Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

• Published in: Nature communications Vol. 13; no. 1; pp. 1677 - 21
• Main Authors: Prummel, Karin D., Crowell, Helena L., Nieuwenhuize, Susan, Brombacher, Eline C., Daetwyler, Stephan, Soneson, Charlotte, Kresoja-Rakic, Jelena, Kocere, Agnese, Ronner, Manuel, Ernst, Alexander, Labbaf, Zahra, Clouthier, David E., Firulli, Anthony B., Sánchez-Iranzo, Héctor, Naganathan, Sundar R., O’Rourke, Rebecca, Raz, Erez, Mercader, Nadia, Burger, Alexa, Felley-Bosco, Emanuela, Huisken, Jan, Robinson, Mark D., Mosimann, Christian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.03.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/44; 14; 14/35; 38; 38/39; 38/91; 631/136/142; 631/136/2060; 631/136/334/1874/763; 631/67/1641; 64/116; Animals; Anomalies; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell migration; Cells (biology); Danio rerio; Embryos; Epithelium - metabolism; Gastrulation; Gene expression; Germ cells; HAND2 gene; Homeostasis; Humanities and Social Sciences; Mesoderm; Mesothelioma; Mesothelioma - genetics; Mesothelium; Mice; multidisciplinary; Organs; Origins; Pericardium; Peritoneum; Progenitor cells; Regeneration; Science; Science (multidisciplinary); Stem cells; Transcription factors; Transcription Factors - metabolism; Transcriptomics; Tumors; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29311-7

The mesothelium lines body cavities and surrounds internal organs, widely contributing to homeostasis and regeneration. Mesothelium disruptions cause visceral anomalies and mesothelioma tumors. Nonetheless, the embryonic emergence of mesothelia remains incompletely understood. Here, we track mesothelial origins in the lateral plate mesoderm (LPM) using zebrafish. Single-cell transcriptomics uncovers a post-gastrulation gene expression signature centered on hand2 in distinct LPM progenitor cells. We map mesothelial progenitors to lateral-most, hand2 -expressing LPM and confirm conservation in mouse. Time-lapse imaging of zebrafish hand2 reporter embryos captures mesothelium formation including pericardium, visceral, and parietal peritoneum. We find primordial germ cells migrate with the forming mesothelium as ventral migration boundary. Functionally, hand2 loss disrupts mesothelium formation with reduced progenitor cells and perturbed migration. In mouse and human mesothelioma, we document expression of LPM-associated transcription factors including Hand2, suggesting re-initiation of a developmental program. Our data connects mesothelium development to Hand2, expanding our understanding of mesothelial pathologies. The mesothelium supports homeostasis and regeneration, yet its development origins remain unclear. Here, the authors uncovered the earliest mesothelium progenitor cells in zebrafish, linking Hand2 gene function to mesothelium formation and its re-activation to mesothelioma tumors.