The pulmonary mesenchyme directs lung development
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
References (76)
- et al.
Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function
Cell Stem Cell
(2014) - et al.
Defects in tracheoesophageal and lung morphogenesis in Nkx2.1(-/-) mouse embryos
Dev Biol
(1999) - et al.
Wnt2/2b and beta-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut
Dev Cell
(2009) - et al.
Morphogenesis of the trachea and esophagus: current players and new roles for noggin and Bmps
Differentiation
(2006) - et al.
Bmp4 is required for tracheal formation: a novel mouse model for tracheal agenesis
Dev Biol
(2008) - et al.
Mesenchyme specifies epithelial differentiation in reciprocal recombinants of embryonic lung and trachea
Dev Dyn
(1998) - et al.
Establishment of smooth muscle and cartilage juxtaposition in the developing mouse upper airways
Proc Natl Acad Sci U S A
(2013) - et al.
Basal cells are a multipotent progenitor capable of renewing the bronchial epithelium
Am J Pathol
(2004) - et al.
Fibroblast growth factor 10 plays a causative role in the tracheal cartilage defects in a mouse model of Apert syndrome
Pediatr Res
(2009) - et al.
PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis
Cell
(1996)
Reversal of nicotine-induced alveolar lipofibroblast-to-myofibroblast transdifferentiation by stimulants of parathyroid hormone-related protein signaling
Lung
Peroxisome proliferators alter lipid acquisition and elastin gene expression in neonatal rat lung fibroblasts
Am J Physiol
Thy-1 signals through PPARgamma to promote lipofibroblast differentiation in the developing lung
Am J Respir Cell Mol Biol
Molecular determinants of lung development
Ann Am Thorac Soc
Patterning and plasticity in development of the respiratory lineage
Dev Dyn
Intersections between pulmonary development and disease
Am J Respir Crit Care Med
Development of the pulmonary vasculature: current understanding and concepts for the future
Pulm Circ
Tissue crosstalk in lung development
J Cell Biochem
Lung development: orchestrating the generation and regeneration of a complex organ
Development
The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain
Development
Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung
Development
Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm
Development
beta-Catenin promotes respiratory progenitor identity in mouse foregut
Proc Natl Acad Sci U S A
Hyperactive Wnt signaling changes the developmental potential of embryonic lung endoderm
J Biol
Signaling through BMP receptors promotes respiratory identity in the foregut via repression of Sox2
Development
Aberrant Bmp signaling and notochord delamination in the pathogenesis of esophageal atresia
Dev Dyn
Inhibition of Tgf beta signaling by endogenous retinoic acid is essential for primary lung bud induction
Development
A retinoic acid-dependent network in the foregut controls formation of the mouse lung primordium
J Clin Invest
Suppression of Bmp4 signaling by the zinc-finger repressors Osr1 and Osr2 is required for Wnt/beta-catenin-mediated lung specification in Xenopus
Development
Multiple roles and interactions of Tbx4 and Tbx5 in development of the respiratory system
PLoS Genet
Long noncoding RNAs are spatially correlated with transcription factors and regulate lung development
Genes Dev
Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung
Development
Conditional gene inactivation reveals roles for Fgf10 and Fgfr2 in establishing a normal pattern of epithelial branching in the mouse lung
Dev Dyn
Localized Fgf10 expression is not required for lung branching morphogenesis but prevents differentiation of epithelial progenitors
Development
Heparan sulfates expressed in the distal lung are required for Fgf10 binding to the epithelium and for airway branching
Am J Physiol Lung Cell Mol Physiol
Wnt ligands signal in a cooperative manner to promote foregut organogenesis
Proc Natl Acad Sci U S A
High throughput genomic screen identifies multiple factors that promote cooperative Wnt signaling
PLoS One
Mesothelial- and epithelial-derived FGF9 have distinct functions in the regulation of lung development
Development
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