Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

Abstract

The mesothelium forms epithelial membranes that line the bodies cavities and surround the internal organs. Mesothelia widely contribute to organ homeostasis and regeneration, and their dysregulation can result in congenital anomalies of the viscera, ventral wall defects, and mesothelioma tumors. Nonetheless, the embryonic ontogeny and developmental regulation of mesothelium formation has remained uncharted. Here, we combine genetic lineage tracing, in toto live imaging, and single-cell transcriptomics in zebrafish to track mesothelial progenitor origins from the lateral plate mesoderm (LPM). Our single-cell analysis uncovers a post-gastrulation gene expression signature centered on hand2 that delineates distinct progenitor populations within the forming LPM. Combining gene expression analysis and imaging of transgenic reporter zebrafish embryos, we chart the origin of mesothelial progenitors to the lateral-most, hand2-expressing LPM and confirm evolutionary conservation in mouse. Our time-lapse imaging of transgenic hand2 reporter embryos captures zebrafish mesothelium formation, documenting the coordinated cell movements that form pericardium and visceral and parietal peritoneum. We establish that the primordial germ cells migrate associated with the forming mesothelium as ventral migration boundary. Functionally, hand2 mutants fail to close the ventral mesothelium due to perturbed migration of mesothelium progenitors. Analyzing mouse and human mesothelioma tumors hypothesized to emerge from transformed mesothelium, we find de novo expression of LPM-associated transcription factors, and in particular of Hand2, indicating the re-initiation of a developmental transcriptional program in mesothelioma. Taken together, our work outlines a genetic and developmental signature of mesothelial origins centered around Hand2, contributing to our understanding of mesothelial pathologies and mesothelioma.

GATA4/5/6 family transcription factors are conserved determinants of cardiac versus pharyngeal mesoderm fate

“…etv2, fli1b, kdrl), pronephric (cluster 2: acy3.2, hnf1bb, foxj1a), presomitic (cluster 10: tbx16, bambia), somitic (cluster 16: myod1, ttn.1, myf5), and two cranial-pharyngeal (cluster 3: twist1b, thbs3b; cluster 7: pitx3, foxf2a) populations. We also observed a likely mesothelium progenitor population (cluster7: hand2, cxcl12a, cdx4) 39 ( Supplementary Fig. 1.5).…”

GATA4/5/6 family transcription factors are conserved determinants of cardiac versus pharyngeal mesoderm fate

“…We also observed a likely mesothelium progenitor population (cluster 7: hand2 , cxcl12a , and cdx4 ) (fig. S1, N to P) ( 29 ).…”

The centrosomal protein 83 (CEP83) regulates human pluripotent stem cell differentiation towards the kidney lineage

“…The expression of several LPM genes ( OSR1 , FOXF1 , FOXF2 , FENDRR , HAND1 , HAND2 and CXCL12 ) was strongly up-regulated in KO cells compared to WT cells suggesting that an LPM-like cell pool persisted in D25 KO organoids ( Figure 6A-I ). To further substantiate the potential differentiation of the CEP83 -mutant cells into broadly LPM-like cells, we compared genes that were upregulated genes in D25 organoids (in total, 397 genes) with LPM genes that were previously identified by single cell transcriptomics of sorted post-gastrulation LPM cells from developing zebrafish 33, 59, 60 . Our targeted comparison documented that CEP83 -/- organoids showed significant enrichment for expression of orthologs of early LPM genes (p=0.006) ( Figure 6-figure supplement 2) , including OSR1 , CXCL12 , HAND1/2 , KCTD12 , PIK3R3 , and ZBTB2 .…”