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Stem and niche cell dynamics in normal and pathological conditions

Project description

Stem and niche cell remodelling in response to pathological conditions

Cellular quiescence in adult stem cells is thought to preserve their properties as they are in a state that is less responsive to external cues. However, the examination of quiescent skeletal muscle stem and niche cells in influenza virus infection and cancer cachexia models revealed remodelling in their cellular and molecular properties. The ERC-funded STENIPATH project will study the response of stem and niche cells in one tissue to pathologies present at a distal site. These cells will be characterised using multiple approaches to assess the extent to which their functional properties are altered.

Objective

Coherent tissue growth and repair require an interplay between stem cells and their local and systemic environment. The dynamics of this process remains poorly defined particularly at the intersection with disease. Cellular quiescence is adopted by many adult stem cells, conferring them several features including a smaller cell volume and reduced metabolic demand, suggesting that quiescence preserves stem cell properties making them less responsive to external cues. We examined the status of skeletal muscle stem (MuSC) and niche cells during an influenza virus infection (lung) and cancer cachexia (tumour) in mice. Unexpectedly, quiescent MuSCs remodelled their cellular, metabolic, and transcriptome properties extensively, and tissue regeneration was impaired, prompting us to define a novel cell state, GPath. Whether GPath represents a coordinated response of stem cells to pathology, or uncontrolled deregulation, is unclear.
MuSCs exhibit remarkable diversity in gene regulation and function in distinct anatomical locations (head/limb). We discovered that cranial MuSCs display higher resistance to the pathologies compared to those in limb. These observations have led us into a novel area of research, to the best of my knowledge largely unexplored in model organisms and humans: how stem and niche cells in one organ respond to pathologies present at a distal site. We will examine the response of muscle and blood stem and niche cells to distal pathologies by defining their cellular, metabolic, molecular, epigenetic, and functional properties, and their modes of cell division. We will employ diverse multiomics approaches and novel medium/high-throughput intravital and ex vivo imaging pipelines. This work should provide new knowledge and tools to address an important, but under-investigated area of research where stem cell biology and pathologies converge. The knowledge gained will be widely applicable to other stem cell systems and inform on human pathologies.

Host institution

INSTITUT PASTEUR
Net EU contribution
€ 2 499 600,00
Address
RUE DU DOCTEUR ROUX 25-28
75724 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
Links
Total cost
€ 2 499 600,00

Beneficiaries (1)