Wnt7b stimulates embryonic lung growth by coordinately increasing the replication of epithelium and mesenchyme

Department of Molecular and Cellular Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
Development (Impact Factor: 6.46). 06/2008; 135(9):1625-34. DOI: 10.1242/dev.015495
Source: PubMed


The effects of Wnt7b on lung development were examined using a conditional Wnt7b-null mouse. Wnt7b-null lungs are markedly hypoplastic, yet display largely normal patterning and cell differentiation. In contrast to findings in prior hypomorphic Wnt7b models, we find decreased replication of both developing epithelium and mesenchyme, without abnormalities of vascular smooth muscle development. We further demonstrate that Wnt7b signals to neighboring cells to activate both autocrine and paracrine canonical Wnt signaling cascades. In contrast to results from hypomorphic models, we show that Wnt7b modulates several important signaling pathways in the lung. Together, these cascades result in the coordinated proliferation of adjacent epithelial and mesenchymal cells to stimulate organ growth with few alterations in differentiation and patterning.

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Available from: Qiao Zhou, Oct 03, 2015
    • "Wnt7b, for instance, is detected in the lung epithelium as early as E9.5 and its loss results in lung hypoplasia (Shu et al., 2002). Wnt7b was shown to stimulate embryonic lung growth by coordinately increasing the replication of both epithelium and mesenchyme via different frizzled receptors (Rajagopal et al., 2008). Wnt5a regulates distal lung formation and its loss results in lung overgrowth, including expansion of the stromal interstitium (Li et al., 2002). "
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    ABSTRACT: Wnt signaling is essential to many events during organogenesis, including the development of the mammalian lung. The Wnt family member Wnt4 has been shown to be required for the development of kidney, gonads, thymus, mammary and pituitary glands. Here, we show that Wnt4 is critical for proper morphogenesis and growth of the respiratory system. Using in situ hybridization in mouse embryos, we identify a previously uncharacterized site of Wnt4 expression in the anterior trunk mesoderm. This expression domain initiates as early as E8.25 in the mesoderm abutting the tracheoesophageal endoderm, between the fusing dorsal aortae and the heart. Analysis of Wnt4(-/-) embryos reveals severe lung hypoplasia and tracheal abnormalities; however, aortic fusion and esophageal development are unaffected. We find decreased cell proliferation in Wnt4(-/-) lung buds, particularly in tip domains. In addition, we observe reduction of the important lung growth factors Fgf9, Fgf10, Sox9 and Wnt2 in the lung bud during early stages of organogenesis, as well as decreased tracheal expression of the progenitor factor Sox9. Together, these data reveal a previously unknown role for the secreted protein Wnt4 in respiratory system development. Copyright © 2015. Published by Elsevier Inc.
    Developmental Biology 08/2015; DOI:10.1016/j.ydbio.2015.08.017 · 3.55 Impact Factor
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    • "Functions of trophic macrophages that support organogenesis include apoptotic clearance of cellular debris associated with tissue remodelling [47], regulation of angiogenesis through the production of angiogenic factors [48,49] and by physically directing vascular development [50]. Macrophages act as potent effector cells producing a range of important trophic mediators such as insulin-like growth factor-1 (IGF-1) [51], wingless-type MMTV integration site family, member 7b (Wnt7b) [52], transforming growth factor-β (TGF-β) [53] and MMP9 [54], which are involved in epithelial proliferation and matrix reorganisation. These processes are all essential in lung development, particularly in alveolarisation. "
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    ABSTRACT: Background Lung immaturity due to preterm birth is a significant complication affecting neonatal health. Despite the detrimental effects of supplemental oxygen on alveolar formation, it remains an important treatment for infants with respiratory distress. Macrophages are traditionally associated with the propagation of inflammatory insults, however increased appreciation of their diversity has revealed essential functions in development and regeneration.Methods Macrophage regulatory cytokine Colony-Stimulating Factor-1 (CSF-1) was investigated in a model of neonatal hyperoxia exposure, with the aim of promoting macrophages associated with alveologenesis to protect/rescue lung development and function. Neonatal mice were exposed to normoxia (21% oxygen) or hyperoxia (Hyp; 65% oxygen); and administered CSF-1 (0.5 ¿g/g, daily¿×¿5) or vehicle (PBS) in two treatment regimes; 1) after hyperoxia from postnatal day (P)7-11, or 2) concurrently with five days of hyperoxia from P1-5. Lung structure, function and macrophages were assessed using alveolar morphometry, barometric whole-body plethysmography and flow cytometry.Results and discussionSeven days of hyperoxia resulted in an 18% decrease in body weight and perturbation of lung structure and function. In regime 1, growth restriction persisted in the Hyp¿+¿PBS and Hyp¿+¿CSF-1 groups, although perturbations in respiratory function were resolved by P35. CSF-1 increased CSF-1R+/F4/80+ macrophage number by 34% at P11 compared to Hyp¿+¿PBS, but was not associated with growth or lung structural rescue. In regime 2, five days of hyperoxia did not cause initial growth restriction in the Hyp¿+¿PBS and Hyp¿+¿CSF-1 groups, although body weight was decreased at P35 with CSF-1. CSF-1 was not associated with increased macrophages, or with functional perturbation in the adult. Overall, CSF-1 did not rescue the growth and lung defects associated with hyperoxia in this model; however, an increase in CSF-1R+ macrophages was not associated with an exacerbation of lung injury. The trophic functions of macrophages in lung development requires further elucidation in order to explore macrophage modulation as a strategy for promoting lung maturation.
    Respiratory Research 09/2014; 15(1):110. DOI:10.1186/s12931-014-0110-5 · 3.09 Impact Factor
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    • "Furthermore, one of its downstream signaling targets, β-catenin, has also been localized histochemically in FF (Chilosi et al. 2003). Wnt7B is an important signaling glycopeptide that coordinates proliferation of adjacent epithelium and mesenchymal cells (Rajagopal et al. 2008) and regulates vascular growth during early lung development (Shu et al. 2002). Accordingly, it has been proposed to have a potentially significant impact on the progression of IPF in the adult lung (Morrisey 2003; Meuten et al. 2012). "
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    ABSTRACT: The fibroblast growth factor (FGF) family of signaling ligands contributes significantly to lung development and maintenance in the adult. FGF9 is involved in control of epithelial branching and mesenchymal proliferation and expansion in developing lungs. However, its activity and expression in the normal adult lung and by epithelial and interstitial cells in fibroproliferative diseases like idiopathic pulmonary fibrosis (IPF) are unknown. Tissue samples from normal organ donor human lungs and those of a cohort of patients with mild to severe IPF were sectioned and stained for the immunolocalization of FGF9. In normal lungs, FGF9 was confined to smooth muscle surrounding airways, alveolar ducts and sacs, and blood vessels. In addition to these same sites, lungs of IPF patients expressed FGF9 in a population of myofibroblasts within fibroblastic foci, hypertrophic and hyperplastic epithelium of airways and alveoli, and smooth muscle cells surrounding vessels embedded in thickened interstitium. The results demonstrate that FGF9 protein increased in regions of active cellular hyperplasia, metaplasia, and fibrotic expansion of IPF lungs, and in isolated human lung fibroblasts treated with TGF-β1 and/or overexpressing Wnt7B. The cellular distribution and established biologic activity of FGF9 make it a potentially strong candidate for contributing to the progression of IPF.
    Journal of Histochemistry and Cytochemistry 06/2013; 61(9). DOI:10.1369/0022155413497366 · 1.96 Impact Factor
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