title: Endothelial MMP14 is required for endothelial-dependent growth support of human airway basal cells.
abstract: Human airway basal cells are the stem (or progenitor) population of the airway epithelium, and play a central role in anchoring the epithelium to the basement membrane. The anatomic position of basal cells allows for potential paracrine signaling between them and the underlying non-epithelial stromal cells. In support of this, we have previously demonstrated that endothelial cells support growth of basal cells during co-culture through vascular endothelial growth factor A (VEGFA)-mediated signaling. Building on these findings, we found, by RNA sequencing analysis, that basal cells expressed multiple fibroblast growth factor (FGF) ligands (FGF2, FGF5, FGF11 and FGF13) and that only FGF2 and FGF5 were capable of functioning in a paracrine manner to activate classical FGF receptor (FGFR) signaling. Antibody-mediated blocking of FGFR1 during basal-cell-endothelial-cell co-culture significantly reduced the endothelial-cell-dependent basal cell growth. Stimulation of endothelial cells with basal-cell-derived growth factors induced endothelial cell expression of matrix metallopeptidase 14 (MMP14), and short hairpin RNA (shRNA)-mediated knockdown of endothelial cell MMP14 significantly reduced the endothelial-cell-dependent growth of basal cells. Overall, these data characterize a new growth-factor-mediated reciprocal 'crosstalk' between human airway basal cells and endothelial cells that regulates proliferation of basal cells.
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Bi-Sen
authors.initials: BS
authors.lastname: Ding
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Gomi
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA geneticmedicine@med.cornell.edu.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Walters
mesh_terms: D001485:Basement Membrane / Q000166:cytology / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D051521:Fibroblast Growth Factor 5 / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008024:Ligands; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis / Q000235:genetics*; D019899:Paracrine Communication / Q000235:genetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
chemical_list: C496449:FGF5 protein, human; D008024:Ligands; D016222:Fibroblast Growth Factor 2; D051521:Fibroblast Growth Factor 5; D005346:Fibroblast Growth Factors; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: Airway basal cell; Crosstalk; Endothelial cell; MMP14; Progenitor cell