Molecular regulation is compartmentalized within individual cells. Intracellular and intercellular mechanisms coordinate to modulate cellular functions. Despite substantial advancements in understanding the regulation and interaction of various molecular processes, it remains challenging to relate these molecular insights to quantifiable cellular and tissue functions in mammals. To address this critical knowledge gap, our research focuses on understanding how molecular mechanisms quantitatively regulate cellular functions and organismal phenotypes in mice and humans. Using blood and immune cell regeneration as our primary model, we investigate the molecular mechanisms regulating and coordinating individual hematopoietic stem and progenitor cells (HSPCs) by precisely quantifying and dynamically tracking blood and immune cell regeneration across molecular, cellular, tissue, and organismal levels. We aim to provide insights into how molecular machinery operates within individual cells and interacts across different cells to coordinate cellular and tissue functions at different magnitudes.

1. Investigating cell-intrinsic mechanisms by leveraging cell-cell variability

Heterogeneity in blood and immune cell production among individual HSPCs presents an exciting opportunity to uncover the molecular mechanisms driving this variability. We have previously demonstrated that HSCs derived from the same clone produce similar amounts of blood and immune cells in different recipients, suggesting that cell-intrinsic mechanisms play an important role (Science Advances, 2024). By comparing HSPCs with distinct characteristics of blood and immune cell production, our research strives to uncover novel regulatory mechanisms that quantitatively govern blood and immune cell regeneration.

2. Exploring cell-extrinsic mechanisms by modeling cell-cell spatial interactions and signal transduction

While cell identity, spatial organization and interactions are well characterized in most tissues, hardly anything is known about cellular spatial organization and dynamic interactions within the bone marrow, where blood and immune cells are constantly regenerated. Spatial interactions among cells define their exposure to external signals and play a pivotal role in shaping cell fate decisions. To addresses this key knowledge gap in the field, we will explore the mechanisms and impacts of cell-cell interactions in the bone marrow.

3. Tracking the temporal dynamics of blood and immune cell regeneration

Tissue formation, regeneration, repair, and aging unfold over time. Understanding the temporal dynamics of these processes is crucial as it reveals the orchestrated sequences of cellular events, signaling pathways, and regulatory mechanisms that control tissue size and function. The temporal order also provides insights into the precise interactions and dependencies of the cellular and molecular elements within the network. By investigating the temporal dynamics of a stem cell network, our research aims to shed light on a fundamental question in development and regeneration: how cell fate is determined by the complex convergence of intrinsic and extrinsic factors