Stem and niche cell dynamics in normal and pathological conditions

Introduction

Coherent tissue growth and repair require an interplay between stem cells and their local and systemic environment. The dynamics of this process remain poorly defined, particularly at the intersection with disease.

Cellular Quiescence

Cellular quiescence is adopted by many adult stem cells, conferring them several features including a smaller cell volume and reduced metabolic demand. This suggests that quiescence preserves stem cell properties, making them less responsive to external cues.

Research Focus

We examined the status of skeletal muscle stem (MuSC) and niche cells during an influenza virus infection (lung) and cancer cachexia (tumor) in mice. Unexpectedly, quiescent MuSCs remodeled their cellular, metabolic, and transcriptome properties extensively, and tissue regeneration was impaired. This prompted us to define a novel cell state, GPath. Whether GPath represents a coordinated response of stem cells to pathology or uncontrolled deregulation is unclear.

Diversity of MuSCs

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 the limb.

Novel Research Area

These observations have led us into a novel area of research, which to the best of my knowledge is largely unexplored in model organisms and humans: how stem and niche cells in one organ respond to pathologies present at a distal site.

Methodology

We will examine the response of muscle and blood stem and niche cells to distal pathologies by defining their:

1. Cellular properties
2. Metabolic properties
3. Molecular properties
4. Epigenetic properties
5. Functional properties
6. Modes of cell division

We will employ diverse multiomics approaches and novel medium/high-throughput intravital and ex vivo imaging pipelines.

Expected Outcomes

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.