Thursday, May 2, 2024
5/2/2024
PROJECT SUMMARY The heart combines several cell types and lineages to form a functional unit. The pericardium forms the pericardial cavity and outer-most epithelial layers around the heart. Often regarded as mere heart-surrounding mesothelium, the highly specialized pericardium provides mechanical support to the heart, sustains heart muscle and coronary vessel growth, coordinates the response to inflammation, and supports myocardial remodeling upon injury. Pericardial defects remain underdiagnosed and result in severe complications upon heart or lung surgery. Decoding the mechanisms of pericardium formation is critical to understanding congenital heart anomalies and improve regenerative approaches for heart injury and post-surgical healing. What developmental mechanisms endow the pericardium with its unique properties, how it controls its dynamic interaction with the heart, and how we can harness its plasticity in therapeutic settings, remain understudied. Studying pericardium formation has remained challenging due to missing means to visualize, track, and isolate earliest embryonic cells leading to its development. The goal of our research proposal is to uncover the mechanisms that drive pericardium development in coordination with the heart from lateral plate mesoderm (LPM); we will combine our unique in vivo tools in zebrafish for in toto live imaging, lineage tracing, enhancer discovery, and single cell-based transcriptome analysis. The zebrafish is an ideal model to study cardiac development with genetically malleable, visually transparent embryos. We established leading genetic means to observe, track, and isolate the earliest LPM progenitors, and we have used these advances to image first steps in LPM emergence, heart development, and mesothelium formation. Uniquely suited to pursue pericardium development, we now lineage-mapped and live-imaged its origin not among cardiac, but mesothelium progenitors, challenging our view of the pericardium as heart lineage per se. With single-cell approaches, mutants, and gene-regulatory experiments, we found that expression and function of the transcription factor Hand2 supports pericardial progenitors in the LPM, in part in cooperation with canonical Wnt signaling. We hypothesize that the pericardium forms as mesothelial lineage with input from Hand2 to convey unique properties in development and disease. In Aim 1, we will test the distinct lineage origins of pericardial versus heart progenitors using photocovertible- and multispectral Cre/lox-lineage labeling plus single-cell multiomics to define the gene-regulatory trajectory of pericardium formation. In Aim 2, we will test the synergy of Hand2 with canonical Wnt signaling and will pursue how individual target genes are controlled. Our work advances our concepts of pericardial orgins and mechanisms of its development, regeneration, and pathologies. Our molecular insights help guide and improve the in vitro generation of pericardial cells for regenerative applications.
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