Year: 2023
Type: dissertation
Abstract: Telomerase exhibits non-canonical functions that play key roles in both progenitor and cancer cells. In the adult organism, the adult mammalian kidney shows a high sensitivity to telomerase non-canonical functions. Thus, conditional overexpression of the protein component of telomerase TERT in adult mice triggers the reprogramming of kidney epithelial cells into dedifferentiated and proliferating cells, ultimately leading to renal failure. However, the molecular mechanisms underlying this ability of TERT to reprogram the kidney epithelium in vivo remain unknown. In this study, we performed high-throughput sequencing on TERT-activated kidney epithelial cells that have been FACS sorted along their cellular reprogramming. This approach allowed us to identify potential master regulators and effectors of TERT-induced reprogramming. In addition, pathway analysis unexpectedly showed that one of the first signaling pathways targeted by TERT during reprogramming involves remodeling and interaction with the extracellular matrix (ECM). In situ analysis further showed remodeling of ECM in the kidney upon TERT induction in adult mice. Using and in vitro culture system of primary kidney epithelial cells, we found that TERT promotes cell adhesion during the initial step of reprogramming. Assessment of telomerase functions in aged mice further revealed that aging restrains the ability of TERT to reprogram kidney epithelial cells. High-throughput sequencing approaches carried out on aged animals highlighted the molecular mechanisms involved in the impairment of TERT functions upon aging of kidney epithelium. Finally, in vitro Hydrogel-based culture systems revealed that age-associated stiffness of the microenvironment is not involved in the repression of TERT functions on kidney epithelial cells.Our findings demonstrate that the ECM plays a crucial role in implementation of telomerase non-canonical functions in vivo, and open new perspectives for the modulation of these functions in kidney diseases associated with the upregulation of telomerase.
Author: Soubeiran, Nicolas
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W6982292485
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