Sulfation of extracellular matrices modifies growth factor effects on type II cells on laminin substrata

Sannes, Philip L.; Khosla, Jody; Li, Chengming; Pagan, Ines

doi:10.1152/ajplung.1998.275.4.l701

Cited by 24 publications

(40 citation statements)

References 28 publications

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“…The observation that the regions or microdomains of the BM of the alveolus are quantitatively less sulfated beneath type II compared with type I cells (15)(16)(17) led to the proposal that sulfation of ECMs, in their soluble (shed) and insoluble (matrixbound) forms, are key factors in controlling the responsiveness of alveolar epithelial cells to growth factors (16,(18)(19)(20). Evidence in support of this contention has been obtained with in vitro studies, where under-sulfated or desulfated ECMs promote Figure 3.…”

Section: Discussionmentioning

confidence: 97%

“…Alveolar type II cells were isolated from pathogen-free 200-to 250-g Fischer F-344 CDF rats (Charles River Laboratory, Wilmington, MA) following the procedure of Dobbs (32) with minor modifications (19). All procedures were approved by the North Carolina State University Institutional Animal Care and Use Committee.…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

“…Desulfated heparin was obtained by subjecting high-molecular-weight heparin to solvolytic desulfation with dimethyl sulfoxide (33) resulting in Ͼ 85% desulfation as previously described (19). Cells were treated with or without the following factors: 500 g/ml of high-molecular-weight heparin, 500 g/ml of desulfated high-molecular-weight heparin, 100 ng/ml FGF-1, 100 ng/ml FGF-2, or 20 ng/ml FGF-7.…”

Section: Effects Of the Sulfation Level Of Heparinmentioning

confidence: 99%

“…These conditions help support and maintain type II cell morphology and function. These results, in conjunction with evidence that under-sulfated ECMs could further contribute to type II cell proliferation in vitro (18,19), led us to hypothesize that the heavily sulfated BMZ associated with type I cells could promote the differentiation of type II cells into type I cells and, in the process, diminish or alter surfactant protein gene expression. Soluble high-molecular-weight heparin was used as a model for testing this basic hypothesis, appreciating at the same time that it is equally applicable for modeling the bioactivity of shed cell-surface sulfated proteoglycan ectodomains (24-26) which, in vivo, might also be expected to alter the responsiveness of type II cells in vivo to heparin-binding growth factors, such as FGFs.…”

mentioning

confidence: 92%

“…This observation led to the proposal that such "under-sulfation" could influence, perhaps permitting or promoting, responsiveness to growth factors and thus account in part for their respective phenotypes and division of labor (16)(17)(18)(19). In support of this notion, desulfated or otherwise low sulfate-containing ECMs have been shown to promote FGF-1-and FGF-2-stimulated DNA synthesis in isolated type II cells, while heavily sulfated components of ECMs (e.g., heparin) inhibit or reduce this response (18,19). More recently, FGF-2 gene and protein expression and gene expression of FGF-1 and FGF-R2, but not FGF-R1, have been shown to be down-regulated by heparin (20).…”

mentioning

confidence: 99%

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Heparin and Fibroblast Growth Factors Affect Surfactant Protein Gene Expression in Type II Cells

Leiner

Newman²,

Li³

et al. 2006

Am J Respir Cell Mol Biol

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The stimulation and maintenance of the pulmonary alveolar type II cell's capacity to biosynthesize, store, and secrete surfactant proteins (SPs) are modulated to a great extent by growth factors, extracellular matrix (ECM) components, and hormones. It is possible that differences in ECM composition, as exist between type I and II cells normally or as might occur with excessive cell surface shedding during inflammation or injury states, may specifically alter SP expression. Here, isolated type II cells were exposed to the model sulfated ECM heparin; desulfated heparin; and/or fibroblast growth factor (FGF)-1, -2, or -7 for 24 h to examine by quantitative realtime polymerase chain reaction their effects on SP gene expression. Aquaporin 5 (AQP-5) gene expression was also examined as a phenotypic marker for the type I cell. SP-B mRNA abundance was increased 4-to 8-fold by all three FGFs. Heparin at low concentrations (5 g/ml) or desulfated heparin at high concentrations (500 g/ ml) enhanced the effects of FGF-2 and -7, while high heparin concentrations (500 g/ml) were inhibitory. In contrast, SP-B mRNA abundance was increased by heparin in a dose-and sulfationdependent manner when used in combination with FGF-1. SP-C and AQP-5 mRNA levels were increased by heparin alone in a doseand sulfation-dependent manner, while all FGFs lacked effect on SP-C or AQP-5 mRNA levels. These data indicate that heparin can be stimulatory to SP gene expression depending on concentration, degree of sulfation, and surrounding FGF environment, and that heparin plays a significant role in modulating alveolar epithelial cell phenotype in vitro.Keywords: extracellular matrix; fibroblast growth factor; keratinocyte growth factor; surfactant protein-B; surfactant protein-C The pulmonary alveolar surface is lined primarily by two epithelial cell types, the alveolar type I cell and the alveolar type II cell. The squamous type I cell accounts for ‫ف‬ 40% of the alveolar epithelial cells by number and covers 95% of the alveolar surface (1). In contrast, the cuboidal type II cell accounts for ‫ف‬ 60% of alveolar epithelial cells by number, yet covers only 5% of the alveolar surface (1). Their striking morphologic differences reflect their specialized and intricately complementary functions within the deep lung. The squamous (0.2 m) type I cell, with its large surface area, facilitates the efficient diffusion of respiratory gases across the lung epithelium. To maintain this surface area available for gas exchange, pulmonary surfactant, which consists of a mixture of phospholipids and associated proteins, is synthesized and secreted by the type II cell to lower surface tension in the alveoli and prevent their collapse (2). The type II cell,

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Section: Discussionmentioning

confidence: 97%

Section: Cell Culture and Treatmentmentioning

confidence: 99%

Section: Effects Of the Sulfation Level Of Heparinmentioning

confidence: 99%

mentioning

confidence: 92%

mentioning

confidence: 99%

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Heparin and Fibroblast Growth Factors Affect Surfactant Protein Gene Expression in Type II Cells

Leiner

Newman²,

Li³

et al. 2006

Am J Respir Cell Mol Biol

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Temporal Changes in Expression of FoxA1 and Wnt7A in Isolated Adult Human Alveolar Epithelial Cells Enhanced by Heparin

Apparao

Newman

Zhang

et al. 2010

The Anatomical Record

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Pre- and postnatal developmental studies of the lung have provided compelling evidence demonstrating multiple factors that orchestrate alveolar epithelial cell differentiation. The extent to which reactivation of certain developmental pathways in the adult might influence the course of differentiation of alveolar type 2 cells (AT2) into AT1 cells is not known. In this study, we examined selected members of the forkhead (Fox) family of transcription factors and the Wnt (wingless) family of signaling proteins for expression during human alveolar cell differentiation in vitro and determined their potential responses to sulfated components of extracellular matrix (ECM), like those shed from cell surfaces or found in basement membrane and modeled by heparin. Isolated adult human AT2 cells cultured over a nine day period were used to define the temporal profile of expression of targeted factors during spontaneous differentiation to AT1 cells. FoxA1 protein was up-regulated at early to intermediate time points, where it was strongly elevated by heparin. Gene expression of Wnt7A increased dramatically beginning on day 3 and was enhanced even further on days 7 and 9 by heparin, while protein expression appeared at days 7 and 9. These temporal changes of expression suggest that sulfated ECMs may act to enhance the increase in FoxA1 at the critical juncture when AT2 cells commence the differentiation process to AT1 cells, in addition to enhancing the increase in Wnt7A when the AT1 cell phenotype stabilizes. Collectively, these factors may act to modulate differentiation and stabilize cell numbers in the adult human pulmonary alveolus.

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Heparan Sulfates in the Lung: Structure, Diversity, and Role in Pulmonary Emphysema

Smits

Shworak

Dekhuijzen

et al. 2010

The Anatomical Record

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There is an emerging interest in the extracellular matrix (ECM) of the lung, especially in the role it plays in development and disease. There is a rapid change from the classical view of the ECM as a supporting structure towards a view of the ECM as a regulatory entity with profound effects on proliferation, migration, and differentiation of pulmonary cells. In the ECM, a variety of molecules is present in a highly organized pattern. Next to the abundant fiber-forming molecules such as collagens and elastin, a large number of less abundant molecules are part of the ECM, including proteoglycans. In this review, we will focus on one class of proteoglycans, the heparan sulfate proteoglycans. We will particularly address the structure, biosynthesis, and function of their saccharide moiety, the heparan sulfates, including their role in development and (patho)-physiology. Anat Rec,

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Sulfation of extracellular matrices modifies growth factor effects on type II cells on laminin substrata

Cited by 24 publications

References 28 publications

Heparin and Fibroblast Growth Factors Affect Surfactant Protein Gene Expression in Type II Cells

Heparin and Fibroblast Growth Factors Affect Surfactant Protein Gene Expression in Type II Cells

Temporal Changes in Expression of FoxA1 and Wnt7A in Isolated Adult Human Alveolar Epithelial Cells Enhanced by Heparin

Heparan Sulfates in the Lung: Structure, Diversity, and Role in Pulmonary Emphysema

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