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Tiozzo, Caterina (2009) Role of Pten in lung development. [Ph.D. thesis]

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Abstract (english)

Rationale: Pten is a tumor-suppressor gene, involved in stem cell homeostasis and tumorigenesis. In mouse, Pten expression is ubiquitous and begins as early as 7 days of gestation. Pten-/- mouse embryos die early during gestation indicating a critical role for Pten in embryonic development.
Objective: To test the role of Pten in lung development and injury, we conditionally deleted Pten throughout the lung epithelium by crossing Ptenflox/flox with Nkx2.1-cre driver mice and throughout the lung mesenchyme by crossing Ptenflox/flox with Nkx2.1-cre driver or Dermo1-cre driver. The resulting PtenNkx2.1-cre mutants were analyzed for lung defects and response to injury.
Results: PtenNkx2.1-cre embryonic lungs showed airway epithelial hyperplasia with no branching abnormalities. In vitro culture of mutant lungs also showed an altered responsed to TGF-? when in vivo In adult mice, PtenNkx2.1-cre lungs exhibit increased progenitor cell pools comprised of basal cells in the trachea, CGRP/CC10 double-positive neuroendocrine cells in the bronchi and CC10/SpC double positive cells in the bronchioalveolar duct junction (BADJ). Pten deletion impacted differentiation of various lung epithelial cell lineages, with decreased number of terminally differentiated cells. Over time, PtenNxk2.1-cre epithelial cells residing in the BADJ underwent proliferation, and formed uniform masses, supporting the concept that the cells residing in this distal niche may also be the source of pro-carcinogenic “stem” cells. Finally, increased progenitor cells in all the lung compartments conferred an overall selective advantage to naphthalene injury compared to wild type control mice.
PtenDermo1cre embryonic lungs, moreover, showed normal lung development but increased collagen1 and extracellular matrix production.
Conclusions: Pten has a pivotal role in lung stem cell homeostasis, cell differentiation and consequently resistance to lung injury in the epithelium, Further studies are necessary to clarify the real role of Pten in lung mesenchyme.

Abstract (italian)

Rationale: Pten e’ un gene coinvolto nell’omeostasi delle cellule staminali e nella formazione di tumori. Nei topi, Pten inizia ad essere presente 7 giorni dopo il concepimento. Pten ha un ruolo critico nello sviluppo embrionale: gli embrioni di topo Pten-/-, infatti, muoiono molto presto durante la gestazione.
Scopo dello studio: Studiare il ruolo di Pten nello sviluppo polmonare, eliminando Pten nell’epitelio polmonare, incrociando Ptenflox/flox con topi portatori di Nkx2.1-cre; Pten e’ stato anche eliminato dal mesenchima polmonare incrociando Ptenflox/flox con topi Dermo1-cre. I risultanti PtenNkx2.1cre sono stati analizzati alla ricerca di difetti nello sviluppo polmonare.
Risultati: I polmoni PtenNkx2.1-cre hanno evidenziato in vitro una alterata risposta al TGF-?. In vivo non presentavano nessuna alterazione nel branching bensi una iperplasia polmonare nelle vie aerre. Nei topi adulti, I polmoni PtenNkx2.1-cre presentavano un aumentato pool di cellule progenitori in tutti i distretti: nella trachea, le cellule basali, nei bronchi le cellule neuroepiteliali, positive per CGRP/CC10 ed infine, nella giunzione tra gli alveoli e I bronchi terminali (BADJ), le cellule positive per Spc/CC10. L’assenza di Pten ha un impatto nella differenziazione cellulare, con un diminuito aumento delle cellule all’ultimo stadio di differenziazione. Nel tempo, le cellule epiteliali PtenNxk2.1-cre residenti a livello del BADJ proliferano e formano delle masse di tipo tumorale; questi dati supportano l’idea che le cellule presenti in questa niche possano essere l’origine delle cosidette “pro-carcinogenic stem cells”. L’aumento delle cellule progenitrici, inoltre, conferisce un selettivo vantaggio dopo danno polmonare. I topi con Pten eliminato nell’epitelio, invece, non evidenziavano ne uno sviluppo polmonare alterato ne una alterata differenziazione delle cellule mesenchimali; tuttavia, dimostravano un aumentata deposizione di collagene1 e di matrice extracellulare. Conclusioni: Pten ha un ruolo importante nell’omeostasi delle cellule progenitori del polmone, nella differenziazione epiteliale polmonare e nella resistenza dopo danno. Ulteriori studi sono necessary per chiarire l’esatto ruolo di Pten nel mesenchima polmonare.

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EPrint type:Ph.D. thesis
Tutor:Chiandetti, Lino
Supervisor:MInoo, Parviz and Bellusci, Saverio
Data di deposito della tesi:28 January 2009
Anno di Pubblicazione:28 January 2009
Key Words:Pten, lung development, lung progenitor cells.
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Pediatria
Codice ID:1591
Depositato il:28 Jan 2009
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