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Integrins ₁, ₆, and ₃ contribute to mechanical strain-induced differentiation of fetal lung type II epithelial cells via distinct mechanisms

¹Division of Neonatology, Department of Pediatrics, Women and Infants Hospital of Rhode Island; ²Division of Hematology and Oncology, Department of Medicine, Rhode Island Hospital, Brown Medical School, Providence, Rhode Island; and ³Vascular Biology Program, Departments of Pathology and Surgery, Children's Hospital, Harvard Medical School, Boston, Massachusetts

Submitted 26 April 2005 ; accepted in final form 14 September 2005

Mechanical forces regulate lung maturation in the fetus by promoting type II epithelial differentiation. However, the cell surface receptors that transduce these mechanical cues into cellular responses remain largely unknown. When distal lung type II epithelial cells isolated from embryonic day 19 rat fetuses were cultured on flexible plates coated with laminin, fibronectin, vitronectin, collagen, or elastin and exposed to a level of mechanical strain (5%) similar to that observed in utero, transmembrane signaling responses were induced under all conditions, as measured by ERK activation. However, mechanical stress maximally increased expression of the type II cell differentiation marker surfactant protein C when cells were cultured on laminin substrates. Strain-induced alveolar epithelial differentiation was inhibited by interfering with cell binding to laminin using soluble laminin peptides (IKVIV or YIGSR) or blocking antibodies against integrin ₁, ₃, or ₆. Additional studies were carried out with substrates coated directly with different nonactivating anti-integrin antibodies. Blocking integrin ₁ and ₆ binding sites inhibited both cell adhesion and differentiation, whereas inhibition of ₃ prevented differentiation without altering cell attachment. These data demonstrate that various integrins contribute to mechanical control of type II lung epithelial cell differentiation on laminin substrates. However, they may act via distinct mechanisms, including some that are independent of their cell anchoring role.

laminin; surfactant protein C

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