Unit:
Specialty Molecular Biomedicine Mechanisms of Disease, Molecular and Cellular Therapies, and BioinnovationLibrary of the School of Health Sciences
Author:
Arvaniti Vasiliki-Zoi
Supervisors info:
Βασιλική Κολιαράκη, Ερευνήτρια Β΄, Ε.ΚΕ.Β.Ε. "Αλέξανδρος Φλέμιγκ"
Γεώργιος Κόλλιας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κωνσταντίνος Παληκαράς, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Original Title:
Characterization of the age-associated intestinal stroma
Translated title:
Characterization of the age-associated intestinal stroma
Summary:
Aging constitutes a major risk factor for most cancers, including colorectal cancer. Common manifestations of intestinal aging include morphological changes, impaired barrier function, reduced regeneration ability, and dysbiosis. Fibroblasts are important regulators of intestinal homeostasis and carcinogenesis, through extracellular matrix remodeling and paracrine interactions with neighboring cells. They have also been implicated in age-related phenotypes in other organs. However, their contribution to the development of age-associated pathologies in the intestine is still unclear. To investigate age-driven alterations of the intestinal stroma and their impact on tissue function, we performed single-cell RNA sequencing of isolated mesenchymal cells from the intestine of naturally aged (18-20 months-old) and young (2-4 months-old) mice. Bioinformatic analysis revealed changes in the relative abundance of distinct fibroblast subsets in the aged gut, characterized by a significant reduction in PDGFRαHi cells, which was confirmed by flow cytometry and immunohistochemical analyses. Moreover, deregulated gene expression analysis showed differences in the expression profiles of PDGFRαLo fibroblasts and trophocytes, including increased expression of activation markers and inflammatory molecules, along with downregulation of ECM components in older mice. These changes were further corroborated by proteomic analysis of decellularized colonic tissue and in vitro experiments, showing altered matrix organization during aging. Co-cultures of fibroblasts from aged and young mice with tumor organoids revealed that the former enhanced organoid growth, suggesting an increase in the tumor-promoting potential of fibroblasts with age. Finally, the role of microbiota in these changes was explored with the use of fecal microbiota transplantation experiments that revealed that some of the stromal changes in the aged gut, i.e. the reduction of PDGFRαHi cells, are microbiota-dependent. Overall, our results offer an insight into the properties of aged fibroblasts and their capacity to support age-associated tumorigenesis in the gut.
Main subject category:
Health Sciences
Keywords:
Fibroblasts, Intestine, Aging, Carcinogenesis, Microbiome
Number of references:
166
File:
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Arvaniti_Vasiliki-Zoi_MSc.pdf
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File access is restricted until 2027-09-20.
