Unit:
Specialty Molecular Biomedicine Mechanisms of Disease, Molecular and Cellular Therapies, and BioinnovationLibrary of the School of Health Sciences
Author:
Papacharisi Eleni
Supervisors info:
Βασιλική Κολιαράκη, Γ' Ερευνήτρια, ΕΚΕΒΕ Φλέμινγκ
Γιώργος Κόλλιας, Καθηγητής, Ιατρικής, ΕΚΠΑ
Μαριέττα Αρμακά, Γ' Ερευνήτρια, ΕΚΕΒΕ Φλέμινγκ
Original Title:
Therapeutic potential of mesenchymal-targeted approaches in intestinal disease
Translated title:
Therapeutic potential of mesenchymal-targeted approaches in intestinal disease
Summary:
Intestinal mesenchymal cells (IMCs) comprise a highly heterogeneous population with distinct origin, function and molecular markers that participate actively in intestinal development, as well as in colitis and colitis-associated cancer (CAC), through their involvement in regulation of inflammation and modification of the tumor microenvironment. Recent findings have proposed signaling pathways and specific proteins that could be useful in order to target activated mesenchymal cells, however, the identification of the potential therapeutic effect of diverse IMC subpopulations in intestinal disease remain elusive. In this study we addressed two potential ways to target mesenchymal subpopulations; by their specific deletion based on diphtheria toxin (DT) administration in engineered DT-sensitive transgenic mice, which was applied in homeostasis and CAC, and by transplantation, applied principally in colitis and tissue damage. We analyzed the systemic and topical routes of DT treatment and standardized among different dosing schemes the one that would result in efficient deletion of the ColVI mesenchymal subpopulation and low toxicity to the mice. Hence, we showed that the topical, but not systemic, route of DT administration represents a prosperous strategy of eliminating ColVIcre+ cells of the colon both in homeostasis and colorectal cancer. On the other hand, targeting of mesenchymal cells in colitis by their transplantation, either through implantation to the intestinal mucosa or topical transplantation specifically in the ulcers, would require further standardization to prove a promising therapeutic approach. Collectively, our results reveal the efficiency of the diphtheria toxin system, which in addition to other Cre lines could represent a valuable tool to gain insight in the contribution of mesenchymal subpopulations in intestinal development and tumorigenesis and to design novel therapeutic approaches targeting the tumor microenvironment.
Main subject category:
Health Sciences
Keywords:
Intestinal mesenchymal cells, ColVIcre cells, Intestinal homeostasis, Colitis-associated cancer, Diphtheria toxin system, Mesenchymal cell transplantantion
Number of references:
119
