Endothelial MMP14 is required for endothelial dependant growth support of human airway basal cells

Human airway basal cells (BC) are the stem/progenitor population of the airway epithelium, and play a central role in anchoring the epithelium to the basement membrane. The anatomic position of BC allows for potential paracrine signaling between BC and the underlying non-epithelial stromal cells. In support of this, we previously demonstrated endothelial cells (EC) support growth of BC during co-culture via vascular endothelial growth factor A (VEGFA)-mediated signaling. Building on these findings, RNA sequencing analysis demonstrated that BC express multiple fibroblast growth factor (FGF) ligands (FGF2, 5, 11 and 13) with only FGF2 and FGF5 capable of functioning in a paracrine manner to mediate FGFR1 signaling. Antibody mediated blocking of FGFR1 during BC-EC co-culture significantly reduced EC dependent BC growth. Stimulation of EC via BC-derived growth factors resulted in EC expression of matrix metallopeptidase 14 (MMP14) and shRNA mediated knockdown of EC MMP14 significantly reduced EC dependent growth of BC. Overall, these data characterize a novel growth factor mediated reciprocal “cross-talk” between human airway BC and EC that regulates proliferation of BC.