plus de 26 types cellulaires épithéliaux, immunitaires et mésenchymateuses. Cet atlas illustre l'hétérogénéité cellulaire présente dans les voies respiratoires. Son analyse révèle une différence d'expression des gènes entre le nez et les voies respiratoires pulmonaires que j’ai caractérisé dans les cellules suprabasales, sécrétrices et multiciliées. Mes travaux ont également permis d'améliorer la caractérisation de certaines populations de cellules rares, comme les cellules "hillock", déjà décrites chez la souris. En conclusion, mon travail contribue à une meilleure compréhension des dynamiques de différenciation et d'hétérogénéité cellulaire dans les voies respiratoires humaines saines. La ressource ainsi constituée sera extrêmement utile dans tout projet futur visant à analyser avec précision les conditions spécifiques des maladies respiratoiresImprovements made in nucleic acid sequencing and cell handling technologies now offer the opportunity to analyze simultaneously the content of numerous single cells (RNA, DNA, ...) by global and unbiased approaches. This single-cell ‘omics’ revolution provides a new framework to revisit the “Cell Theory”, elaborated over several centuries, and essentially based on morphological and functional features. The many cell modalities now accessible at single- cell level, such as their transcriptome, spatial localization, developmental trajectories, enrich considerably this definition, and set a renewed context to precisely reassess the definition of ‘cell types’, ‘cell states’ as well as their different interactions and fates.My thesis work initially set up ad hoc approaches and statistical framework to analyze appropriately these single-cell data, which deeply differ from standard bulk RNA-seq. High variance, presence of a huge percentage of null values, large volume of data are among the specific characteristics of these datasets. My work was centered on the main experimental model of my host laboratory, e.g. the human airway epithelium. Human airways are lined by a pseudostratified epithelium mainly composed of basal, secretory, goblet and multiciliated cells. Airways also constitute a true cellular ecosystem, in which the epithelial layer interacts closely with immune and mesenchymal cells. This coordination between cells ensures proper defense of the respiratory system and its correct regeneration in case of external aggression and injuries. A better understanding of the operating sequences in normal and physiopathological situations is relevant in pathologies such as chronic obstructive pulmonary disease, asthma or cystic fibrosis.First, I characterized at a single cell level the precise and cell-specific sequence of events leading to functional regeneration of the epithelium, using a 3D model of human cells. I then built a single-cell atlas of the different cell types that are lining healthy human airways from the nose to the 12th generation of bronchi.By applying computational and statistical approaches, I have identified cell lineage hierarchies and was able to reconstruct a comprehensive cell trajectory roadmap in human airways. I not only confirmed previously described cell lineages, but I have also discovered a novel trajectory that links goblet cells to multiciliated cells, identifying novel cell populations and molecular interactors involved in the process of healthy human airway epithelium regeneration. The profiling of 12 healthy volunteers then generated a dataset of 77,969 cells, derived from 35 distinct locations. The resulting atlas is composed of more than 26 epithelial, immune and stromal cell types demonstrating the cellular heterogeneity present in the airways. Its analysis has revealed a strong proximo-distal gradient of expression in suprabasal, secretory, or multiciliated cells between the nose and lung airways. My work has also improved the characterization of rare cells, including “hillock” cells that have been previously described in mice.In conclusion, this work probably represents one of the first single-cell investigations in human airways. It brings original contributions to our understanding of differentiation’s dynamics and cellular heterogeneity in healthy human airways. The resulting resource will be extremely useful for any future single-cell investigators and also for establishing a very useful joint between clinical and biological works. As such, it will constitute a reference in any future project aiming to precisely analyze specific disease conditions
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Beckstead, Benjamin L. "Control of epithelial differentiation by cell-instructive scaffolds /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/8096.
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Capra, J. (Janne). "Differentiation and malignant transformation of epithelial cells:3D cell culture models." Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526218236.
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Abstract The epithelial cells form barriers that compartmentalize the organs. Carcinomas are cancers stemming from epithelial cells and are the most common cancer type. The aim of this study was to understand the differentiation and malignant transformation of epithelial Madin-Darby canine kidney (MDCK) cells and to analyse the electrophysiological parameters which regulate their transport capacity. Emphasis was placed on comparing different culture environments, both in 2D and 3D. First, the effects of drugs or basal extracellular fluid composition on MDCK cell, cyst and lumen volumes were analysed using time-lapse microscopy. The results showed that MDCK cells were capable of both water secretion and reabsorption. The cells were able to perform these functions in a hyperpolarizing or depolarizing environment; change in osmolality of basal fluid was not required. Taken together, these results validate MDCK cells as a good basic model for studying kidney function. Next, the aim was to analyse the effect of 2D and 3D culture environments on the gene expression of untransformed MDCK and temperature sensitive ts-Src -transformed MDCK cells and the changes a single oncogene can induce. Microarray analysis revealed a decrease in the expression of survivin, an inhibitor of apoptosis protein, when switching the untransformed cells from 2D environment to 3D. This downregulation of survivin occurs in adult tissues as well, indicating that the cells grown in 3D are closer to the in vivo state than 2D cells. Src oncogene induced disintegration of cell junctions, but did not downregulate E-cadherin expression. The last part was to study further the factors controlling survivin expression and its significance to cell survival. MDCK cells grown in 3D did not suffer apoptosis if the cells remained in contact with the extracellular matrix. If MDCK cells were denied of ECM contacts they were more susceptible to apoptosis than survivin-expressing ts-Src MDCK cells. Finally, if cells were denied of cell-cell junctions, cells lacking survivin suffered apoptosis even though they had proper cell-matrix contacts. Taken together, these results highlighted the importance of cellular contacts to the cells: MDCK cells needed ECM contacts to differentiate and cell-cell contacts to avoid apoptosisTiivistelmä Epiteelisolut ovat erikoistuneet toimimaan rajapintana elimen ja ympäristön välillä. Ihmisten yleisin syöpä on epiteelisoluista alkunsa saanut karsinooma. Tämän tutkimuksen tarkoituksena oli ymmärtää Madin-Darby-koiran munuaisen solujen (MDCK) erilaistumista ja pahanlaatuistumista sekä analysoida sähköfysiologisia tekijöitä, jotka säätelevät näiden solujen kuljetustoimintaa. Erityisenä kiinnostuksen kohteena oli erilaisten kasvuympäristöjen vertailu. Farmakologisten aineiden tai basaalisen, solunulkopuolisen nesteen koostumuksen vaikutusta MDCK-solujen, -kystan sekä luumenin kokoon tutkittiin valomikroskooppisten aikasarjojen avulla. Tulokset osoittivat MDCK-solujen olevan kykeneviä sekä veden eritykseen että absorptioon, niin hyperpolarisoivassa kuin depolarisoivassakin ympäristössä. Basaalisen nesteen osmolaliteetin muutosta ei tarvittu. Nämä tulokset osoittavat MDCK-solujen olevan hyvä munuaisen tutkimuksen perusmalli. Seuraavaksi analysoitiin kaksi- ja kolmiulotteisten (2D ja 3D) viljely-ympäristöjen vaikutusta ei-transformoitujen MDCK-solujen ja lämpötilaherkkien ts-Src-transformoitujen MDCK-solujen geenien ilmentymiseen sekä yhden onkogeenin aktivoimisen aikaansaamia muutoksia. Microarray-analyysi osoitti apoptoosin estäjän, surviviinin, ilmentymisen vähenemisen, kun kasvuympäristö vaihdettiin 2D-ympäristöstä 3D-ympäristöön. Koska surviviinin väheneminen on normaali tapahtuma aikuisissa kudoksissa, voitiin todeta, että 3D-ympäristössä kasvatetut solut ovat lähempänä luonnonmukaista olotilaa kuin 2D-ympäristössä kasvaneet. Src-onkogeeni sai aikaan soluliitosten hajoamisen, mutta ei vähentänyt E-kadheriinin ilmentymistä. Tutkimuksen viimeinen osa keskittyi surviviinin ilmentymistä säätelevien tekijöiden analysoimiseen ja surviviinin merkitykseen solujen eloonjäämiselle. 3D-ympäristössä kasvaneet MDCK-solut eivät kärsineet apoptoosista edellyttäen, että solut pysyivät kosketuksissa soluväliaineeseen. Jos solut irtautuivat soluväliaineesta, ne päätyivät herkemmin apoptoosiin kuin surviviinia ilmentävät ts-Src MDCK-solut. Mikäli solujen väliset liitokset pakotettiin avautumaan, solut joutuivat apoptoosiin, vaikka ne olivat kosketuksissa soluväliaineeseen. Yhteenvetona nämä tulokset korostavat solujen kontaktien merkitystä: MDCK-solut tarvitsevat soluväliainekontakteja erilaistumiseen ja solujen välisiä kontakteja välttyäkseen apoptoosilta
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Kautsky, Mikael B. "The role of retinoic acid receptors in oral epithelial differentiation /." Thesis, Connect to this title online; UW restricted, 1997. http://hdl.handle.net/1773/6395.
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Sun, Xiaojuan. "Studies on mesothelial differentiation : prognostic and therapeutic approaches to malignant mesothelioma /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-513-5/.
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Ferraris, Corinne. "Pluripotentialité des kératinocytes épidermiques et cornéens chez les mammifères." Grenoble 1, 1994. http://www.theses.fr/1994GRE10090.
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Afin d'etudier les potentialites de l'epiderme et de l'epithelium corneen a former des annexes cutanees telles que les follicules pileux ainsi que les glandes sebacees et sudoripares, des recombinaisons heterotopiques heterospecifiques ont ete realisees puis greffees sur la souris nude. L'origine des cellules constituant ces structures differenciees, a ete identifiee par hybridation in situ avec une sonde alu reconnaissant l'adn humain, et par marquage differentiel des noyaux de lapin et de souris a l'aide du fluorochrome de hoechst. L'epiderme embryonnaire est capable de former des ensembles pilo-sebaces ainsi que des glandes sudoripares selon l'origine du derme auquel il se trouve associe, mais ne peut apparemment pas se transformer en epithelium corneen. L'etude des potentialites de l'epiderme adulte a ete effectuee de deux manieres. Des keratinocytes humains provenant de peau mammaire ont ete cultives pour obtenir un epiderme de culture. Apres 15 jours de greffe, l'epiderme humain de culture a forme des bourgeons pileux et a participe a la formation de follicules pileux d'origine mixte (homme-souris) lorsqu'il a ete reassocie a un derme trichogene. Apres un mois de greffe, les cellules epitheliales humaines ont ete remplacees par des cellules cicatricielles de la souris hote. Dans un deuxieme temps, des follicules pileux ainsi que des ensembles pilo-sebaces ont ete induits dans une peau cicatricielle humaine provenant d'une region pileuse ou glabre par l'insertion de cellules cultivees de papilles dermiques de rat adulte. L'epithelium corneen, recombine avec un derme trichogene ou un derme plantaire s'est transdifferencie en formant un epiderme caracterise par une couche granuleuse auquel sont associes des ensembles pilo-sebaces ainsi que des glandes sudoripares. Ainsi, l'epithelium corneen possede une grande plasticite, car meme lorsque les keratinocytes corneens expriment les keratines k3 et k12, leur differenciation peut encore etre modulee en fonction des fibroblastes auxquels ils sont associes. L'ensemble de ses resultats soulevent le probleme de l'identification des cellules souches epidermiques, ainsi que la comprehension des mecanismes moleculaires responsables de la formation des annexes cutanees
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Hedengran, Faulds Malin. "Estrogen receptor signalling in mammary epithelial cells /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-936-6/.
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Ribeiro, Ana Sofia dos Santos Marques. "Lipidomics of mammary epithelial cells throughout differentiation." Master's thesis, Universidade de Aveiro, 2012. http://hdl.handle.net/10773/9683.
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Mestrado em BioquímicaA glândula mamária desenvolve-se maioritariamente após o nascimento. O seu desenvolvimento é regulado por alterações hormonais que ocorrem em diferentes etapas da vida reprodutiva adulta como puberdade, gravidez, lactação e involução. A necessidade de renovação do tecido epitelial devido a contínua remodelação do tecido sugere a existência de células estaminais mamárias (MSCs), que podem suportar ciclos contínuos de proliferação e diferenciação e apoptose. As MSCs demonstraram várias semelhanças com os tipos de cancro da mama com pior prognóstico e têm sido alvo de vários estudos, uma vez que o estudo do seu programa de diferenciação pode contribuir para um melhor entendimento do desenvolvimento e progressão tumoral. Várias proteínas envolvidas no metabolismo e sinalização lipídica parecem estar altamente reguladas durante a diferenciação das MSCs em diferentes linhas celulares. As proteínas e os fosfolípidos (PLs) estão ambos presentes na membrana celular. PLs são um grupo bastante diverso de biomoléculas essenciais para a manutenção da integridade estrutural celular e sinalização celular. Alterações em lípidos particulares pode refletir alterações na atividade metabólica e/ou ambiente, o que afeta a sinalização celular. Assim, o objectivo deste trabalho foi utilizar uma abordagem lipidómica para analisar o perfil fosfolipídico de células epiteliais mamárias em diferentes estágios de diferenciação (MSC, pré-diferenciação e diferenciação funcional) para identificar espécies moleculares associadas a alterações no metabolismo dos PLs. Para atingir este objectivo foi usada uma abordagem lipidómica que combinou cromatografia de camada fina (TLC) e cromatografia líquida de alta resolução (HPLC) com espectrometria de massa (MS). Esta abordagem permitiu a identificação e quantificação de uma grande variedade de espécies de PLs. Os resultados obtidos neste trabalho demonstraram que a fosfatidiletanolamina (PE) apresenta um aumento em conteúdo relativo com a progressão para a diferenciação, enquanto que para as outras classes de PLs não se observaram alterações significativas quando comparados os três estágios de diferenciação. Além disso, apesar de as espécies moleculares observadas serem as mesmas para os 3 tipos de células, foram encontradas diferenças nas abundâncias relativas de algumas espécies moleculares de fosfatidilcolinas, PEs, fosfatidilinositois e fosfatidilgliceróis entre os estados de diferenciação. Esta análise pode contribuir para uma melhor compreensão do processo de diferenciação de células epiteliais mamárias e da sua susceptibilidade ao desenvolvimento de cancro da mama.
The mammary gland develops mainly after birth. It’s development is regulated by hormonal changes that occur at different stages of the adult reproductive life such as puberty, pregnancy, lactation and involution. The need of renovation of the epithelial tissue due to continuous tissue remodeling, suggest the existence of mammary stem cells (MSCs), which can support continuous cycles of proliferation, differentiation, and apoptosis. MSCs show several similarities with breast cancer types with worse prognosis and have been a target of several studies, as study of their differentiation program may provide better understanding of tumor development and progression. Several proteins involved in lipid metabolism and lipid signaling seem to be highly regulated throughout differentiation of MSCs into different epithelial lineages. Proteins and phospholipids (PLs) are both present in the cellular membrane. PLs are very diverse group of biomolecules essential for the maintenance of cellular structure integrity and cellular signaling. Changes in particular lipids may reflect alterations in metabolic activity and/or environment, which affect cellular signaling. Thus, the aim of this work was to use a lipidomic approach to analyze the phospholipid profile of mammary epithelial cells in distinct differentiation stage (MSC, predifferentiation and functional differentiation) in order to identify molecular species associated to changes in PL metabolism. To achieve this goal we used a lipidomic approach that combined thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) with mass spectrometry (MS). This approach allows the identification and quantification of a great variety of PL species. The results obtained in this work indicate that phosphatidylethanolamine (PE) show an increase in relative content with the progression to differentiation, while in the case of the other PL classes no significant changes were observed, when comparing the three types of cell. Besides, though the molecular species observed were the same for the 3 cell types, differences in the relative abundance of some molecular species of phosphatidylcholine, PE, phosphatidylinositol and phosphatidylglycerol, presented between differentiation states, were detected. This analysis can contribute to a better understanding of the process of differentiation of mammary epithelial cells and their susceptibility to the development of breast cancer.
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McCauley, Heather A. "Two Novel Roles for TGFß Signaling in Epithelial Differentiation and Cancer." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447689079.
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Stiening, Chad Michael. "GENOMIC REGULATION OF BOVINE MAMMARY EPITHELIAL CELL GROWTH AND DIFFERENTIATION." Diss., Tucson, Arizona : University of Arizona, 2005. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1252%5F1%5Fm.pdf&type=application/pdf.
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Alam, Tahirah. "Changes in gene expression during human prostate epithelial cell differentiation." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1444338/.
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The prostate is the most common site of disease in the human male. An understanding of its normal growth and development is required in order to elucidate the underlying mechanisms of prostatic diseases, namely benign prostatic hyperplasia (BPH) and prostate carcinoma. The prostate epithelium consists of three distinct cells types: basal, luminal and neuroendocrine cells. Several authors have postulated that there is a putative stem cell population in the prostate epithelium that gives rise to all three of these cell types. The stem cells are thought to reside in the basal cell layer and upon cell division give rise to an intermediate, transit amplifying (TA) cell. TA cells undergo rapid proliferation before undergoing terminal differentiation into a luminal or neuroendocrine cell. Despite accumulating evidence for the existence of prostatic stem cells, the regulation of cell growth and differentiation in the normal and diseased prostate is poorly understood. The aims of this research project are to identify genes that are involved in the regulation of growth and differentiation in the normal human prostate. As a model for investigating epithelial cell differentiation, a conditionally immortalised prostate epithelial cell line was employed. BPH cells were conditionally immortalised using a SV40 construct containing the large T antigen to give rise to the prostate epithelial cell line PrE2.8 (Daly-Burns et al., in preparation). These cells exhibit a basal phenotype at the permissive temperature of 33 C and are highly proliferative. When switched to 39 C, growth of the PrE2.8 cells is inhibited and they begin to differentiate. Using the differential display technique and microarray analysis, changes in gene expression between a proliferative and a non-proliferative phenotype were investigated. The protein expression of genes of interest were then confirmed in prostate tissue using immunohistochemistry. These genes may represent early markers of prostate epithelial cell differentiation and may also play a role in the progression of BPH and prostate cancer.
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Rane, Jayant. "Control of gene expression in prostate epithelial cell differentiation hierarchy." Thesis, University of York, 2012. http://etheses.whiterose.ac.uk/3854/.
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The aim of present investigation is to elucidate the complex stem cell (SC) dynamics within prostate cancer, which can be exploited to design novel diagnostic and therapeutic strategies for the management of prostate cancer. In order to determine the precise transcriptional and microRNA regulatory mechanisms modulating SC self-renewal and differentiation, unique cellular assays have been developed in our lab. These assays utilise homogeneous cell sub-populations enriched from patient-derived prostate cultures. Occasionally, cell line models and patient-derived mouse prostate cancer xenografts were also employed. Using a prospective bioinformatic analysis of gene expression data from Birnie et. al., 2008, we have identified LCN2, CEACAM6, and S100p as candidate genes for regulation of prostate SC differentiation. These genes are over-expressed in differentiated cells, compared to SC, and have a more similar expression pattern with each other than with any other gene. Since their promoters have binding sites for 32 common transcription factors, the genes may therefore form a co-regulated network and/or have similar functions. Retinoic acid treatment can also induce the expression of all these genes, suggesting that LCN2, CEACAM6, and S100p may play an important role in retinoic acid-mediated prostate epithelial SC differentiation. The genes could also be so-regulated by miR-128, miR-188, and miR-548c, based on an analysis of the miRNA expression by microarray generated in this work. Patient-derived prostate epithelial sub-populations enriched from PrEC, BPH, PCa, and CRPC were profiled for the expression of 766 miRNAs. This analysis identified a very specific prostate cancer SC miRNA signature, and showed that miRNA expression can distinguish between PCa and CRPC. The integration of this miRNA microarray data with gene expression microarray data showed that pathways regulating both the cell cycle (SC quiescence) and cell-cell interaction (SC-stromal niche interaction) could be significantly influenced by miRNAs during differentiation. A lack of telomerase expression/activity in prostate cancer SCs, in contrast to their differentiated progeny also points towards the quiescent nature of these cells. The telomerase studies further revealed that BPH is a disease sustained by progenitor proliferation and that inhibition of telomerase in BPH derived SCs can suppress their self-renewal; while cancer SC self-renewal is not affected by telomerase inhibition. We anticipate that these results, with further functional studies, will comprehensively establish a detailed knowledge base for regulatory mechanisms active in prostate SC and prostate cancer SC differentiation. This data will be invaluable in formulating efficient management strategies for prostate cancer.
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Conly, Alyssa Kay. "Proteomic Analysis of Mammary Epithelial Cell Development." DigitalCommons@CalPoly, 2014. https://digitalcommons.calpoly.edu/theses/1149.
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In this set of studies, a proteomic approach was used to investigate the protein profile of the mammary epithelial cell (MEC) through different stages of mammary development. The HC11 cell line was used to investigate protein changes between undifferentiated and differentiated MEC, which represent the pregnant and lactating states of the cells. This comparison revealed an interesting differential expression profile underscoring many recognized processes that occur in differentiated MECs, while others unveiled differences between MEC differentiation in vitro and in vivo. Primary MEC were also isolated from virgin, pregnant, and primiparous quiescent mice to compare the virgin state of the cell to the other two stages of development. These comparisons added to a previous dataset of primary isolated MEC and generated data that implied a surprising level of activity in virgin MEC relative to the other stages of development investigated. Differentially expressed proteins in the virgin and primiparous quiescent comparison also added to evidence of persisting changes occurring in the gland after a full term pregnancy that are implicated in the risk for breast cancer development. Data sets generated in the same manner from differentiating MEC were used in the development of a database to help manage the growing list of differentially expressed proteins and aid in the identification of potential interesting patterns of regulation during mammary development and differentiation.
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Yoshioka, Masahiro. "Distinct effects of EGFR inhibitors on epithelial- and mesenchymal-like esophageal squamous cell carcinoma cells." Kyoto University, 2018. http://hdl.handle.net/2433/230998.
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Binti, Kamarudin Taty Anna. "Differentiation of human pluripotent stem cells into corneal epithelial like cells." Thesis, University of Newcastle upon Tyne, 2018. http://hdl.handle.net/10443/4182.
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Cornea is the clear outermost protective layer of the eye which enables transmission of light onto the retina. The corneal epithelium is regenerated by limbal stem cells (LSCs), whose loss/dysfunction results in limbal stem cell deficiency (LSCD). Transplantations of ex vivo expanded autologous LSCs from patient's healthy eye onto the affected eye have provided a successful treatment for unilateral LSCD. This however is not applicable to patient with total bilateral LSCD, whose both eyes are affected. This thesis investigated the potential of human induced-pluripotent stem cell (hiPSCs) to differentiate into corneal epithelial-like cells as a source of autologous stem cell treatment for patients with total bilateral LSCD, and tested the engraftment of the differentiated cells in LSCD mouse model. Combined addition of bone morphogenetic protein 4 (BMP4), all trans-retinoic acid (RA) and epidermal growth factor (EGF) for the first nine days of differentiation followed by cell-replating on collagen-IV coated surfaces with a corneal-specific-epithelial cell media for an additional 11 days, resulted in step wise differentiation of human embryonic stem cells (hESCs) to corneal epithelial progenitors and mature corneal epithelial-like cells. Differences in the ability of hiPSCs lines to undergo differentiation to corneal epithelial-like cells were observed. These were dependent on the level of endogenous BMP signalling and could be restored via activation of this signalling pathway by a specific TGFβ inhibitor (SB431542). The hESC and hiPSCs-derived corneal epithelial cells were transplanted into a LSCD mouse model where they survived up to 14 days, but failed to provide long term engraftment and corneal surface regeneration. The findings showed a differential ability of hESCs and hiPSCs lines to generate corneal epithelial cells which is underlined by the endogenous BMP signalling pathway activity. However, the engraftment and functionality of the differentiated cells in the LSCD animal model has yet to be improved.
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Yu, Wenjie. "A Pitx2-Irx1 regulatory network controls dental epithelial stem cell differentiation during tooth development." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/6020.
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Tooth development is precisely controlled by epithelium-mesenchyme interactions, coordinated signaling pathways and associated transcription factors. Although the processes involved in tooth development are well established, details of the cellular and molecular mechanisms that control tooth development are not fully understood. One of the primary unknown mechanisms is the regulation of dental epithelial stem cells (DESCs), including DESC specification, proliferation and differentiation. In this dissertation, I have addressed this gap in knowledge by studying the role of Pituitary homeobox 2 (Pitx2) and Iroquois 1 (Irx1) in teeth at the cellular and molecular level in mice. PITX2 contains mutations of which are associated for Axenfeld-Rieger syndrome (ARS) in humans and is also required for early tooth development. All the background knowledge is included in Chapter I. In Chapter II, I describe the conditional ablation of Pitx2 in the dental epithelium using a Krt14Cre driver line (Pitx2cKO mice). Knocking out Pitx2 in teeth led to delayed epithelial invagination at bud stage and disruption of tooth morphogenesis at cap stage. At the cellular level, Pitx2 mediates DESC differentiation, daughter cell proliferation in bud stage tooth and regulates enamel knot formation in cap stage tooth. At the molecular level, Pitx2 acts as an upstream regulator of the sonic hedgehog (Shh) signaling pathway by regulating the expression of Shh in the dental epithelial signaling center during early tooth development. In addition, I demonstrated that Pitx2 directly controls the transcription of Irx1. In Chapter III, I determined the cellular and molecular mechanisms of Irx1 in mice. Irx1 general knockout mice were generated by replacing the entire Irx1 gene body with a LacZ reporter gene. Irx1 null mice are neonatal lethal and this lethality is due to pulmonary immaturity with defective surfactant protein secretion. In teeth, Irx1 is expressed in the outer enamel epithelium (OEE) and stratum reticulum (SR) and mediates DESC to OEE and SR differentiation through regulation of Forkhead box protein J1 (Foxj1) and Sex determining region Y-box9 (Sox9).
In summary, I identified a Pitx2-Irx1 regulatory network that controls DESC differentiation in teeth, which provided the field with a better understanding of tooth development and tooth regeneration.
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Jehn, Birgit. "The role of transcription factor AP-1 during terminal differentiation and programmed cell death of mammary epithelial cells /." [S.l.] : [s.n.], 1994. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Kurpios, Natasza Anna Hassell J. A. "Experimental approaches to study mammary epithelial stem cells: Role of the ETS gene PEA3 during stem cell differentiation." *McMaster only, 2005.
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Sundberg, Ulla. "Differential expression pattern of CEACAM1 isoforms in polarized epithelial cells, its regulation and some functional consequences /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-774-6/.
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Han, Dongjun. "Role of Oct4 in pXEN cell differentiation and MET process." Doctoral thesis, Humboldt-Universität zu Berlin, 2021. http://dx.doi.org/10.18452/23002.
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Primitive extraembryonale Endoderm (pXEN) Stam-Zelllinien der Ratte repraesentieren wahrscheinlich die festgelegten Vorläufer des extraembryonalen. Die im mesenchymalen Zustand gehaltenen pXEN-Zellen können in vitro weiter zu parietalen und viszeralen Endoderm-ähnlichen Zellen differenzieren. pXEN-Zellen zusätzlich halten moderate Konzentrationen des ICM-Markers Oct4 aufrecht. Die Bedeutung von Oct4 in pXEN-Zellen ist jedoch unbekannt.
Bei höheren Zelldichten, beobachteten wir eine erhöhte Oct4-Expression und gleichzeitig eine Tendenz zu Epithelialisierung (MET) und viszeral endodermaler (VE) Differenzierung. Um zu klären, ob die Oct4-Expression kausal beteiligt ist, modulierten wir die Oct4-Konzentration. Transienter Knockdown von Oct4 reduzierte tendenziell die Expression von MET / VE-assoziierten Genen; umgekehrt förderte die Doxycycline-induzierte Expression eines menschlichen Oct4-Transgens die MET / VE-Differenzierung und verhinderte die Bildung charakteristischer Gang-Strukturen. Im letzteren Fall ging dem MET eine anfängliche Zell-Verlängerung und eine erhöhte Zellmotilität voraus.
Da ein GSK3-Inhibitor und Activin A auch den MET / VE-Phänotyp stimulierten, fragten wir uns, ob Oct4 über die Wnt/β-Catenin oder TGFβ Signalwege wirkt. Die verschiedene Schritte der Wnt/β-Catenin Signalgebung hemmen, blockierten die hOct4-induzierte MET- und VE-Expression nicht. Im Gegensatz dazu verhinderte Repsox, ein Inhibitor von Alk5 (TGFBR1), das hOct4-induzierte MET und die Expression von MET- und VE-Genen und stimulierte eher die Expression von parietalen Endoderm (PE) Genen.
Zusammengefasst zeigen diese Daten eine Rolle für Oct4 bei der MET / VE-Differenzierung auf, wahrscheinlich durch Stimulation eines TGFβ Signalweges. Weiterführende Experimente sind erforderlich um zu bestimmen, wie die zwei Prozesse der MET- und VE-Differenzierung innerhalb der extraembryonalen Endoderm-Linie unterschieden und in Beziehung gesetzt werden.Rat primitive extraembryonic endoderm (pXEN) cell lines appear to represent the committed precursors of the extraembryonic endoderm. The pXEN cells maintained in the mesenchymal state can further differentiate to the parietal endoderm and visceral endoderm like-cells in vitro. In addition, pXEN cells maintain moderate levels of the ICM marker Oct4, a transcription factor that plays important roles in pluripotency, plasticity, and differentiation. However, the significance of Oct4 in pXEN cell lineage specification is unknown. We observed that rat pXEN cells show increased Oct4 expression at higher densities, a condition that also promotes their epithelialization (MET) and visceral endodermal (VE) differentiation. In order to elucidate whether the Oct4 expression is causally involved, we modulated the Oct4 levels. Transient knockdown of Oct4 tended to reduce the expression of MET/VE-associated genes; conversely, the doxycycline-induced expression of a human Oct4 transgene promoted MET/VE differentiation and prevented the formation of characteristic duct structures. In the latter case, the MET was preceded by an initial elongation and increased cell motility. Since GSK3 inhibitor and Activin A also stimulated the MET/VE phenotype, we then asked whether Oct4 acts through the Wnt/β-catenin or TGFβ pathways. Wnt inhibitors did not block the hOct4-induced MET and VE expression. By contrast, Repsox, an inhibitor of Alk5 (TGFBR1), prevented the hOct4-induced MET and the expression of MET and VE genes and rather stimulated the expression of parietal endoderm (PE) genes. Taken together, these data indicate a role for Oct4 in MET/VE differentiation via stimulation of TGFβ signaling. Further work is needed to determine how the two MET and VE differentiation processes are distinguished and related within the extraembryonic endoderm lineage.
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Hansson, Annette. "Modeling of multi-step oral carcinogenesis in vitro : assessment of growth, differentiation and apoptosis markers /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-445-3/.
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Jin, Xin. "Towards differentiation of mouse embryonic stem cells to thymic epithelial progenitor cells." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/12227.
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The thymus is the major site for T-cell generation and thus is important for the adaptive immune system. Development of a properly selected, functional T-cell repertoire relies on interactions between developing T cells and a series of functionally distinct thymic stroma cell types including the cortical and medullary thymic epithelial cells (TECs). The thymus is one of the first organs to degenerate in normal healthy ageing. Related to this, there is strong interest in developing protocols for improving thymus function in patients by cell replacement or regenerative therapies. Thymic epithelial progenitor cells (TEPCs) represent a potential source of cells for thymus transplantation. However, the only source of these cells for transplantation is currently fetal thymus tissue. If TEPCs could be generated from pluripotent cells, this could provide an alternative source of cells for transplantation. The work described in this thesis therefore had two central aims (i) to test the stability of thymic epithelial progenitor cells in vivo and (ii) to investigate the possibility of generating TEPCs or TECs from mouse embryonic stem (ES) cells. The forkhead transcription factor, Foxn1, is essential for the development of a functionally mature thymic epithelium, but is not necessary for formation of the thymic primordium or for medullary thymic epithelial sub-lineage specification. By reactivating Foxn1 expression postnatally in mice carrying a revertible hypomorphic allele of Foxn1, Foxn1R, I herein demonstrate that TEPCs that can express only low levels of Foxn1 mRNA can persist postnatally in the thymic rudiment in mice until at least 6 months of age, and retain the potential to give rise to both cortical and medullary thymic epithelial cells (cTECs and mTECs). These data demonstrate that the TEPC-state is remarkably stable in vivo under conditions of low Foxn1 expression. In parallel with this work, I confirmed the possibility of generating Foxn1-expressing cells from mouse ES cells by using a Foxn1 reporter cell line. As the thymic epithelium has a single origin in the third pharyngeal pouch (3pp) endoderm, I then tested whether or not TEPCs and /or TECs were generated during ES cell differentiation via existing protocols for generating anterior definitive endoderm differentiation cells from mouse ES cells. From this work, I showed that genes expressed in the 3pp and/or TEPC,-including Plet-1, Tbx1, Hoxa3 and Pax9, were induced by differentiation of ES cells using these protocols. I further showed that cells expressing both Plet-1, a marker of foregut endoderm and 3pp, and EpCAM, a marker of proliferating epithelial cells, were induced using a novel protocol (2i ADE) for generating ES cells from ADE. However, gene expression analysis and functional testing suggested that the majority of these cells were non-thymus lineage. I subsequently developed a novel protocol which combined this 2i ADE protocol with co-culturing of the differentiating ES cells with fetal thymic lobes, and demonstrated that this further induced 3pp and TEPC related genes. Finally, I modified the culture conditions in this protocol to conditions predicted to better support TEPC/TEC, and showed that in these conditions, the TEPC-specific markers Foxn1 and IL-7 were induced more strongly than in any other conditions tested. The data presented in this thesis therefore represent an advance towards an optimized protocol for successfully generating TEPCs from ES cells in vitro.
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Madgwick, Daniel. "Functional role of connexin 46 in lens epithelial cell differentiation and growth." Thesis, Manhattan, Kan. : Kansas State University, 2008. http://hdl.handle.net/2097/704.
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Rooney, Nicholas. "Investigating the role of Integrin Linked Kinase in mammary epithelial cell differentiation." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/investigating-the-role-of-integrin-linked-kinase-in-mammary-epithelial-cell-differentiation(7ea57786-1b8a-4391-bfbf-2cda9977877e).html.
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Epithelial cell adhesion to the surrounding extracellular matrix (ECM) is necessary for their proper behaviour and function. During pregnancy and lactation mammary epithelial cells (MECs) require signals imparted by specific β1 integrin-laminin interactions for their functional differentiation in response to Prolactin (Prl) and for the correct formation of polarised secretory acini. Downstream of β1 integrin (β1Itg), the scaffold protein Integrin Linked Kinase (ILK) has been identified as the key signal transducer that is required for both Prl driven lactational differentiation and the establishment of apico-basal polarity in MECs. ILK is a multifunctional adaptor protein that links integrins to the actin cytoskeleton and Rho GTPases such as Rac1. ILK forms a ternary IPP (ILK-PINCH-Parvin) complex with PINCH and Parvins, which are central to its adaptor functions. However, it is not known which of ILKs interacting partners are important for controlling tissue-specific gene expression, or what acts downstream of the IPP complex. In this thesis I have now established that inducible ILK deletion in MECs from ILKfl/flCreER mice, prevents phosphorylation of Stat5 leading to a failure of Prl induced milk expression. In addition I have established a 3-dimensional culture model using the EpH4 mammary epithelial cell line, which respond to Prl treatment and form polarised acini similar to primary cells. In these cells knocking down β1Itg and ILK by lentiviral shRNA delivery was confirmed to have a profound effect on β-Casein production. Expression of ILK mutants that disrupt its protein-protein interactions, showed that mutation of K220 and E359 in the kinase domain also reduced milk production. This means that ILKs kinase domain is important for MEC differentiation, and suggests that Parvin binding (which is disrupted by these mutations) is key in mediating ILKs differentiation functions. Using a complimentary shRNA approach, knockdown of the βParvin binding Rac guanine nucleotide exchange factor αPix also prevented MEC differentiation. This identified for the first time that αPix is required for differentiation and suggests a route by which ILK, via it’s interaction with Parvin, can link integrins to αPix and Rac activity. Interestingly, αPix depletion did not disrupt the IPP complex or polarity, suggesting that αPix represents a differentiation specific bifurcation point in β1Itg-ILK adhesive signalling. Together, this work has helped to establish how ILK is involved in MEC differentiation and has identified a new role for the downstream Rac GEF αPix. In addition, this work contributes to our understanding of the molecular mechanisms by which cell adhesion regulates fundamental cell biological behaviours.
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Suzuki, Rami Noriko. "Differentiation of transformed and non-transformed human mammary epithelial cells." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405212.
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Pichitsiri, Watchara. "Renal allograft failure : a study of the drivers of epithelial cell de-differentiation." Thesis, University of Newcastle upon Tyne, 2013. http://hdl.handle.net/10443/2035.
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Kidney transplantation is the gold standard renal replacement therapy for patients with end-stage renal disease. Despite advances in immunosuppressive therapy, chronic allograft dysfunction remains the commonest cause of renal allograft failure in living recipients. The typical pathology of this disease includes chronic inflammation with tubular atrophy and interstitial fibrosis. Although the origin of the excess fibroblasts and myofibroblasts remains controversial, the process of epithelial to mesenchymal transition might play a role. This study was designed to test the linked hypotheses that the immunosuppressive drug, Cyclosporine A and graft infiltrating T cells can induce allograft pathology by alteration of the bioavailability of fibrogenic TGF-β. An initial series of experiments examined the induction of mesenchymal transition by treatment of cultured human renal tubular epithelial cells with immunosuppressive concentrations of Cyclosporine A. Drug treated cells showed characteristic morphological changes associated with increased expression of the mesenchymal marker S100A4 and reduced expression of the epithelial marker E-cadherin; similar changes were induced by the addition of TGF-β1. The phenotypic change induced by Cyclosporine A was not the consequence of an increased response to autocrine TGF-β and could not be inhibited by specific blockade of the ALK5 component of the TGF-β receptor. Further studies showed in vitro that contact between activated T cells and renal tubular epithelial cells could induce mesenchymal transition by a mechanism that was dependent on activation of the TGF-β receptor complex. A final series of experiments defined a mechanism by which T cells activate latent TGF-β allowing subsequent receptor stimulation leading to either T cell or epithelial cells differentiation. The latency associated peptide binds to and inhibits native TGF-β but can be displaced by both thrombospondin-1 and neuropilin-1, producing active TGF-β. In this study it was shown that cytoplasmic thrombospondin-1 is exported and expressed on the surface of activated T cells following brief interaction with renal tubular epithelial cells; neuropilin-1 was also expressed by a mean 18% of activated human T cells. Inhibition of these two molecules with a blocking LSKL peptide sequence inhibited the normal response of activated human T cells to latent TGF-β1. This study demonstrated that both Cyclosporine A and T cells can induce renal epithelial to mesenchymal cell transition. However, the former process seems independent of TGF-β whilst the latter requires TGF-β receptor stimulation and might be regulated in vivo by T cell-mediated activation of latent TGF-β within the allograft.
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Lin, Yuan-Min. "Stem cell differentiation and biomaterial processing for the engineering of pulmonary epithelial tissue." Thesis, Imperial College London, 2009. http://hdl.handle.net/10044/1/5539.
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The standard approach of tissue engineering is to develop a cell-seeded scaffold which has morphology and mechanical properties similar to those of the target tissue. The scaffold material should possess surface properties so that the seeded cells can maintain proper activity, function and morphology. In terms of engineering of pulmonary epithelial tissue, a major challenge is to obtain sufficient cells because of the difficulty in isolating and culturing primary pulmonary epithelial cells in vitro, especially type II pneumocytes. To overcome this problem, a method to differentiate pulmonary progenitors, which possessed most of the features of type II pulmonary epithelial cells, from murine embryonic stem cells (mESCs) was investigated in this study. The first aim of this project was to increase the differentiation efficiency of type II pneumocyte progenitors from mESCs by enhancing the efficiency of an established differentiation protocol using extracellular matrix (ECM), growth factors and bioactive peptides. In the first study, mESCs were differentiated on tissue culture plastic (TCP) and poly(D,L-lactide) (PDLLA) films coated with ECM proteins, collagen, laminin, fibronectin and Matrigel. The results demonstrated that all protein coatings can enhance the wettability of the TCP and PDLLA films and, moreover, laminin and Matrigel can enhance the differentiation of mESCs into pulmonary progenitors. In the second study, growth factors that are commonly thought to affect the development of embryonic lung, including fibroblast growth factors (FGFs) 1, 2, 7 and 10, were added to the differentiation culture at various concentrations and the subsequent expression of surfactant protein C, a marker of type II pneumocytes and their progenitors, was measured. It was found that FGF1 alone and FGF10 in combination with Matrigel coating enhanced the differentiation of mESCs into pulmonary progenitors. In another study, mESCs were differentiated on PDLLA films grafted with the bioactive peptides RGD and YIGSR. Preliminary result showed that YIGSR enhanced the differentiation of mESCs into pulmonary progenitors. The second aim of this project was to develop 2D environments and 3D scaffolds made of PDLLA suitable for the culture of human pulmonary epithelial cells (A549 line). PDLLA has advantages of biocompatibility and biodegradability, but a major drawback is its hydrophobic nature. To make the surface of PDLLA films hydrophilic, it was modified using a variety of methods, i.e. by grafting the bioactive peptides RGD and YIGSR, by introducing amines using aminolysis and by creating amine-terminated and carboxylic acid-terminated tree-like branched architectures on to the surface. The surface properties of modified PDLLA films were evaluated using various techniques. The culture of A549 cells on PDLLA films demonstrated that surface modifications can affect the attachment, focal adhesion point formation, activity and population size, depending on the type and the concentration of the bioactive peptides or functional groups presented on the surface of PDLLA films. The challenge of culturing pulmonary epithelial cells in 3D is to generate scaffolds with proper porous structures which allow sufficient medium diffusion in and waste disposal out of the scaffolds. The influence of the preparation conditions, i.e. coarsening time and coarsening period of a liquid-liquid phase separation system and freezing temperature of a solid-liquid phase separation system, on the porous morphology and the subsequent pulmonary epithelial cell culture were examined. Scaffolds that possessed alveolus-like round pores and ladder-like pores were prepared using liquid-liquid phase separation and solid-liquid phase separation, respectively. Culture of A549 cells on the PDLLA scaffolds demonstrated that cell penetration into and activity on the scaffolds are influenced by the pore size and the pore throat size of the scaffolds. In conclusion, the results of this project demonstrated that the differentiation of mESCs into pulmonary epithelial progenitors can be enhanced by external signals i.e. from ECM proteins, FGFs and bioactive peptides. The responses of pulmonary epithelial cells to the PDLLA scaffolds can be enhanced by surface modifications using bioactive peptides and functional groups and scaffolds that can serve as a culture environment for pulmonary epithelial cells were prepared accordingly. Taken together, the results of these studies provide a basis for future engineering of pulmonary epithelial tissue, an area of tissue engineering that lags behind that of other major organs.
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Malton, Joanne. "Modulation of squamous differentiation in vitro in human bronchial epithelial cells." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275628.
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Borutinskaite, Veronika Viktorija. "Characterization of proteins involved in differentiation and apoptosis of human leukemia and epithelial cancer cells." Doctoral thesis, Linköpings universitet, Klinisk mikrobiologi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-11741.
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Today, cancer is understood as an epigenetic as well as a genetic disease. The main epigenetic hallmarks of the cancer cell are DNA methylation and histone modifications. The latter changes may be an optimal target for novel anticancer agents. The main goal of using histone deacetylase inhibitors (HDACIs) would be restoration of gene expression of those tumor-suppressor genes that have been transcriptionally silenced by promoter-associated histone deacetylation. However, HDACIs have pleiotropic effects that we are only just starting to understand. These may also be responsible for the induction of differentiation, cell-cycle arrest and pro-apoptotic effects. There are now so many HDACIs available, with such different chemical structures and biological and biochemical properties, that it is hopeful that at least some of them will succeed, probably in combination with other agents or therapies. In our studies we focussed ourselves on studies some new HDACIs, that can be useful for treating cancers, including leukemia and epithelial cancer. To do that, we used novel HDACIs, like BML-210, and their combination with the differentiation inducer all-trans retinoic acid (ATRA). Cell differentiation and proliferation in general, and specific gene expression require de novo protein synthesis and/or post-translational protein modifications. So, we tried to identify proteins in general and specifically the proteins that could be important for the cell differentiation process, and when and where in the cell the proteins appear. We delineated that HDACIs inhibited leukemia (NB4 and HL-60) cell growth in a time- and dose-dependent way. Moreover, BML-210 blocked HeLa cell growth and promoted apoptosis in a time-dependent way. Combining of BML-210 with ATRA induced a differentiation process in leukemia cell lines that lead to apoptosis. This correlated with cell cycle arrest in G0/G1 stage and changes in expression of cell cycle proteins (p21, p53), transcription factors (NF-κB, Sp1) and their binding activity to consensus or specific promoter sequences. We also assessed histone modifications, i.e. H3 phosphorylation and H4 hyperacetylation due to HDACI, leading to chromatin remodeling and changes in gene transcriptions. We have also studied changes in protein maps caused by HDACIs and differentiation agents, identifying differences for a few proteins due to growth inhibition and induction of differentiation in NB4 cells using BML-210 alone or in combination with ATRA. These proteins are involved in cell proliferation and signal transduction, like Rab, actin and calpain. One of them was alpha-dystrobrevin (α-DB). To further study possible roles of the latter, we determined changes of α-DB protein isoform expression that correlated with induction of differentiation. We thus identified a novel ensemble of α-DB interacting proteins in promyelocytic leukemia cells, including tropomyosin 3, actin, tubulin, RIBA, STAT and others, being important in cytoskeleton reorganization and signal transduction. Using confocal microscopy, we determined that α-DB co-localizes with HSP90 and F-actin in NB4 and HeLa cells. We also revealed that it changes sub-cellular compartment after treatment with ATRA and/or BML-210. α-DB silencing affected F-actin expression in HeLa cells, further supporting the idea that α-DB is involved in cytoskeleton reorganization in cells. Altogether, our results suggest that α−DB may work as a structural protein during proliferation and differentiation processes of human cancer cells. Based on our findings, we suggest that HDACIs, like BML-210, can be promising anticancer agents, especially in leukemia treatment, by inducing apoptosis and regulating proliferation and differentiation through the modulation of histone acetylations and gene expression.
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Veerapraditsin, Thanaporn. "Interaction between the HPV-16 negative regulatory element and cellular proteins during epithelial cell differentiation." Thesis, University of Glasgow, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404384.
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Amemiya, Kaori. "Adult human retinal pigment epithelial cells capable of differentiating into neurons." Kyoto University, 2007. http://hdl.handle.net/2433/135754.
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Clubbs, Elizabeth Ann. "INFLUENCE OF SOY ISOFLAVONES ON THE PROLIFERATION AND DIFFERENTIATION OF PROSTATE EPITHELIAL CELLS." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1208956436.
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Gotoh, Shimpei. "Generation of Alveolar Epithelial Spheroids via Isolated Progenitor Cells from Human Pluripotent Stem Cells." Kyoto University, 2015. http://hdl.handle.net/2433/195967.
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Final publication is available at http://dx.doi.org/10.1016/j.stemcr.2014.07.005. Shimpei Gotoh, Isao Ito, Tadao Nagasaki, Yuki Yamamoto, Satoshi Konishi, Yohei Korogi, Hisako Matsumoto, Shigeo Muro, Toyohiro Hirai, Michinori Funato, Shin-Ichi Mae, Taro Toyoda, Aiko Sato-Otsubo, Seishi Ogawa, Kenji Osafune, Michiaki Mishima, Generation of Alveolar Epithelial Spheroids via Isolated Progenitor Cells from Human Pluripotent Stem Cells, Stem Cell Reports, Volume 3, Issue 3, 9 September 2014, Pages 394-403, ISSN 2213-6711.Kyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第18681号
医博第3953号
新制||医||1007(附属図書館)
31614
京都大学大学院医学研究科医学専攻
(主査)教授 妻木 範行, 教授 江藤 浩之, 教授 瀬原 淳子
学位規則第4条第1項該当
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Sizemore, Nywana. "Effect of human papillomavirus 16 immortalization on retinoic acid regulation of epidermal growth factor responsiveness and differentiation of normal ectocervical epithelial cells." Case Western Reserve University School of Graduate Studies / OhioLINK, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=case1058216018.
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Pekalski, Marcin. "Renal allograft regjection : The role of TGFB in the differentiation on intragraft T cells and tubular epithelium." Thesis, University of Newcastle Upon Tyne, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.506537.
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Zhang, Hang. "Theoretical and Computational Studies on the Dynamics and Regulation of Cell Phenotypic Transitions." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/65159.
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Cell phenotypic transitions, or cell fate decision making processes, are regulated by complex regulatory networks composed of genes, RNAs, proteins and metabolites. The regulation can take place at the epigenetic, transcriptional, translational, and post-translational levels to name a few.
Epigenetic histone modification plays an important role in cell phenotype maintenance and transitions. However, the underlying mechanism relating dynamical histone modifications to stable epigenetic cell memory remains elusive. Incorporating key pieces of molecular level experimental information, we built a statistical mechanics model for the inheritance of epigenetic histone modifications. The model reveals that enzyme selectivity of different histone substrates and cooperativity between neighboring nucleosomes are essential to generate bistability of the epigenetic memory. We then applied the epigenetic modeling framework to the differentiation process of olfactory sensory neurons (OSNs), where the observed 'one-neuron-one-allele' phenomenon has remained as a long-standing puzzle. Our model successfully explains this singular behavior in terms of epigenetic competition and enhancer cooperativity during the differentiation process. Epigenetic level events and transcriptional level events cooperate synergistically in the OSN differentiation process. The model also makes a list of testable experimental predictions. In general, the epigenetic modeling framework can be used to study phenotypic transitions when histone modification is a major regulatory element in the system.
Post-transcriptional level regulation plays important roles in cell phenotype maintenance. Our integrated experimental and computational studies revealed such a motif regulating the differentiation of definitive endoderm. We identified two RNA binding proteins, hnRNPA1 and KSRP, which repress each other through microRNAs miR-375 and miR-135a. The motif can generate switch behavior and serve as a
noise filter in the stem cell differentiation process. Manipulating the motif could enhance the differentiation efficiency toward a specific lineage one desires.
Last we performed mathematical modeling on an epithelial-to-mesenchymal transition (EMT) process, which could be used by tumor cells for their migration. Our model predicts that the IL-6 induced EMT is a stepwise process with multiple intermediate states.
In summary, our theoretical and computational analyses about cell phenotypic transitions provide novel insights on the underlying mechanism of cell fate decision. The modeling studies revealed general physical principles underlying complex regulatory networks.Ph. D.
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Santos, Cravo Ana Maria. "The role of epithelial cell de-differentiation in the context of improved chemotherapy applied to pancreatic cancer." Thesis, University of Bath, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.642055.
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In cancer, epithelial cell de-differentiation is a feature of rapidly dividing cells under non-controlled growth and it often reflects a change in the gene expression pattern; however, the relationship between proliferation and alterations in cellular differentiation has not yet been identified. This work examined how changes in the characteristics of cells that discriminate their differentiated and proliferative states can be used to improve on current pancreatic cancer chemotherapeutic strategies. PepT1, a high substrate-capacity and low-affinity transporter system, has been suggested as an attractive drug delivery target for pancreatic cancer. Through a combination of immunological assays, PepT1 normally restricted to the apical surfaces in polarised intestinal epithelial cells, was shown to distribute at the cell membrane of non-polarised cancerous ductal cells. Anti-inflammatory or anti-cancer agents, like ibuprofen or gemcitabine, were conjugated to selected amino acids to enhance their uptake via PepT1. Studies with these conjugates demonstrated enhanced uptake into pancreatic cancer cells, AsPc-1 and HPAFII. Subsequent studies investigated how cell polarity that is typically disrupted in cancer can be modulated to affect the balance of epithelial differentiation versus proliferation. Pharmacological attenuation of YAP (c-Yes associated protein) using a β adrenergic agonist, dobutamine, increased functional tight junction (TJ) structures and diminished proliferation rates of two pancreatic cancer cells, AsPc-1 and HPAFII. Dobutamine also primed an apoptotic cell response. When given in combination with gemcitabine, dobutamine further reduced cell proliferation. Overall, these studies have provided support for using PepT1 as a method to target pancreatic cancer cells for the delivery of anti-cancer agents. Additionally, dobutamine was identified as a potential pharmacological agent to suppress the proliferation of pancreatic cancer cells by altering increasing cell programming that drives epithelial cell differentiation.
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Fu, Xin [Verfasser], Edith [Akademischer Betreuer] Pfitzner, and Christoph [Akademischer Betreuer] Englert. "Epigenetic gene regulation of differentiation and epithelial-mesenchymal transition in mammary epithelial cells / Xin Fu. Gutachter: Edith Pfitzner ; Christoph Englert." Jena : Thüringer Universitäts- und Landesbibliothek Jena, 2012. http://d-nb.info/1018652736/34.
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Bischof, Ashley Gibbs. "Extracellular Matrix as a Key Mediator of Mammary Tumor Cell Normalization." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10780.
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Some epithelial cancers can be induced to revert to quiescent differentiated tissues when combined with embryonic mesenchyme; however, the mechanism of this induction is unknown. This dissertation is based on the hypothesis that because extracellular matrix (ECM) plays a critical role during organ development in the embryo, it also may mediate the differentiation-inducing effects of embryonic mesenchyme on cancer cells. To test this hypothesis, I first optimized methods to isolate ECMs from whole tissues or cultured cells, and to repopulate them with cultured cells, using embryonic tooth as a model system. In Chapter 2, I describe these studies and use them to demonstrate that embryonic ECM is sufficient to regulate odontogenic signaling, cell fate decisions and histodifferentiation during normal tooth development. In Chapter 3, I adapt these methods to show that culture of breast cancer cells with ECM derived from embryonic mammary mesenchyme decreases tumor cell proliferation, and stimulates differentiation, including formation of hollow acini and ducts as well as enhanced expression of estrogen receptor-alpha and decreased migration. Further, when the inductive ECMs were injected into fast-growing breast tumors in mice, they significantly inhibited cancer expansion. Critically, the differentiation observed with ECM was the same as that observed in co-culture with mammary mesenchyme cells, showing that ECM is playing a dominant role in tumor cell normalization. In Chapter 4, I then set out to determine the mechanism by which embryonic ECM normalizes tumor cells, I analyzed the contributions of bound cytokines, ECM composition and mechanics. Western blot analysis revealed several bound growth factors, which remained following decellularization; however, removal of these growth factors using high salt washes had no effect on ECM-mediated normalization of tumors. Further, using proteomics analysis I identified eleven ECM proteins present only within inductive ECMs and by testing these proteins in 3D culture, I found three proteins -- collagen III, biglycan and SPARC -- that increased lumen formation to a similar extent as embryonic ECM. These data confirm that mesenchyme-induced tumor cell normalization is mediated by the insoluble ECM, and reveal the identity of some of the inductive molecules responsible for these effects.
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Dixon, I. S. "The differentiation of normal and transformed human cervical epithelial cells in vitro and in vivo." Thesis, University of Cambridge, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.355672.
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