Muscle stem cell-niche interactions
and Notch signalling. We combine mouse genetics with high throughput approaches to dissect the signalling crosstalk during the establishment, maintenance and activation of the quiescent cells. Our work has contributed to the notion that muscle stem cells (MuSCs) are architects of their own niche and Notch a driving force for the build-up of a dynamic extracellular matrix. Acknowledging the central role of the stem cell-niche interaction we have developed specialised protocols for the isolation of true quiescent cells and identified a new state of early activation.
The microenvironment is critical for stem cell maintenance and can be of cellular and non-cellular composition, including secreted growth factors and extracellular matrix (ECM). Several signalling pathways, including Notch, have been reported to regulate muscle stem cell quiescence, yet the composition and source of niche molecules remain largely unknown. Identifying the diverse factors of the niche and their modes of interaction is a major challenge and a prerequisite for the use of MuSCs in regenerative medicine. Our aim is to construct a comprehensive Notch-MuSC-ECM network involved in the maintenance of quiescence of stem cell of the muscle, and potentially other tissues.
Early cellular response to homeostatic changes
Cells dynamically interact with the microenvironment, which determines their properties and gene-expression profile. Tissue damage leads to dramatic modifications of the microenvironment yet the early cellular responses in vivo remain ill-defined. In order to capture and analyse the biological function of the primary cellular response to perturbed homeostasis, we are employing specialised single-cell and -nucleus transcriptomic approaches. Focusing on two highly regenerating tissues, the skeletal muscle and the liver, we identified a conserved stress response signature that did not depend on the cell type but rather the duration of the stimulus. This prevalent response was also detected in published datasets across tissues, demonstrating high conservation but also indicating a significant degree of data distortion in single-cell atlases. Using quiescent muscle stem cells as a paradigm of cell activation and self-renewal, we are currently investigating the signalling pathways that are involved in the quiescence-to-activation transition and how these can be used to maintain and propagate muscle stem cells in the context of regenerative medicine.