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Quantitative proteome analysis of alveolar type-II cells reveals a connection of integrin receptor subunits beta 2/6and WNT signaling

Mukhametshina RT, Ruhs A, Singh I, Hasan D, Contreras A, Mehta A, Nikam VS, Ahlbrecht K, Carraro G, Cabrera-Fuentes HA, Jiang D, Voswinckel R, Seeger W, Bellusci S, Scharffetter-Kochanek K, Bagaeva TV, Preissner KT, Boettger T, Braun T, Krüger M, Barreto G.

J Proteome Res. 2013 Dec 6;12(12):5598-608.

LOEWE Research Group Lung Cancer Epigenetic, ‡Division of Biomolecular Mass Spectrometry, §Department of Lung Development and Remodeling, and ∥Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, member of the Universities of Giessen and Marburg Lung Center (UGMLC) and German Center of Lung Research (DZL) , Parkstraße 1, 61231 Bad Nauheim, Germany.

Abstract

 Alveolar type-II cells (ATII cells) are lung progenitor cells responsible for regeneration of alveolar epithelium during homeostatic turnover and in response to injury. Alveolar type-II cells have been related to diverse lung diseases including pulmonary fibrosis, chronic obstructive pulmonary disease, emphysema, cystic fibrosis as well as lung cancer. Characterization of the mechanisms regulating the expansion and differentiation of Alveolar type-II cells will have a profound impact on the understanding and treatment of lung diseases. However, Alveolar type-II cells have been characterized by the expression of Surfactant Protein C (SFTPC) which is a secreted protein, making it difficult to attain a homogeneous population of these cells. The identification of novel Alveolar type-II cells-surface proteins which can be used for sorting and enrichment of these cells is essential for further characterization. Combining a high resolution mass spectrometry-based membrane proteomic approach using lungs of SILAC mice with a microarray based transcriptome analysis of Alveolar type-II cells, we identified 16 proteins that are enriched in the membrane fraction of Alveolar type-II cells and whose genes are highly expressed in these cells. Two of these proteins, integrin receptor subunits beta 2 and 6 (ITGB2 and ITGB6), were confirmed by immunohistochemistry, flow cytometry, western blot and qRT-PCR. Integrins are heterodimeric transmembrane cell surface receptors that mediate attachment to the extracellular matrix as well as cell-cell adhesion. Integrins are involved in lung development and differentiation, lung inflammation, pulmonary fibrosis, pulmonary edema following acute lung injury, or malignant transformation. Furthermore, analysis of the Itgb2/ mice demonstrated its requirement for proper WNT signaling in the lung. Moreover, our data supports the existence of a subpopulation of SFPTC-positive cells in the alveolar epithelium that express Itgb2 and Itgb6, suggesting that there might be at least two different types of Alveolar type-II cells in the adult lung. Further characterization of these cells after sorting and enrichment of a homogeneous cell population could have a profound impact on our understanding of the regulatory mechanisms controlling the proper balance between expansion and differentiation of Alveolar type-II cells. Detailed analysis in the regenerative potential of these ITGB2- and ITGB6-positive cells using lung injury models would be pertinent to appreciate their clinical applications. To summarize, our data show that ITGB2 and ITGB6 are attractive diagnostic and therapeutic targets for intervention in several lung diseases.

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Quantitative proteome analysis of alveolar type-II cells reveals a connection of integrin receptor subunits beta 2/6and WNT signaling. Global Medical Discovery