Mechanisms and consequences of cell state transitions during heart regeneration

ongoing

Organs consist of cells with a large diversity of specialized roles. A fundamental question is how these cells mount a coordinated response in space and time to maintain or restore organ function after perturbation. Recent progress in single-cell genomics has generated the opportunity to understand this process on a system-wide scale. We will use the adult zebrafish heart as a powerful model system to dissect how regeneration after injury is orchestrated by the activation response of multiple different cell types. To understand how activated cell states are generated and how they interact to drive the regenerative process, we will: 1) Define which cell types react to injury and measure their activation profiles. We will develop new experimental and computational strategies for measuring cell states, including a “molecular time machine” that records the past transcriptome of single cells based on RNA labeling. 2) Discover the mechanisms that induce cell state activation upon injury. We will combine single-cell transcriptomics and open chromatin profiling to infer gene regulatory networks, and we will use functional experiments to validate the identified pathways. 3) Reveal pro-regenerative cell types and understand their role in the regenerative process. We will combine spatial transcriptomics and computational analysis to identify putative cellular interactions, and we will use targeted cell type depletion and signaling inhibition to confirm our findings. In this manner, we will provide the first comprehensive view of how cell type activation leads to a synergistic response in organ regeneration. Furthermore, the approaches and concepts developed in this project will be applicable to other systems in regeneration and beyond. Finally, understanding the underlying mechanisms in zebrafish, the preeminent model for heart regeneration, will open up exciting avenues for awakening the dormant regenerative potential of the human heart.