Mesothelial mobilization in the developing lung and heart differs in timing, quantity, and pathway dependency

Abstract

The mesothelial lining of the lung, the visceral pleura, and of the heart, the epicardium, derive from a common multipotent precursor tissue, the mesothelium of the embryonic thoracic cavity that also contributes to organ-specific mesenchymal cell types. Insight into mesothelial mobilization and differentiation has prevailedin the developing heart while the mesenchymal transition and fate of the visceral pleura are poorly understood. Here, we use the fact that the early mesothelium of both the lung and the heart expresses the transcription factor gene Wt1, to comparatively analyze mesothelial mobilization in the two organs by a genetic cre-loxP-based conditional approach. We show that epicardial cells are mobilized in a large number between E12.5 and E14.5, whereas pleural mobilization occurs only sporadically and variably in few regions of the lung in a temporally highly confined manner shortly after E12.5. Mesothelium-specific inactivation of unique pathway components using a Wt1creERT2 line excluded a requirement for canonical WNT, NOTCH, HH, TGFB, PDGFRA, and FGFR1/FGFR2 signaling in the mesenchymal transition of the visceral pleura but indicated a deleterious effect of activated WNT, NOTCH, and HH signaling on lung development. Epicardial mobilization was negatively impacted on by loss of HH, PDGFRA, FGFR1/2 signaling. Epicardial overactivation of WNT, NOTCH, and HH disturbed epicardial and myocardial integrity. We conclude that mesothelial mobilization in the developing lung and heart differs in timing, quantity and pathway dependency, indicating the organ specificity of the program.

Epicardial TGFβ and BMP Signaling in Cardiac Regeneration: What Lesson Can We Learn from the Developing Heart?

“…When looking at the propagation of TGFβ and BMP signaling at the level of the SMADs, an inducible KO of Smad4 specifically in cells expressing the epicardial marker WT1 did not induce severe cardiac malformations in the mouse embryo. Interestingly, these embryos displayed a reduced number of EPDCs and cardiac fibroblasts [64], indicating compromised epicardial EMT and invasion. The fact that the overall cardiac phenotype was not severely affected in this KO embryo, suggests that SMAD-independent signaling pathways are also involved in epicardial behavior.…”

“…Furthermore, cultured chick epicardial cells express TGFBR2 and ALK5, suggesting that TGFβ signaling in epicardial cells can occur [60]. The fact that mouse embryos with an epicardial specific knock-out of Alk5 [63] or Smad4 [64] display an aberrant phenotype indicates that Alk5 and Smad4 are present in the developing mouse heart.…”

TBX2-positive cells represent a multi-potent mesenchymal progenitor pool in the developing lung

“…Mesenchymal and epithelial development is also supported by the embryonic mesothelium which forms shortly after specification of the lung bud. The mesothelium provides crucial signals to maintain mesenchymal proliferation and may act as a minor cell source for the pulmonary mesenchyme [13–15] (for recent reviews on lung development and structure see [16, 17]).…”

Embryonic mesothelium in motion: a systematic study

“…E. El Agha also acknowledges the support of the Cardio-Pulmonary Institute (CPI, EXC 2026, Project ID: 390649896), University Hospital Giessen and Marburg (UKGM), and the German Center for Lung Research (DZL). (8) show that pleural mobilization is a rare, occasional event during early lung development and it happens during a tight time window while epicardial mobilization is robust and it happens during a broader time window. PDGFR␣, FGFR1/FGFR2 and HH signaling pathways are required for epicardial mobilization.…”

“…In this issue of American Journal of Physiology-Lung Cellular and Molecular Physiology, Lüdtke et al (8) address a timely and controversial issue in cardiopulmonary development; i.e., mobilization and contribution of the mesothelial lining to mesenchymal cells of the embryonic heart and lung. They employ the Cre-loxP system in genetically modified mice to follow the fate of mesothelial cells during embryogenesis.…”