Niche geometry as the regulator of communal metabolism and cell fate

Introduction

Tissue renewal by adult stem cells is regulated by a multitude of cell intrinsic and extrinsic mechanisms, which jointly guide decisions between stem cell self-renewal and differentiation. Change between these two cellular fates is considered to result from transcriptional events that sequentially alter the function of the whole cell – including its metabolism.

Metabolic Influence on Cell Fate

However, recent findings by us and others demonstrate that metabolism can actually actively influence cell fate. Moreover, metabolites can be exchanged between neighboring cells in the stem cell niche, raising the question of how cell fate can be accurately controlled.

Hypothesis

I hypothesize that the fate of tissue stem cells is controlled by metabolism running jointly within the surrounding cellular community, and the geometry of the niche regulates stem cells via effects on this communal metabolism.

Research Objectives

In order to first identify metabolic pathways capable of altering cell fate, we will:

1. Establish the exact order of metabolic and transcriptional events that distinguish the two daughter cells in the first hours after asymmetric cell division.
2. Assess the extent and impact of metabolite sharing in the stem cell niche by developing methods capable of detecting the exchange of metabolites that are produced specifically in one cell type and used by others.
3. Study the impact of niche geometry by developing artificial scaffolds instructing custom niche topology, and investigate the communal metabolism and stem cell fate regulation on tissue mimetic and non-physiologic niche geometries.

Research Tools

The work is enabled by our unique research tools allowing identification of cells with distinct fates based on the chronological age of organelles they inherit in cell division.

Stem Cell Systems

Moreover, we study two stem cell systems with opposing dynamics, providing insights on general principles and increasing the robustness of the study plan.

Potential Impact

Our work also has the potential to uncover metabolic tools advancing protocols for future cellular therapy.