Journal article
Discoidin domain receptor-2 (DDR2) enhances secondary alveolar septation in mice by activating integrins and modifying focal adhesions
American journal of physiology. Lung cellular and molecular physiology, Vol.324(3), pp.L307-L324
03/06/2023
DOI: 10.1152/ajplung.00169.2022
PMCID: PMC9988528
PMID: 36719983
Abstract
The extracellular matrix (ECM) of the pulmonary parenchyma must maintain the structural relationships among resident cells during the constant distortion imposed by respiration. This dictates that both the ECM and cells adapt to changes in shape, while retaining their attachment. Membrane-associated integrins and discoidin domain receptors (DDR) bind collagen and transmit signals to the cellular cytoskeleton. Although the contributions of DDR2 to collagen deposition and remodeling during osseous development are evident, it is unclear how DDR2 contributes so lung development. Using mice (smallie, Slie/Slie, DDR2D) bearing a spontaneous inactivating deletion within the DDR2 coding region we observed a decrease in gas-exchange surface area and enlargement of alveolar ducts. Compared to fibroblasts isolated from littermate controls, DDR2D fibroblasts, spread more slowly, developed fewer lamellipodia, and were less responsive to the rigidity of neighboring collagen fibers. Activated β1-integrin (CD29) was reduced in focal adhesions (FA) of DDR2D fibroblasts, less phospho-zyxin localized to and fewer FA developed over ventral actin stress fibers, and the adhesions had a lower aspect ratio compared to controls. However, DDR2-deletion did not reduce cellular displacement of the ECM. Our findings indicate that DDR2, in concert with collagen-binding β1-integrins, regulates the timing and location of focal adhesion-formation and how lung fibroblasts respond to ECM rigidity. Reduced rigidity-sensing and mechano-responsiveness may contribute to the distortion of alveolar ducts, where the fiber cable-network is enriched and tensile forces are concentrated. Strategies targeting DDR2 could help guide fibroblasts to locations where tensile forces organize parenchymal repair.
Details
- Title: Subtitle
- Discoidin domain receptor-2 (DDR2) enhances secondary alveolar septation in mice by activating integrins and modifying focal adhesions
- Creators
- Stephen E McGowan - University of Iowa
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Lung cellular and molecular physiology, Vol.324(3), pp.L307-L324
- DOI
- 10.1152/ajplung.00169.2022
- PMID
- 36719983
- PMCID
- PMC9988528
- eISSN
- 1522-1504
- Grant note
- 2 I01 BX000508-09 / U.S. Department of Veterans Affairs (VA)
- Language
- English
- Electronic publication date
- 01/31/2023
- Date published
- 03/06/2023
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; International Programs; Internal Medicine
- Record Identifier
- 9984363653202771
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