PErPetuating Stemness: From single-cell analysis to mechanistic spatio-temporal models of neural stem cell dynamics

Introduction

Neural stem cell (NSC) populations in the vertebrate brain generate adult-born neurons for plasticity, growth, and repair. Neurogenic and gliogenic capacity, based on long-term NSC maintenance, functionally define “stemness”.

Stemness and Heterogeneity

Stemness embodies massive NSC heterogeneity at the single cell level and requires control of maintenance or differentiation decisions at the population level. These features remain mechanistically unreconciled.

Hypothesis

We hypothesise that spatiotemporal interactions among heterogeneous NSCs are coordinated to control the population behaviour.

Project Overview

Thus, we propose a multi-dimensional project exploring these features in time and space, to decode the mechanistic principles of stemness. To this end, we bring together experimental and theoretical groups with complementary expertise in NSC biology, biostatistics, and mathematical modelling.

Methodology

In an iterative experimental-mathematical approach, we will:

1. Solve the topology of individual NSC trajectories in transcriptomic space.
2. Identify local cell-cell coordination mechanisms that impact these trajectories in situ.
3. Decode the resulting systemic properties and outputs of NSC ensembles at long-term and large spatial scales.

Expected Outcomes

This programme will result in original methods, including:

• Retrospective transcriptomics in single cells.
• Innovative barcode transfers.
• A novel mathematical framework to describe structured spatio-temporal population dynamics.

Biological Model Systems

We will focus on two biological model systems:

1. The adult mouse ventricular sub-ventricular zone.
2. Zebrafish pallium.

These systems display comparable heterogeneity but differ in spatial organisation and fate dynamics.

Conclusion

Together, PEPS will uncover the general principles and regulatory mechanisms of perpetuating stemness in time and space. It will lay the conceptual and methodological foundation to manipulate stem cell systems to improve their stability or output, and also produce new methods of universal value for studying cellular systems.