Endothelial-fibroblast interactions in diabetic foot ulcer: deciphering the intercellular communication responsible for the chronic wound persistence
Diabetic foot ulcer (DFU), a severe complication of diabetes affecting approximately 18.6 million people worldwide each year, is associated with high rates of amputation and mortality. Like other chronic wounds, DFUs exhibit impaired healing due to a dysregulated cascade of cellular signalling and behavioural events that normally ensure rapid closure of the skin barrier. Among the key cellular players, fibroblasts and endothelial cells are central to the proliferative and remodelling phases of wound repair – processes that are notably dysfunctional in chronic wounds. Although endothelial-fibroblast crosstalk is recognized as an essential driver of normal skin healing, the specific mechanisms governing their interaction in DFU is poorly understood.
The main objective of this PhD project is to decipher the intercellular communication between endothelial cells and fibroblasts that underlies the chronicity of DFU. Particular attention will be devoted to extracellular vesicle-associated microRNAs (miRNAs), which are pivotal regulators of intercellular communication through modulation of gene expression in recipient cells. By characterizing the repertoire of pro- and anti-healing miRNAs exchanged between endothelial cells and fibroblasts, this project seeks to uncover novel molecular targets and therapeutic strategies to promote wound repair in diabetic foot ulcers.
The combined effects of hypoxia and matrix stiffness on the pathophysiology of pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease characterized by excessive extracellular matrix (ECM) deposition, increased tissue stiffness, and localized hypoxia. These alterations disrupt cell–cell interactions within the alveolo-capillary barrier and drive fibrotic progression. This project aims to investigate, under controlled in vitro conditions, the combined impact of mechanical stiffness and hypoxic stress on the fate and phenotype of pulmonary cell types and their intercellular communication. To achieve this, biomimetic polyacrylamide hydrogels with tunable stiffness and specific ECM protein coatings will be developed to support the co-culture of alveolar epithelial cells, endothelial cells, fibroblasts, and macrophages. Cellular responses will be assessed through proteomics, imaging, and secretome profiling. The goal is to identify key mechano- and chemo-dependent pro-fibrotic factors, providing new insights into IPF pathogenesis and opening avenues for targeted therapeutic strategies and lung tissue regeneration.
PtSeipin : linking lipid droplets biogenesis and degradation in the diatom Phaeodactylum tricornutum
Microalgae encompass a wide diversity of organisms and have attracted increasing interest due to their ability to produce biomolecules of biotechnological and industrial relevance. In particular, they can accumulate oil within lipid droplets (LDs) in response to abiotic stresses such as nitrogen deprivation. This oil accumulation holds great potential for biofuel production.We recently demonstrated that knockout of the gene encoding Seipin, a protein involved in LD biogenesis, leads to a strong oil accumulation in the diatom Phaeodactylum tricornutum. Moreover, this accumulation appears to result from an absence of LD degradation in the Seipin-deficient mutants. These findings suggest that, in this diatom, LDs are programmed to undergo degradation soon after their formation, thus inhibiting LD degradation could prove a promising strategy to increase their oil content.This project aims to elucidate the mechanisms underlying LD degradation and, more specifically, the connections between their biogenesis and degradation. Three main research axes will be pursued:
1. Identify PtSeipin interaction partners involved in LD degradation, using both candidate-based and unbiased approaches.
2. Characterize the LD degradation pathways disrupted in PtSeipin knockout mutants by combining electron microscopy with transcriptomic and proteomic analyses.
3. Investigate how microalgae utilize oil during the recovery phase after stress, through fluxomic approaches.
Combination of ionizing radiation and radio-enhancing molecules in breast cancer models
The proposed program aims to evaluate the efficacy of molecules enhancing the effects of radiotherapy, in models of breast cancer. Several molecules targeting and inhibiting the Base Excision Repair pathway will be tested for radiopotentiation efficacy in the in vitro and in vivo models.
The proposed inhibitors are already being investigated in vitro, both in the laboratory and by collaborators. We have shown that inhibition of the mechanisms targeted leads to an impairment in DNA damage repair following genotoxic stress. During this project, we will evaluate the effects of inhibitors on DNA damage repair induced by irradiation of different types (conventional, ultra-high dose rate, even extreme dose rate) and the associated mechanisms.
Variability in response to therapeutic combinations is frequently observed when moving from in vitro to in vivo models. We will therefore evaluate the inhibitors on cell line models well characterized in the laboratory, and corresponding to different breast cancer subtypes. On the other hand, the studies will be completed by a validation of the effects observed in vitro on a murine model of breast cancer. This xenograft model, developed in immunocompetent animals, will enable us to monitor the clinical, histological and immune response of the animals and their tumors, in order to confirm the interest of the molecules for therapeutic application in support of radiotherapy.
The proposed program will benefit from the laboratory's collaborations with physicists and chemists, and IRCM's experimental facilities and platforms (irradiation, animal experimentation, microscopy, cytometry, etc.).