Roles of matricryptins (bioactive extracellular matrix fragments) in adipose tissue

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Studying the instructive cues provided by the extracellular matrix (ECM) is crucial, and represents an emerging field for adipose tissue. Matricryptins are bioactive fragments generated by the proteolytic remodeling of the ECM. Importantly, these fragments exert intrinsic biological activities that can differ from those of their parent biomolecules. Matricryptins have been shown to regulate cell behavior, in particular for endothelial cells. We hypothesize that selected recombinant matricryptins can stimulate angiogenesis in adipose tissue while preserving the key metabolic functions of this tissue. We will use a biomimetic model of adipose tissue engineered in vitro featuring a microvasculature of endothelial cell-derived capillary networks. Our method is based on the capacity of adipose-derived stromal/stem cells (ASCs) to produce and assemble an abundant endogenous ECM while differentiating into adipocytes. Our specific aims are to: Ia. Determine the impact of selected matricryptin supplementation on endothelial cells and the developing microvasculature in engineered adipose tissues. Ib. Assess if these matricryptins affect adipocyte functions and adipogenesis. II. Determine the endogenous profiles of expression and release of matricryptins in adipose tissues. Aim Ia. Matricryptin candidates have been selected for their reported proangiogenic properties in specific contexts while their roles in adipose tissue are unknown. They will be supplemented into the culture media during adipose tissue formation in vitro and dose-response studies will be carried out. Detailed characterization of the capillary networks formed in matricryptin-enriched or control cultures will be performed by live monitoring as well as confocal microscopy. Aim Ib. The impact on lipolysis will be assessed by quantifying glycerol release by adipocytes upon isoproterenol stimulation. Adipokines with angiomodulatory actions will be quantified. The extent of differentiation of ASCs into adipocytes in presence of matricryptins will also be performed. Aim II. We will determine the endogenous profiles of expression and release of matricryptins in adipose tissue in absence of exogenously added matricryptins. We will identify and quantify the major matricryptins present in human adipose tissue using quantitative mass spectrometry on samples of engineered and native adipose tissues. Impact: The study of matricryptins in adipose tissues has been mostly focused so far on a single matricryptin, endotrophin. Our findings will reveal the capacity of other matricryptins to act as regulators of angiogenesis and/or adipogenesis in adipose tissue. This work will lead to a better understanding of the molecular mechanisms through which ECM components and their bioactive fragments can modulate the microenvironment and impact cell behavior during adipose tissue development and remodeling. Producing a map of matricryptin expression in adipose tissue will contribute novel basic knowledge.