Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Author:
Melissari Maria-Theodora
Dissertation committee:
Γεώργιος Κόλλιας, Καθηγητής, Ιατρική Σχολή, Ε.Κ.Π.Α., Επιβλέπων
Αναστάσιος Φιλίππου, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, Ε.Κ.Π.Α.
Αντώνιος Χατζηγεωργίου, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, Ε.Κ.Π.Α.
Κωνσταντίνος Παληκαράς, Επίκουρος Καθηγητής, Ιατρική Σχολή, Ε.Κ.Π.Α.
Βασιλική Κολιαράκη, Ερευνήτρια Β΄, Ερευνητικό Κέντρο Βιοϊατρικών Επιστημών "Αλέξανδρος Φλέμινγκ"
Μαρία Αρμακά, Ερευνήτρια Β΄, Ερευνητικό Κέντρο Βιοϊατρικών Επιστημών "Αλέξανδρος Φλέμινγκ"
Μιχάλης Βερυκοκάκης, Ερευνητής Γ΄, Ερευνητικό Κέντρο Βιοϊατρικών Επιστημών "Αλέξανδρος Φλέμινγκ"
Original Title:
Χαρακτηρισμός, προέλευση και ρόλος των διαφορετικών πληθυσμών μεσεγχυματικών κυττάρων του εντέρου
Translated title:
Identification and functional characterization of mesenchymal cell lineages in the intestine
Summary:
It is well established that mesenchymal cells in the intestinal stem cell niche play a fundamental role to the maintenance of epithelial stem cells and consequently intestinal homeostasis. In contrast, the role of mesenchymal cells outside the stem cell niche is largely unexplored. In this work, we used the Col6a1Cre mouse as a tool to target mesenchymal cells and delineate further their identity and role in homeostasis, intestinal morphogenesis, and colitis. Col6a1Cre mice targeted distinct fibroblast subsets outside the stem cell niche and perivascular cells that can be further distinguished by the combination of the CD201, PDGFRα and αSMA markers. The predominant targeted subpopulation is the PDGFRαhi CD201+ CD34- telocytes at the top of colonic crypts. Col6a1-Cre+ cells were the dominant source of BMPs and non-canonical Wnts, and expressed genes related to epithelial differentiation. In acute DSS colitis, they produced pro-inflammatory mediators, but retained their homeostatic properties and distinct topology. During intestinal development, Col6a1-Cre+ cells were found as PDGFRαhi CD201+ cell aggregates in the “villus clusters” which have a well-established role in villi formation. To explore the physiological functions of Col6a1-Cre+ cells, we employed Col6a1DTR mice that enabled us to deplete Col6a1-Cre+ cell after diphtheria toxin administration. Depletion of Col6a1-Cre+ cells ablated almost completely PDGFRαhi CD201+ CD34- telocytes and compromised several aspects of epithelial homeostasis; Bmp7 and Wnt5a were significantly downregulated, enteroendocrine cells were reduced, and the topological distribution of proliferative cells wase dysregulated. However, the intestinal architecture appeared normal, implying compensatory mechanisms. Indeed, depletion of PDGFRαhi CD201+ CD34- telocytes, triggered PDGFRαlo CD201 -CD34+ cells to proliferate, occupy subepithelial locations and alter their gene expression profile to partially compensate for telocyte loss and support homeostasis. Depletion of Col6a1-Cre+ cells in the colon after acute DSS colitis was also followed by CD34+ mesenchymal cell plasticity showing that Col6a1-Cre+ cells were dispensable for tissue regeneration. In contrast, Col6a1-Cre+ cells played an essential role during intestinal development, as depletion of Col6a1-Cre+ cells in the small intestine and colon of Col6a1DTR embryos abolished villi and crypt morphogenesis. Overall, our findings delineated the identity of Col6a1-Cre+ cells, elucidated their crucial developmental role in villi morphogenesis and unraveled a regulatory role in epithelial homeostasis. Lastly, our work revealed a previously unappreciated plasticity among mesenchymal subpopulations in homeostasis and tissue regeneration.
Main subject category:
Health Sciences
Keywords:
Mesenchymal cells, Large intestine, Fibroblasts, Telocytes, Villi morphogenesis
Number of references:
152
File:
File access is restricted until 2025-06-28.
PhDthesis_Melissari.pdf
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File access is restricted until 2025-06-28.
