Engineering cell/ECM interactions in lung disease
Patrick Link, PhD
Postdoctoral Research Fellow
Department of Physiology and Biomedical Engineering
Cell characteristics are regulated through a variety of mechanisms, such as cytokines, the mechanical environment, or epigenetics. In lung diseases, abnormal regulation of multiple mechanisms combine to determine a shift from a healthy state toward a disease state. In lung diseases such as pulmonary fibrosis or pulmonary hypertension, cells become activated, which results in increased extracellular matrix deposition, increased cellular contractility, and increased tissue stiffness. I present work here, which is essential to defining the extracellular matrix as an important driver of diseased cell states.
Using models of lung disease, I quantified changes to baseline cellular phenotype. I questioned whether a disease state could modulate cellular contraction. I found fibroblasts isolated from patients with pulmonary fibrosis had an increased baseline contractile state which could only be significantly changed through combined silencing of transcriptional co-factors YAP and TAZ. These data show disease state can reprogram cellular contractile phenotype.
Then, I wanted to identify if the extracellular matrix could regulate cellular phenotype independent of substrate stiffness. Using hydrogels of healthy and diseased stiffnesses, I coated the gels with decellularized extracellular matrix from healthy and diseased tissue. I identified significant changes in cellular phenotype for healthy cells coated on normal stiffness-diseased extracellular matrix. Combined, these research works show that early changes in extracellular matrix composition shift cell state toward propagating disease.