The pulmonary mesenchyme directs lung development

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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.

Introduction

Development of the respiratory system proceeds through a well-described series of steps beginning with division of the anterior common foregut tube into the respiratory endoderm ventrally and the esophagus dorsally. The respiratory tract then undergoes extensive branching to form the proximal conducting airways, followed by distal septation generating the gas exchange units, or alveoli, of the mature lung. These processes are coupled with coordinated differentiation of the airway and distal lung epithelium leading to a regionally specific pattern of cell types. Formation of a functional lung also requires simultaneous development of both the pulmonary vascular system (central systemic circulation) and bronchial vascular system (local lung circulation). The genetic and epigenetic regulation, as well as the specialized intra-cellular, inter-cellular, and extracellular mechanisms responsible for proper development of the respiratory system continue to be elucidated. Each of the steps in lung development is reliant upon inductive cues and reciprocal interactions between the pulmonary epithelium and the surrounding mesenchyme. Loss of or abnormalities in this crucial interaction can lead to severe anatomical and functional defects in the airway and alveoli. Many of the phenotypes associated with such abnormalities result in lethality or severe morbidity in humans and are being investigated in biochemical, cellular, tissue culture, organ explant, and animal models. Despite its importance in directing airway and alveoli development, many aspects of the activities and regulatory mechanisms of the lung mesenchyme are not well understood, a deficit recognized at a recent workshop hosted by the National Heart, Lung, and Blood Institute [1]. In this review, we will discuss recent (primarily within the past 2–3 years) advances in respiratory development, focusing on the role of the lung mesenchyme (Figure 1). For more comprehensive discussions of lung development, please see recently published reviews including [2, 3, 4, 5, 6, 7].

Section snippets

The mesenchyme provides crucial signals for respiratory lineage specification

Specification of the respiratory system takes place in the ventral anterior foregut endoderm, as indicated by the expression of Nkx2-1 (also named Ttf1) beginning at embryonic day (E) 8.25 in mice [8, 9, 10]. Collective work on respiratory lineage specification implicates the surrounding ventral mesenchyme as a crucial source of signals, including FGF, WNT, BMP, RA, and TGFβ, that direct endodermal expression of Nkx2-1 in a temporal and spatial context dependent fashion [10, 11, 12, 13, 14, 15,

The mesenchyme provides crucial signals that drive epithelial branching morphogenesis

Following specification and physical separation of the respiratory lineage precursors from the esophagus within the anterior foregut, future conducting airways and alveolar regions are laid down according to a proximal-distal blueprint, through largely stereotypical branching events directed by cues from the adjacent mesenchyme. A cardinal mesenchymal signal that drives branching is FGF10 [24, 25]. Its restricted expression in the distal mesenchyme at sites of future branch destination led to

The mesenchyme provides crucial signals that direct epithelial differentiation

Following branching morphogenesis, the conducting airway epithelium undergoes differentiation, influenced by signals from the neighboring mesenchyme.

This influence was first demonstrated in tissue recombination experiments showing that proximal tracheal mesenchyme could induce distal lung epithelium to take on a more proximal cell fate, whereas distal lung mesenchyme could induce proximal tracheal epithelium to take on a more distal cell fate [39]. The identities of these inductive cues from

The mesenchyme receives cellular contribution from the cardiac mesoderm before differentiating into multiple lineages

In addition to its role as a source of signals for epithelial specification, branching and differentiation, the mesenchyme itself undergoes a regionally distinct differentiation program and gives rise to airway and vascular smooth muscle, endothelium, pericytes, and airway cartilage cells, among others (Figure 2). A recent study by Peng et al. identified a cardiopulmonary precursor population (CPP) with overlapping expression of Wnt2, Gli1, and Isl1 [45••]. Lineage tracing based on these

The mesenchyme receives multiple signals to generate the lung vasculature

The processes of vascular development in the lung have been the source of considerable debate with both angiogenesis and vasculogenesis mechanisms being implicated. Prior work has suggested that proximal pulmonary vascular formation occurs through angiogenesis, with sprouting of vessels occurring in parallel to lung bud outgrowth while distal lung vessel formation occurs through vasculogenesis with endothelial cells deriving from mesenchymal vascular precursors [54, 55, 56]. Additional lineage

The mesenchyme contains key cell types that drive alveolar maturation

Following the pseudoglandular stage when the lung undergoes branching morphogenesis, the organ progresses through the canalicular, saccular, and alveologenesis stages during which the distal gas exchange units mature. Focusing on the distal lung, these steps result in a transition from columnar branching tip epithelium to thin walled airway septae required for efficient gas exchange. Accompanying the cell shape change is epithelial differentiation, generating type I and type II pneumocytes. The

Summary and future directions

Although much of the attention of lung development research has been focused on the lung epithelium, the mesenchyme is shaping up to be the new arena with an abundance of open questions. Strong lines of evidence, some of which are outlined above, unequivocally demonstrate that the lung mesenchyme is a crucial source of inductive cues for the epithelium as they progress through development together. Furthermore, recent findings reveal unanticipated complexity in the lung mesenchymal populations,

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank the members of the Sun laboratory for helpful discussions and suggestions, particularly Jamie Verheyden and Kelsey Branchfield. We also thank Elizabeth Hines for the smooth muscle and cartilage labeled trachea image included in Figure 2. DJM is supported by funding from the Department of Pediatrics, School of Medicine and Public Health, and by a Translational Research Pilot Award from the Institute for Clinical and Translational Research and the Stem Cell & Regenerative Medicine Center

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