Discoidin domain receptor-2 enhances secondary alveolar septation in mice by activating integrins and modifying focal adhesions.

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 to lung development. Using mice (smallie, Slie/Slie, DDR2Δ) 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 with fibroblasts isolated from littermate controls, DDR2Δ 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 DDR2Δ fibroblasts, less phospho-zyxin localized to and fewer FA developed over ventral actin stress fibers, and the adhesions had a lower aspect ratio compared with 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.