Article

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

ABSTRACT

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
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    • "Wnt7B gene expression has been reported to be upregulated in IPF lungs (Konigshoff et al. 2008) and found to be localized in tissue sections within distinct sites that include cells and the ECM within FF of IPF lungs (Meuten et al. 2012). Wnt7B is known to be important during early lung development as a signaling glycopeptide that directs proliferation of adjacent epithelium and mesenchymal cells (Rajagopal et al. 2008) and controls the growth of vasculature (Shu et al. 2002). This has led to the suggestion that Wnt7B may be reactivated to significantly impact the progression of IPF in the adult lung (Morrisey 2003; Meuten et al. 2012). "
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    ABSTRACT: The wingless (Wnt) family of signaling ligands contributes significantly to lung development and is highly expressed in patients with usual interstitial pneumonia (UIP). We sought to define the cellular distribution of Wnt5A in the lung tissue of patients with idiopathic pulmonary fibrosis (IPF) and the signaling ligands that control its expression in human lung fibroblasts and IPF myofibroblasts. Tissue sections from 40 patients diagnosed with IPF or UIP were probed for the immunolocalization of Wnt5A. Further, isolated lung fibroblasts from normal or IPF human lungs, adenovirally transduced for the overexpression or silencing of Wnt7B or treated with TGF-β1 or its inhibitor, were analyzed for Wnt5A protein expression. Wnt5A was expressed in IPF lungs by airway and alveolar epithelium, smooth muscle cells, endothelium, and myofibroblasts of fibroblastic foci and throughout the interstitium. Forced overexpression of Wnt7B with or without TGF-β1 treatment significantly increased Wnt5A protein expression in normal human smooth muscle cells and fibroblasts but not in IPF myofibroblasts where Wnt5A was already highly expressed. The results demonstrate a wide distribution of Wnt5A expression in cells of the IPF lung and reveal that it is significantly increased by Wnt7B and TGF-β1, which, in combination, could represent key signaling pathways that modulate the pathogenesis of IPF.
    Full-text · Article · Nov 2015 · Journal of Histochemistry and Cytochemistry
    • "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.
    No preview · Article · Aug 2015 · Developmental Biology
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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.
    Full-text · Article · Sep 2014 · Respiratory Research
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