Chapter Three - Lung Organogenesis
Introduction
The concept that lung organogenesis is instructed by coordinated mesenchymal-to-epithelial crosstalk originates in the classical recombination experiments of Alescio and Cassini (1962), in which replacing tracheal mesenchyme with mesenchyme from the lung periphery induced ectopic branching of tracheal epithelium in murine embryonic lung organ culture. This idea was extended in an early review by Warburton and Olver (1997) to include the coordination of genetic, epigenetic, and environmental factors in lung development, injury, and repair. Thereafter, a molecular basis of lung morphogenesis was attempted by Warburton et al. (2000). Over the last decade, significant progress has been made in this field as reviewed by Cardoso and Lu, 2006, Maeda et al., 2007, and others. Nevertheless, the ultimate goal remains as stated by Warburton and Olver (1997), “to devise new rational and gene therapeutic approaches to ameliorate lung injury and augment lung repair … the ideal agent or agents would therefore mimic the instructive role of lung mesenchyme and would correctly induce the temporospatial pattern of lung-specific gene expression necessary to instruct lung regeneration.” To this overall strategy, we can now add (i) the modulation of lung mechanobiology to favor appropriate lung regeneration and (ii) the stimulation of endogenous stem/progenitor cells or supply of exogenous ones for lung regeneration. Therefore, the current review draws together three important strands of information on lung organogenesis as of April 2010: (i) molecular embryology of the lung, (ii) mechanobiology of the developing lung, and (iii) pulmonary stem/progenitor cell biology. Applying advances in these complementary areas of research to lung regeneration and correction of lung diseases remains the therapeutic goal of this field. With the recent human transplanation of a stem/progenitor cell-derived tissue-engineered major airway (Macchiarini et al., 2008), we can clearly see the potential of this field, while recognizing the many problems yet to be solved.
Before concentrating on the molecular biology, mechanobiology, and stem cell biology of the lung, a first step in regenerative strategies is to consider the developmental anatomy of the lung. From this, we can at least see what type of structures we need to generate.
Section snippets
The bauplan: key steps in lung morphogenesis
A diagrammatic overview of lung morphogenesis is given in Fig. 3.1. Three lobes form on the right side and two lobes on the left side in human lung; in mice four lobes form on the right (cranial, medial, and caudal lobes, plus the accessory lobe) and one on the left. In contrast to humans, in the mouse, there are only 12 airway generations and alveolarization occurs entirely postnatally.
The histological stages of lung development
Histologically, lung development and maturation has been divided into four stages: pseudoglandular,
Molecular Embryology of the Lung
This section of the review serves as a comprehensive reference source. For those with no requirement for such detail, the reader is directed to the summary Fig. 3.4.
We will first use a step-wise “process-driven” description of lung growth followed by a catalogue of the biochemical factors involved: many such factors are involved at multiple stages and do not map neatly on to the “process-driven” account. The biochemical factors are considered as follows: growth and transcription factors in
Mechanobiology of the Developing Lung
Mechanical stimuli to lung development have been long appreciated. Recent advances in molecular and stem cell biology allow these fields to be integrated with modern mechanobiology (Ingber, 2003). For example, ECM polymers, in addition to binding and presenting growth factors, provide resistance to deformation, fluid flow, and diffusion, and transmit force over surprisingly long distances. Adhesion molecules regulate cell motility and tissue structure, and these in turn interact through forces
Stem/Progenitor Cell Biology of the Lung
A stem cell describes a self-renewing, primitive, undifferentiated, multipotent source of multiple cell lineages. Such cells are critical for development and growth; pools of adult stem cells are hypothetical sources for tissue regeneration and repair as well as cancers. In contrast to embryonic stem cells and tumor cells, adult stem cells reduce telomere length with age (Warburton et al., 2008).
In the lung, there is limited knowledge about existence of self-renewing cells, whether such cells
The transition to air breathing
Maturation of the surfactant system is one of two key steps to prepare fetal lung for air breathing. During the last 8 weeks of human gestation, fetal lung glycogen is converted into surfactant phospolipids, the most important of which is disaturated phosphatidylcholine (DSPC). This maturation is under the control of, and can be stimulated by, corticosteroids since it is blocked in mice with null mutations of glucocorticoid receptors or corticotrophin-releasing hormone. Human mutations have
Conclusions
Appreciating that distal lung mesenchyme could trigger epithelial airway development has stimulated the search for controls of lung development. Given the mortality and morbidity of lung disease at all stages of life, lung regeneration is a global therapeutic priority. To achieve such goals, clinicians and scientists need to decipher how the lung is formed. Whilst this understanding began with histological analyses, advances in biology have allowed the “molecular embryology” of the lung to be
Acknowledgments
We apologize to those colleagues whose important work in this field we have failed to cite.
Funding sources: National Heart, Lung and Blood Institute, National Institutes of Health, USA, National Science Foundation, USA, California Institute for Regenerative Medicine, Medical Research Council UK, Biotechnology and Biological Sciences Research Council, UK, Foreign and Commonwealth Office UK/USA stem cell collaboration grant, American Heart Association, American Lung Association, and Pasadena
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