Abstract
The periodic cartilage and smooth muscle structures in mammalian trachea are derived from tracheal mesoderm, and tracheal malformations result in serious respiratory defects in neonates. Here we show that canonical Wnt signaling in mesoderm is critical to confer trachea mesenchymal identity in human and mouse. At the initiation of tracheal development, endoderm begins to express Nkx2.1, and then mesoderm expresses the Tbx4 gene. Loss of β-catenin in fetal mouse mesoderm causes loss of Tbx4+ tracheal mesoderm and tracheal cartilage agenesis. The mesenchymal Tbx4 expression relies on endodermal Wnt activation and Wnt ligand secretion but is independent of known Nkx2.1-mediated respiratory development, suggesting that bidirectional Wnt signaling between endoderm and mesoderm promotes trachea development. Activating Wnt, Bmp signaling in mouse embryonic stem cell (ESC)-derived lateral plate mesoderm (LPM) generates tracheal mesoderm containing chondrocytes and smooth muscle cells. For human ESC-derived LPM, SHH activation is required along with WNT to generate proper tracheal mesoderm. Together, these findings may contribute to developing applications for human tracheal tissue repair.
Highlights
The periodic cartilage and smooth muscle structures in mammalian trachea are derived from tracheal mesoderm, and tracheal malformations result in serious respiratory defects in neonates
We address the following key issues: (1) tracheal endoderm secretes Wnt ligands; (2) tracheal mesoderm responds to endodermal Wnt ligands to specify a
Nkx2.1null embryos retained Tbx[4] expression in the ventrolateral mesoderm of a single Tr–E tube, the segregation was defective (Fig. 1b), indicating that mesodermal induction of the trachea is independent of endodermal Nkx2.1
Summary
The periodic cartilage and smooth muscle structures in mammalian trachea are derived from tracheal mesoderm, and tracheal malformations result in serious respiratory defects in neonates. Activating Wnt, Bmp signaling in mouse embryonic stem cell (ESC)-derived lateral plate mesoderm (LPM) generates tracheal mesoderm containing chondrocytes and smooth muscle cells. Previous studies have demonstrated that development of tracheal/ lung endoderm is initiated by graduated expression of mesodermal Wnt2/2b and Bmp[4] along the dorsal-ventral axis[4,5,6,7]. The Sox2+ endoderm at the dorsal side develops into the esophagus by E10.5 (Fig. 1a)[9] These studies have demonstrated that mesodermal cells secrete growth factors (e.g., Wnt and Bmp) to induce respiratory endoderm identity[4,5,6]. After induction of endodermal Nkx2.1 expression at E9.5, tracheal/lung mesoderm is defined by Tbx4/5 at E10.5, which are markers for tracheal/lung mesoderm and required for proper mesenchymal development (Fig. 1a)[10].
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