Current concepts on lung development

Abstract

Recent molecular genetic and embryonic organ culture studies have implicated several novel regulatory processes in the coordination of lung development. Failure of pulmonary initiation results from interruptions of the sonic hedgehog/patched/Gli and Nkx 2.1 signaling pathways. Sonic hedgehog null mutants and Gli2/Gli3 compound null mutants each exhibited failed tracheoesophageal septation. However, proximodistal epithelial differentiation is disrupted by compound Gli mutation, but is preserved in sonic hedgehog mutants. Null mutation of Nkx 2.1 also abrogates tracheoesophageal septation in association with thyroid and pituitary agenesis. Primary tracheal branching is regulated by fibroblast growth factor-10 signaling; in the murine fibroblast growth factor-10 null phenotype, the lung fails to separate from the foregut and morphogenesis is arrested distal to the trachea. Several genes in the fibroblast growth factor-10 pathway have homologous roles in fruit fly tracheal organogenesis, and corresponding Drosophila mutations yield strikingly similar phenotypes. Recent data also indicate that airway branching can be regulated by vascular endothelial growth factor, suggesting mutual regulation of airway and vascular development. The bases of pulmonary left-right asymmetry and laterality have also been investigated. The transforming growth factor-beta superfamily members Lefty-1, Lefty-2, and nodal comprise a regulatory pathway whose function is required for the development of left-right asymmetry, whereas left-right laterality is dependent on regulation of dynein expression by the transcription factor hepatocyte nuclear factor-4. Terminal lung differentiation is modulated by yet another set of signals. Hoxa5 null mutants exhibit tracheal occlusion and surfactant protein deficiency, whereas fibroblast growth factor receptor-2 and -4 compound null phenotypes include abrogated neonatal alveolization, perturbed alveolar myofibroblast differentiation, and persistent neonatal elastin deposition. These new contributions represent substantial advances toward a comprehensive molecular model of pulmonary development.

Human Umbilical Cord Mesenchymal Stem Cells Reduce Fibrosis of Bleomycin-Induced Lung Injury

“…28,29 This medium contains hydrocortisone, human epidermal growth factor, and retinoic acid, which are factors that are required for lung development. 30 uMSCs did not survive beyond 14 days in SAGM. The cellular extensions of the uMSCs retracted and the cells detached from the culture wells.…”

Expression Profiles of the Mouse Lung Identify a Molecular Signature of Time-to-Birth

“…1 c Nk g N where c nk is called the loading of g n in p k and jc nk j signifies the contribution of g n in p k . The first principal component p 1 is the direction of maximal sample variance in A. p 2 is the direction of maximal sample variance in the gene feature space orthogonal to space spanned by p 1 . By mathematical induction, p k is the direction of maximal sample variance in the gene feature space orthogonal to the space spanned by fp 1 , .…”

“…This is an unsupervised analysis, as the sample or phenotype labels are not input parameters. Samples are viewed as points in an N-dimensional space defined by n 5 6,667 gene expression features that can then be summarized into a smaller number of dimensions (1)(2)(3) that are correlated with the directions of maximal sample-tosample variation in the entire dataset. These directions of maximal sample variation are called gene principal components (denoted gene PCs).…”

“…Research effort over the past few decades has elucidated the essential role of many molecules in the establishment of the mammalian lung (1)(2)(3)(4). The initiation of lung formation as a bud off the ventral foregut endoderm (''embryonic'' stage of organ development) occurs during the fifth week of gestation in the human, or Embryonic Day (E)9.5 in the mouse, and is promoted by Gli2/3, Shh, and FGF10.…”

Lung hypoplasia in rats with esophageal atresia and tracheo–esophageal fistula

“…Relatively straightforward pharmacologic models were preferred to knockout mice for retinoic acid receptors (6), thyroid transcription factor 1 (TTF-1) (7), shh/Gli2-Gli3 cascade genes (8), fibroblast growth factor-10 (Fgf10) (9), and Foxf1 (10), Nog (11), and Hox genes (12) in which various components of the VACTERL phenotype are also reproduced. Administration of adriamycin (doxorubicin) to pregnant rats (13) and mice (14) accurately reproduced a phenotype of EA-TEF with VACTERL syndrome (13,15,16).…”