Subventions et des contributions :

Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2022-2023)

Tissue architecture and its mechanical properties are important modulators of the development and function of the heart and blood vessels. My research program consists of inter-related projects that are focused on establishing the relevance of tissue architecture and biomechanical forces, in the maturation of new blood vessels and of heart cells-derived from stem cells. In Objective 1, we will develop a functional “microvasculature-on-a-chip” to study effects of matrix composition and the modulation of endothelial and perivascular cell-cell interactions in vascular permeability in a dynamic platform that accounts for flow. Innovative approaches are needed for generating functional microvasculatures and recapitulating their physiological microenvironments in an accurate and controllable fashion. We will achieve this by use of adipose-derived microvessels that can self-assemble into a vasculature and have all the cell types necessary to form a functional network. This platform will allow for the first time, the generation of complex, functional microvasculatures in vitro in the presence of flow; which represents a significant advancement to existing strategies and solves an important gap in terms of human cell source for these applications. In Objective 2 we will define the influence of traction forces in the formation of specific vessel arterial identity by applying cyclic stretch to vascular cells (endothelial and smooth muscle cells) and investigating if it would preferably lead to the specification of arterial identity. We will assess the expression of specific arterial genes, growth factors involved in perivascular recruitment, cell area, proliferation and cell-cell interaction. The innovation in our studies comes from investigating cyclic stretch as a maturation cue for the proper assignment of arterial identity and represent a potential novel conceptual advance. Since the development of the heart is dependent on the formation of blood vessels, in Objective 3, we will investigate if the presence of blood vessels improves the maturation of the heart cells derived from stem cells. We will test this hypothesis by determining whether the addition of blood vessels or endothelial cells to stem cell-derived heart cells will enhance their maturation. Cell maturation will be determined by assessing the molecular signature, structural and cellular organization, functional properties and electrophysiology. These will be benchmarked against human cardiomyocytes from different stages of development. This is an area of extremely high potential impact where obtaining human adult-like heart cells in culture would be a world first. Collectively, these studies will expand our understanding of the mechanisms of cardiovascular maturation and function and will guide our efforts towards generating complex, functional vascularized human heart tissues in vitro (our long-term goal).