Systems biology approaches to identify developmental bases for lung diseases (original) (raw)
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Cell and tissue research, 2017
To fulfill the task of gas exchange, the lung possesses a huge inner surface and a tree-like system of conducting airways ventilating the gas exchange area. During lung development, the conducting airways are formed first, followed by the formation and enlargement of the gas exchange area. The latter (alveolarization) continues until young adulthood. During organogenesis, the left and right lungs have their own anlage, an outpouching of the foregut. Each lung bud starts a repetitive process of outgrowth and branching (branching morphogenesis) that forms all of the future airways mainly during the pseudoglandular stage. During the canalicular stage, the differentiation of the epithelia becomes visible and the bronchioalveolar duct junction is formed. The location of this junction stays constant throughout life. Towards the end of the canalicular stage, the first gas exchange may take place and survival of prematurely born babies becomes possible. Ninety percent of the gas exchange su...
Molecular Mechanisms of Early Lung Specification and Branching Morphogenesis
Pediatric Research, 2005
The "hard wiring" encoded within the genome that determines the emergence of the laryngotracheal groove and subsequently early lung branching morphogenesis is mediated by finely regulated, interactive growth factor signaling mechanisms that determine the automaticity of branching, interbranch length, stereotypy of branching, left-right asymmetry, and finally gas diffusion surface area. The extracellular matrix is an important regulator as well as a target for growth factor signaling in lung branching morphogenesis and alveolarization. Coordination not only of epithelial but also endothelial branching morphogenesis determines bronchial branching and the eventual alveolar-capillary interface. Improved prospects for lung protection, repair, regeneration, and engineering will depend on more detailed understanding of these processes. Herein, we concisely review the functionally integrated morphogenetic signaling network comprising the critical bone morphogenetic protein, fibroblast growth factor, Sonic hedgehog, transforming growth factor-, vascular endothelial growth factor, and Wnt signaling pathways that specify and drive early embryonic lung morphogenesis. (Pediatr Res 57: 1-12, 2005) Abbreviations BMP, bone morphogenetic protein DKK, Dickkopf EGF (R), epidermal growth factor (receptor) ERK, extracellular regulated kinase FGF (R), fibroblast growth factor (receptor) FN, fibronectin LRP, lipoprotein receptor-related proteins MAP, membrane-associated protein PDGF, platelet-derived growth factor RAR, retinoic acid receptor sFRP, secreted Frizzled-related protein SHH, Sonic hedgehog Sp-C, surfactant protein C TGF-␣ (), transforming growth factor alpha (beta) VEGF (R), vascular endothelial growth factor (receptor)
Developmental biology: Order in the lung
Nature, 2008
Given the lung's thousands of branching airways, its development might be expected to be a highly complex process. Yet a surprisingly simple picture now emerges of when, where and in what order these branches form. Elaborate branching is everywhere in nature. From riverbeds to oilfields, from trees to blood vessels, branching connects the large to the small. The lung is also a prime example of a reproducible branching system, allowing gas to be transported from the air to tissues deep within an animal. Without it-or without the simpler branched ducts found in less complex organisms-oxygen transport by diffusion probably would have limited the evolution of terrestrial animals to less than one millimetre in size. But how does such a sophisticated network develop? Metzger et al. 1 (page 745 of this issue) provide a remarkable, yet simple picture that explains the orderly development of the more than a million branches in the mammalian lung. In mammals, air enters through the nasal and oral cavities and passes through the larynx and trachea before reaching the lung. The trachea branches into two primary bronchi, which, within the lung, further branch into secondary and tertiary bronchi and finally into bronchioles. To investigate the sequence of events leading to this complex, yet highly reproducible network of branches, Metzger et al. studied the early bronchial tree in three dimensions by examining chemically fixed lung tissue from mouse embryos using microscopy.
The molecular basis of lung morphogenesis
Mechanisms of Development, 2000
To form a diffusible interface large enough to conduct respiratory gas exchange with the circulation, the lung endoderm undergoes extensive branching morphogenesis and alveolization, coupled with angiogenesis and vasculogenesis. It is becoming clear that many of the key factors determining the process of branching morphogenesis, particularly of the respiratory organs, are highly conserved through evolution. Synthesis of information from null mutations in Drosophila and mouse indicates that members of the sonic hedgehog/patched/ smoothened/Gli/FGF/FGFR/sprouty pathway are functionally conserved and extremely important in determining respiratory organogenesis through mesenchymal±epithelial inductive signaling, which induces epithelial proliferation, chemotaxis and organ-speci®c gene expression. Transcriptional factors including Nkx2.1, HNF family forkhead homologues, GATA family zinc ®nger factors, pou and hox, helix-loop-helix (HLH) factors, Id factors, glucocorticoid and retinoic acid receptors mediate and integrate the developmental genetic instruction of lung morphogenesis and cell lineage determination. Signaling by the IGF, EGF and TGF-b/BMP pathways, extracellular matrix components and integrin signaling pathways also directs lung morphogenesis as well as proximo-distal lung epithelial cell lineage differentiation. Soluble factors secreted by lung mesenchyme comprise a`compleat' inducer of lung morphogenesis. In general, peptide growth factors signaling through cognate receptors with tyrosine kinase intracellular signaling domains such as FGFR, EGFR, IGFR, PDGFR and c-met stimulate lung morphogenesis. On the other hand, cognate receptors with serine/threonine kinase intracellular signaling domains, such as the TGF-b receptor family are inhibitory, although BMP4 and BMPR also play key inductive roles. Pulmonary neuroendocrine cells differentiate earliest in gestation from among multipotential lung epithelial cells. MASH1 null mutant mice do not develop PNE cells. Proximal and distal airway epithelial phenotypes differentiate under distinct transcriptional control mechanisms. It is becoming clear that angiogenesis and vasculogenesis of the pulmonary circulation and capillary network are closely linked with and may be necessary for lung epithelial morphogenesis. Like epithelial morphogenesis, pulmonary vascularization is subject to a ®ne balance between positive and negative factors. Angiogenic and vasculogenic factors include VEGF, which signals through cognate receptors¯k and¯t, while novel anti-angiogenic factors include EMAP II. q
Thoracic Surgery, 2020
The respiratory system origins from the anterior foregut endoderm. 2. The conducting airways are formed first, followed by the development of alveoli. 3. By branching morphogenesis, lung buds generate an arborized airway tree. 4. During the canalicular stage (week 16-26) the first blood-air barrier is formed and survival becomes possible. 5. Alveolarization continues until adulthood.
Molecular determinants of lung development
Annals of the American Thoracic Society, 2013
Development of the pulmonary system is essential for terrestrial life. The molecular pathways that regulate this complex process are beginning to be defined, and such knowledge is critical to our understanding of congenital and acquired lung diseases. A recent workshop was convened by the National Heart, Lung, and Blood Institute to discuss the developmental principles that regulate the formation of the pulmonary system. Emerging evidence suggests that key developmental pathways not only regulate proper formation of the pulmonary system but are also reactivated upon postnatal injury and repair and in the pathogenesis of human lung diseases. Molecular understanding of early lung development has also led to new advances in areas such as generation of lung epithelium from pluripotent stem cells. The workshop was organized into four different topics, including early lung cell fate and morphogenesis, mechanisms of lung cell differentiation, tissue interactions in lung development, and en...
Developmental paradigms in terminal lung development
BioEssays, 2002
Late lung development comprises the formation of the terminal sac followed by the subdivision of the terminal sac by septa into alveoli and results in the formation of the gas-exchange surface of the lung. This developmentally regulated process involves a complex epitheliummesenchyme interaction via evolutionarily conserved molecular signaling pathways. In addition, there is a continuous process of vascular growth and development. Currently there are large gaps in our understanding of the molecular mechanisms involved in the formation of the gas-exchange surface. In this review, we attempt to integrate and reconcile the morphologic features in late lung development with what is known about the molecular basis for these processes. We describe the formation of the terminal sac and the subsequent formation of the septa, which divide the terminal sac into alveoli, in terms of the classically described developmental stages of induction, morphogenesis and differentiation. We believe that evolutionarily conserved pathways regulate this process and that morphogen gradients are likely to be a central mechanism. In addition, we highlight the importance of the molecular mechanisms involved in the simultaneous development of the vascular bed and its importance in the late development of the lungs.
Early restriction of peripheral and proximal cell lineages during formation of the lung
Proceedings of the National Academy of Sciences, 2002
To establish the timing of lineage restriction among endodermal derivatives, we developed a method to label permanently subsets of lung precursor cells at defined times during development by using Cre recombinase to activate floxed alkaline phosphatase or green fluorescent protein genes under control of doxycyclinedependent surfactant protein C promoter. Extensive or complete labeling of peripheral lung, thyroid, and thymic epithelia, but not trachea, bronchi, or gastrointestinal tract occurred when mice were exposed to doxycycline from embryonic day (E) 4.5 to E6.5. Nonoverlapping cell lineages of conducting airways (trachea and bronchi), as distinct from those of peripheral airways (bronchioles, acini, and alveoli), were established well before formation of the definitive lung buds at E9-9.5. At E11.5, the labeled precursors of peripheral lung were restricted to relatively few cells along the bronchial tubes and clusters in bronchial tips and lateral buds. Thereafter, these cells underwent marked expansion to form the entire gas-exchange region in the lung. This study demonstrates early restriction of endodermal progenitor cells forming peripheral as compared with proximal airways, identifies distinct cell lineages in conducting airways, and distinguishes neuroepithelial and tracheal-bronchial gland cell lineages from those lining peripheral regions of the lung. This system for conditional gene addition or deletion is useful for the study of lung morphogenesis and gene function in vivo, and identifies progenitor cells that may serve as useful targets for cell or gene replacement for pulmonary disorders.