Date of Last Revision
Bachelor of Science
Date of Expected Graduation
Fibroblasts, and their differentiation into myofibroblasts, are important in the pathology of several lung diseases including asthma and idiopathic pulmonary fibrosis (IPF). The differentiation process is dependent on several factors, such as soluble factors like transforming growth factor beta 1 (TGFβ1) and mechanical signals such as matrix stiffness. Additionally, the soluble arachidonic acid metabolite Prostaglandin E2 (PGE2) prevents TGFβ1 induced differentiation of fibroblasts to myofibroblasts, but the molecular mechanism is not completely understood15. Transient Receptor Potential Vanilloid 4 (TRPV4), a mechanosensitive ion channel, has previously been implicated in the differentiation of cardiac fibroblasts12,13. However, the role of TRPV4 in the differentiation of lung fibroblasts and its contribution to lung diseases such asthma has not been explored. Myofibroblasts express the contractile protein alpha smooth muscle actin (α-SMA) and are also distinguished by their excessive production of extracellular matrix (ECM) proteins such as fibronectin. The expression of α-SMA and ECM proteins has been shown to be mediated by serum response factor (SRF) and its co-activator myocardin related transcription factor (MRTF-A)5,6. Therefore, in the current project, we investigate differences in differentiation state between normal human lung fibroblasts (NHLF) and diseased human lung fibroblasts (DHLF). We show that DHLF have higher basal and increased α-SMA and fibronectin expression than NHLF, indicative of enhanced differentiation potential in DHLF. Additionally, we showed that lung fibroblast differentiation is regulated by TRPV4. Furthermore, we found that PGE2 inhibited TGFβ1-induced differentiation.
Hexter, Madison A., "The Role of TGFβ1 and EP Receptors in the Differentiation of Normal and Diseased Lung Fibroblasts" (2016). Williams Honors College, Honors Research Projects. 289.