Monocyte-to-Macrophage Trajectories After Lung Injury: Spatio-temporal investigation, molecular regulation & functional implications for lung regeneration and immunity

Introduction

The lung is particularly exposed to airborne and blood-borne insults. The mechanisms underlying lung tissue repair are therefore of fundamental biological importance and have critical implications for the prevention of life-threatening inflammatory and tissue-damaging responses.

Key Players in Lung Repair

Lung-resident tissue macrophages and inflammatory monocyte-derived macrophages (InfMoMac) are key players in the maintenance of homeostasis, repair responses, and disease pathogenesis. Yet, to date, the complexity of lung macrophage responses after injury is far from being resolved.

Research Objectives

Here, we propose to explore InfMoMac trajectories and functional diversity in an unprecedented manner. To this end, we will use:

1. Mouse models of infectious and non-infectious lung injury
2. Single cell and spatial analyses
3. Robust fate-mapping models
4. Gene targeting approaches

These methods will help us investigate:

• The spatio-temporal regulation
• The subtissular niches
• The intrinsic molecular programs
• The extrinsic stress-, inflammation-, and niche-related signals imprinting the identities and functions of InfMoMac subpopulations

Functional Consequences

We will also examine the functional consequences of the maintenance of InfMoMac for lung immunity to a subsequent challenge.

Human Studies

Finally, we will investigate the interactions of InfMoMac with niche cells in humans by:

• Analyzing the InfMoMac landscape in human injured lungs
• Studying a novel human embryonic stem cell-derived lung organoid model in co-culture with monocyte-derived cells

Conclusion

Based on robust preliminary data, sophisticated models, and cutting-edge technologies, this ambitious project will increase our understanding of the basic mechanisms underlying the fine-tuning of InfMoMac trajectories in response to lung injuries. It will thus provide robust foundations to manipulate their fate in medically relevant conditions such as severe respiratory viral infections and acute respiratory distress syndrome.