HB‐EGF decelerates cell proliferation synergistically with TGFα in perinatal distal lung development

Minami, Seigo; Iwamoto, Ryo; Mekada, Eisuke

doi:10.1002/dvdy.21398

Cited by 19 publications

(15 citation statements)

References 38 publications

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“…TGF-␣ is a known stimulant of angiogenesis and alveolar epithelial differentiation. Pulmonary overexpression of TGF-␣ disrupts lung morphology in mice (14), while paradoxically TGF-␣ knockout also results in a reduction of the terminal gas exchange area (26). The latter corresponds to our findings of reduced TGF-␣ being associated with the development of BPD.…”

Section: Discussionsupporting

confidence: 88%

Early Alterations of Growth Factor Patterns in Bronchoalveolar Lavage Fluid From Preterm Infants Developing Bronchopulmonary Dysplasia

Been

Debeer²,

Iwaarden

et al. 2010

Pediatr Res

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Chronic lung disease of prematurity (bronchopulmonary dysplasia; BPD) is characterized by an arrest in lung development. We hypothesized that early alterations in pulmonary expression of growth factors important for normal lung development would precede development of BPD. Bronchoalveolar lavage fluid (BALF) was obtained from ventilated preterm infants (n ϭ 62) on postnatal d 0, 1, 3, and 7 and analyzed for total phospholipids (PL), VEGF, PDGF-BB, TGF-␣ and -␤1, granulocyte macrophage colony stimulating factor (GM-CSF), and keratinocyte growth factor (KGF). Levels (Ln transformed) were compared between infants developing BPD and BPD-free survivors, adjusted for potential confounders.

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Section: Discussionsupporting

confidence: 88%

Early Alterations of Growth Factor Patterns in Bronchoalveolar Lavage Fluid From Preterm Infants Developing Bronchopulmonary Dysplasia

Been

Debeer²,

Iwaarden

et al. 2010

Pediatr Res

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“…These results are in part consistent with our finding that HB hb/hb valves had a slightly, but significantly, increased number of endocardial cells compared with WT valves at E17.5 (Fig. 4C) Interestingly, although Hbegf-null mice show severe defects in heart chamber formation and distal lung development Minami et al, 2008), we found that HB hb/hb mice did not exhibit these abnormalities (see Fig. S5H,I in the supplementary material).…”

Section: Truncating the Heparin-binding Domain Of Hb-egf Causes Cardisupporting

confidence: 91%

“…These findings suggest that the HB-EGF-HSPG interaction is not essential for cardiac muscle homeostasis, and that when HB-EGF is defective in its interaction with HSPGs, this does not affect HB-EGF signaling in this process. Hbegf-null mice also have abnormal perinatal distal lung development Minami et al, 2008). However, we could not detect any abnormalities in HB hb/hb lung development (see Fig.…”

Section: Research Articlementioning

confidence: 59%

“…The HB hb/hb mice examined in this study did not show any defects in longevity, whereas Hbegf-null mice show postnatal lethality Minami et al, 2008). Hbegf-null mice develop not only cardiac valve defects, but also heart chamber defects, with symptoms that resemble human cardiomyopathy and result in early postnatal lethality Jackson et al, 2003).…”

Section: Research Articlementioning

confidence: 65%

“…ProHB-EGF is also biologically active as a juxtacrine growth factor that signals to neighboring cells in a non-diffusible manner Iwamoto et al, 1999;Iwamoto and Mekada, 2000). Importantly, recent analyses of Hbegf-null mice have implicated a role in several physiological and pathological processes Mine et al, 2005;Shirakata et al, 2005;Xie et al, 2007;Mekada and Iwamoto, 2008;Minami et al, 2008), including cardiac valve development Jackson et al, 2003;Yamazaki et al, 2003;Iwamoto and Mekada, 2006).…”

Section: Introductionmentioning

confidence: 99%

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HB-EGF function in cardiac valve development requires interaction with heparan sulfate proteoglycans

et al. 2010

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SUMMARYHB-EGF, a member of the EGF family of growth factors, plays an important role in cardiac valve development by suppressing mesenchymal cell proliferation. Here, we show that HB-EGF must interact with heparan sulfate proteoglycans (HSPGs) to properly function in this process. In developing valves, HB-EGF is synthesized in endocardial cells but accumulates in the mesenchyme by interacting with HSPGs. Disrupting the interaction between HB-EGF and HSPGs in an ex vivo model of endocardial cushion explants resulted in increased mesenchymal cell proliferation. Moreover, homozygous knock-in mice (HB hb/hb ) expressing a mutant HB-EGF that cannot bind to HSPGs developed enlarged cardiac valves with hyperproliferation of mesenchymal cells; this resulted in a phenotype that resembled that of Hbegf-null mice. Interestingly, although Hbegf-null mice had abnormal heart chambers and lung alveoli, HB hb/hb mice did not exhibit these defects. These results indicate that interactions with HSPGs are essential for the function of HB-EGF, especially in cardiac valve development, in which HB-EGF suppresses mesenchymal cell proliferation.

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Heparan sulfate in lung morphogenesis: The elephant in the room

Thompson

Jesudason

Turnbull

et al. 2010

Birth Defects Research Pt C

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Heparan sulfate (HS) is a structurally complex polysaccharide located on the cell surface and in the extracellular matrix, where it participates in numerous biological processes through interactions with a vast number of regulatory proteins such as growth factors and morphogens. HS is crucial for lung development; disruption of HS synthesis in flies and mice results in a major aberration of airway branching, and in mice, it results in neonatal death as a consequence of malformed lungs and respiratory distress. Epithelial-mesenchymal interactions governing lung morphogenesis are directed by various diffusible proteins, many of which bind to, and are regulated by HS, including fibroblast growth factors, sonic hedgehog, and bone morphogenetic proteins. The majority of research into the molecular mechanisms underlying defective lung morphogenesis and pulmonary pathologies, such as bronchopulmonary dysplasia and pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH), has focused on abnormal protein expression. The potential contribution of HS to abnormalities of lung development has yet to be explored to any significant extent, which is somewhat surprising given the abnormal lung phenotype exhibited by mutant mice synthesizing abnormal HS. This review summarizes our current understanding of the role of HS and HS-binding proteins in lung morphogenesis and will present in vitro and in vivo evidence for the fundamental importance of HS in airway development. Finally, we will discuss the future possibility of HS-based therapeutics for ameliorating insufficient lung growth associated with lung diseases such as CDH.

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HB‐EGF decelerates cell proliferation synergistically with TGFα in perinatal distal lung development

Cited by 19 publications

References 38 publications

Early Alterations of Growth Factor Patterns in Bronchoalveolar Lavage Fluid From Preterm Infants Developing Bronchopulmonary Dysplasia

Early Alterations of Growth Factor Patterns in Bronchoalveolar Lavage Fluid From Preterm Infants Developing Bronchopulmonary Dysplasia

HB-EGF function in cardiac valve development requires interaction with heparan sulfate proteoglycans

Heparan sulfate in lung morphogenesis: The elephant in the room

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