Lung Organogenesis

Warburton, David; El-Hashash, Ahmed; Carraro, Gianni; Tiozzo, Caterina; Sala, F.G.; Rogers, Orquidea; Langhe, Stijn De; Kemp, Paul J.; Riccardi, Daniela; Torday, John S.; Bellusci, Savério; Shi, Wei; Lubkin, Sharon R.; Jesudason, Edwin C.

doi:10.1016/s0070-2153(10)90003-3

Cited by 398 publications

(404 citation statements)

References 458 publications

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“…1) may provide new insights to mechanisms and therapies of lung defects in premature birth. This transition is interrupted by premature birth, especially in very/extremely low birth-weight infants born at the canalicular stage of lung development (gestation week 24 in humans and E17 in mice) (44,45). Interruption to this transition may lead to not only cellular immaturity as a result of insufficient alveolar differentiation, but also structural immaturity as a result of incomplete branching morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

Lung epithelial branching program antagonizes alveolar differentiation

Chang¹,

Alanis²,

Miller

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

171

231

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Mammalian organs, including the lung and kidney, often adopt a branched structure to achieve high efficiency and capacity of their physiological functions. Formation of a functional lung requires two developmental processes: branching morphogenesis, which builds a tree-like tubular network, and alveolar differentiation, which generates specialized epithelial cells for gas exchange. Much progress has been made to understand each of the two processes individually; however, it is not clear whether the two processes are coordinated and how they are deployed at the correct time and location. Here we show that an epithelial branching morphogenesis program antagonizes alveolar differentiation in the mouse lung. We find a negative correlation between branching morphogenesis and alveolar differentiation temporally, spatially, and evolutionarily. Gain-of-function experiments show that hyperactive small GTPase Kras expands the branching program and also suppresses molecular and cellular differentiation of alveolar cells. Loss-of-function experiments show that SRYbox containing gene 9 (Sox9) functions downstream of Fibroblast growth factor (Fgf)/Kras to promote branching and also suppresses premature initiation of alveolar differentiation. We thus propose that lung epithelial progenitors continuously balance between branching morphogenesis and alveolar differentiation, and such a balance is mediated by dual-function regulators, including Kras and Sox9. The resulting temporal delay of differentiation by the branching program may provide new insights to lung immaturity in preterm neonates and the increase in organ complexity during evolution.

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Section: Discussionmentioning

confidence: 99%

Lung epithelial branching program antagonizes alveolar differentiation

Chang¹,

Alanis²,

Miller

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

171

231

View full text Add to dashboard Cite

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“…From 24 weeks of gestation until term, the saccular stage, airspaces widen and alveoli are formed. During the alveolar stage, which persists into the postnatal period up to 3 years of age, maturation of the airways occurs [1]. Concomitant with the expansion of the airways is the adaptation of the microvasculature to optimise the exchange of oxygen and carbon dioxide between the blood and the airways.…”

Section: Normal Pulmonary Vascular Developmentmentioning

confidence: 99%

Pulmonary vascular development in congenital diaphragmatic hernia

et al. 2018

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Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly characterised by a diaphragmatic defect, persistent pulmonary hypertension (PH) and lung hypoplasia. The relative contribution of these three elements can vary considerably in individual patients. Most affected children suffer primarily from the associated PH, for which the therapeutic modalities are limited and frequently not evidence based. The vascular defects associated with PH, which is characterised by increased muscularisation of arterioles and capillaries, start to develop early in gestation. Pulmonary vascular development is integrated with the development of the airway epithelium. Although our knowledge is still incomplete, the processes involved in the growth and expansion of the vasculature are beginning to be unravelled. It is clear that early disturbances of this process lead to major pulmonary growth abnormalities, resulting in serious clinical challenges and in many cases death in the newborn. Here we provide an overview of the current molecular pathways involved in pulmonary vascular development. Moreover, we describe the abnormalities associated with CDH and the potential therapeutic approaches for this severe abnormality. Normal pulmonary vascular developmentHuman lung development can be divided into different stages based on histology, starting with the embryonic stage at 4 weeks of gestation, followed by the pseudoglandular stage in which branching of the lung buds continues. During the canalicular stage, starting at ∼16 weeks of gestation, the terminal bronchioli are formed. From 24 weeks of gestation until term, the saccular stage, airspaces widen and alveoli are formed. During the alveolar stage, which persists into the postnatal period up to 3 years of age, maturation of the airways occurs [1]. Concomitant with the expansion of the airways is the adaptation of the microvasculature to optimise the exchange of oxygen and carbon dioxide between the blood and the airways. We and others have shown that very early in lung development pulmonary vessels are present and connected to the systemic circulation. The vasculature develops in close relation with the airways and is a rate-limiting factor in branching morphogenesis [2][3][4]. This implies that the pulmonary vasculature plays an important role in lung development. The formation of new blood vessels primarily occurs through

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“…progenitor | naphthalene | cell of origin | tumor suppressor gene O ne of the major unresolved issues in the lung field is how undifferentiated epithelial cells generate specialized cell types in the postnatal lung (1)(2)(3). Another pressing challenge is to uncover the cell types and molecular mechanisms that underlie the enormous regenerative capacity of the lung during injury (4).…”

mentioning

confidence: 99%

Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

Song

Yao

Lin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

264

247

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Pulmonary neuroendocrine cells (PNECs) are proposed to be the first specialized cell type to appear in the lung, but their ontogeny remains obscure. Although studies of PNECs have suggested their involvement in a number of lung functions, neither their in vivo significance nor the molecular mechanisms underlying them have been elucidated. Importantly, PNECs have long been speculated to constitute the cells of origin of human small-cell lung cancer (SCLC) and recent mouse models support this hypothesis. However, a genetic system that permits tracing the early events of PNEC transformation has not been available. To address these key issues, we developed a genetic tool in mice by introducing a fusion protein of Cre recombinase and estrogen receptor (CreER) into the calcitonin gene-related peptide (CGRP) locus that encodes a major peptide in PNECs. The CGRP CreER mouse line has enabled us to manipulate gene activity in PNECs. Lineage tracing using this tool revealed the plasticity of PNECs. PNECs can be colabeled with alveolar cells during lung development, and following lung injury, PNECs can contribute to Clara cells and ciliated cells. Contrary to the current model, we observed that elimination of PNECs has no apparent consequence on Clara cell recovery. We also created mouse models of SCLC in which CGRP CreER was used to ablate multiple tumor suppressors in PNECs that were simultaneously labeled for following their fate. Our findings suggest that SCLC can originate from differentiated PNECs. Together, these studies provide unique insight into PNEC lineage and function and establish the foundation of investigating how PNECs contribute to lung homeostasis, injury/repair, and tumorigenesis.progenitor | naphthalene | cell of origin | tumor suppressor gene

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Lung Organogenesis

Cited by 398 publications

References 458 publications

Lung epithelial branching program antagonizes alveolar differentiation

Lung epithelial branching program antagonizes alveolar differentiation

Pulmonary vascular development in congenital diaphragmatic hernia

Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

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