Walking along the Fibroblast Growth Factor 10 Route: A Key Pathway to Understand the Control and Regulation of Epithelial and Mesenchymal Cell-Lineage Formation during Lung Development and Repair after Injury - PubMed (original) (raw)
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Walking along the Fibroblast Growth Factor 10 Route: A Key Pathway to Understand the Control and Regulation of Epithelial and Mesenchymal Cell-Lineage Formation during Lung Development and Repair after Injury
Elie El Agha et al. Scientifica (Cairo). 2014.
Abstract
Basic research on embryonic lung development offers unique opportunities to make important discoveries that will impact human health. Developmental biologists interested in the molecular control of branching morphogenesis have intensively studied the developing lung, with its complex and seemingly stereotyped ramified structure. However, it is also an organ that is linked to a vast array of clinical problems in humans such as bronchopulmonary dysplasia in premature babies and emphysema, chronic obstructive pulmonary disease, fibrosis, and cancer in adults. Epithelial stem/progenitor cells reside in niches where they interact with specific extracellular matrices as well as with mesenchymal cells; the latter are still poorly characterized. Interactions of epithelial stem/progenitor cells with their microenvironments are usually instructive, controlling quiescence versus activation, proliferation, differentiation, and migration. During the past 18 years, Fgf10 has emerged not only as a marker for the distal lung mesenchyme during early lung development, but also as a key player in branching morphogenesis and a critical component of the niche for epithelial stem cells. In this paper, we will present the current knowledge regarding the lineage tree in the lung, with special emphasis on cell-lineage decisions in the lung mesenchyme and the role of Fgf10 in this context.
Figures
Figure 1
Early mouse lung development. (a) Interaction between the cardiac mesoderm, secreting Fgf1 and Fgf2, and the foregut endoderm specifies the _Nkx2.1_-positive territory (in green) from which the thyroid and the lung will form. (b, c) Emergence of the trachea on the ventral side of the foregut endoderm and of the two primitive bronchi. Lower panels in (b) are cross sections. (d) Through successive budding events, the right primitive bronchus gives rise to four lobes (rostral, medial, caudal, and accessory) while the left primitive bronchus gives rise to a unique left lobe. (e) Radioactive in situ hybridization on a section of E10.5 lung showing Fgf10 mRNA expression (in red) in the distal mesenchyme. (f) Schematic of the experiment carried out by Alescio and Cassini [9]. The mesenchyme from the trachea is removed and replaced by distal lung mesenchyme. (g) The grafting of the distal mesenchyme in direct contact with the trachea induces the formation of an ectopic bud (arrow). Br: bronchus; tr: trachea.
Figure 2
Fgf7 and Fgf10 signaling via Fgfr2b controls proliferation versus chemotaxis, respectively. (a)–(c) Mesenchyme-free epithelium from E11.5 lungs was grown for 48 hours in Matrigel in absence (a) or presence of Fgf7 (b) or Fgf10 (c). Note the formation of a cyst-like structure with Fgf7 versus distinct primary and secondary bud formation with Fgf10. (d), (e) Proposed model for Fgf7 versus Fgf10 action via Fgfr2b according to [20]. (d) Fgf7 induces transient signaling and Fgfr2b degradation leading to proliferation. (e) Fgf10 leads to sustained signaling which is associated with Fgfr2b recycling, phosphorylation of Y734 of Fgfr2b, and recruitment of p85/p110/SH3bp4 complex leading to chemotaxis.
Figure 3
Different phases of murine lung development. Note that most epithelial and mesenchymal cell types are formed during the pseudoglandular stage of lung development. AEC: alveolar epithelial cells; Can: canalicular; LIF: lipofibroblasts; NE: neuroendocrine; Pseudogland: pseudoglandular; Sacc: saccular.
Figure 4
Epithelial stem-cell tree during lung development. The initial multipotent progenitor cells (Id2+, Sox9+), present throughout the lung epithelium up to E13.5, give rise to bronchiolar (proximal) and alveolar (distal) progenitors. As development proceeds, subsequent lineages are formed from these proximal (Sox2+) or distal (Id2+, Sox9+) epithelial progenitors. Most of the resulting cell types (such as p63+ basal cells, neuroendocrine cells, AECI, AECII, ciliated cells, and goblet cells) are unipotent. Clara cell progenitors (variant Clara cells) are at least bipotent as they can give rise to the secretory and ciliated lineages. These cells can be distinguished from mature Clara cells by the lack of cytochrome P450 expression. We also propose that the _α_6_β_4-double positive cells and the BASCs (Scgb1a1+, Sftpc+) are formed during lung development. The origin of these cells is still unclear (orange dashed lines). Their respective contribution to the proximal or distal epithelial lineages during normal development is likely minimal (blue dashed lines). BASC: bronchoalveolar stem cell.
Figure 5
_Fgf10_-positive cells represent a population of mesenchymal progenitors. (a) Fgf10 lacZ cells at E12.5 are located in the distal lung mesenchyme. (b) Model for the formation of the parabronchial smooth muscle cells. _Fgf10_-positive cells are amplified and then they differentiate as they relocate proximally (From [33]). (c) Lineage tracing of _Fgf10_-positive cells at E11.5 and E15.5 show that these cells are progenitors for multiple lineages and they become progressively restricted in their differentiation potential (From [34]).
Figure 6
Formation of the different mesenchymal populations during lung development. (a) Schematic of the cells in the distal part of the lung at E13.5 showing the different lung domains including the mesothelium (meso), the submesothelial mesenchyme (SMM), the subepithelial mesenchyme (SEM), and the epithelium (epi). (b) Position of the different mesenchymal cell progenitors at this stage.
Figure 7
Interactions between the different lung domains. (a) Mesothelial-SMM interactions. (b) Epithelial-SEM interactions (mostly endothelial) and mesothelial-SEM interactions. (c) Epithelial-mesenchymal (SEM+SMM) interactions.
Figure 8
Epithelial and mesenchymal cell diversity in the adult mouse lung. The adult mouse lung can be subdivided into proximal (trachea, mainstem bronchi, and conducting airways) and distal (alveoli) domains. Each domain contains a specific set of epithelial and mesenchymal cells. NEB: neuroepithelial body.
Figure 9
Epithelial progenitor cells in the adult lung after injury. (a) AECII serve as progenitors for AECI and they self-renew after hyperoxic injury. (b) In case of more pronounced injury, variant Clara cells serve as progenitors for the secretory and ciliated lineages as well as AECII. More recently, other progenitors have emerged such as (c) the α6_β_4-double positive cells that can give rise to both alveolar and bronchiolar progenitors, (d) the basal-cell-“like” pods giving rise to variant Clara cells and AECII, and (e) the BASC also giving rise to variant Clara cells and AECII.
Figure 10
Resident mesenchymal progenitor cells in the adult lung. Cd45− side population cells can be further characterized as Cd31−, Cd34+, and Sca-1+ mesenchymal cells. These cells were described as supporting the growth of epithelial stem/progenitor cells (epiSPC) that correspond to the α6_β_4-double positive cells. More recently, this subpopulation has also been subdivided into Cd166+, Cd90− and Cd166−, and Cd90+ cells. The latter cells express Fgf10, support the growth of EpiSPC, and contain lipofibroblast progenitors.
References
- Cardoso WV, Lü J. Regulation of early lung morphogenesis: questions, facts and controversies. Development. 2006;133(9):1611–1624. -PubMed
- Rock JR, Hogan BLM. Epithelial progenitor cells in lung development, maintenance, repair, and disease. Annual Review of Cell and Developmental Biology. 2011;27:493–512. -PubMed
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