The pulmonary mesenchyme directs lung development

Abstract

Each of the steps of respiratory system development relies on intricate interactions and coordinated development of the lung epithelium and mesenchyme. In the past, more attention has been paid to the epithelium than the mesenchyme. The mesenchyme is a source of specification and morphogenetic signals as well as a host of surprisingly complex cell lineages that are crucial for normal lung development and function. This review highlights recent research focusing on the mesenchyme that has revealed genetic and epigenetic mechanisms of its development in the context of other cell layers during respiratory lineage specification, branching morphogenesis, epithelial differentiation, lineage distinction, vascular development, and alveolar maturation.

Figure 1

The lung mesenchyme holds a central position in the formation of a functional lung. A diagram delineating the various topics covered in this review.

Figure 2

Lung mesenchyme is derived from and gives rise to multiple lineages. (A) Cardiopulmonary precursor cells (CPPs), characterized by overlapping Wnt2, Gli1, and Isl1 expression at E8.5, give rise to ASM, VSM, PVE, and PCs [45**]. (B) Fgf10 expressing cells labeled at E11.5 give rise to ASM, VSM, and LF cells [47**]. (C) ASM progenitor cells present in the mesenchyme distal to epithelial branching tips migrate proximally and take on a mature smooth muscle cell fate [48**]. (D) Tracheal ASM and cartilage have a mutually antagonistic relationship and form a complementary ring around the airway [40*] and [41*]. Abbreviations: AFG – anterior foregut, ASM – airway smooth muscle, Ht – heart, LF – lipofibroblast, PC – pericyte like (Pdgfrβ positive) cells, PVE – proximal vascular endothelium, VSM – vascular smooth muscle.