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 nonepithelial 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-endothelialcell 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.

Concise Review: Paracrine Functions of Vascular Niche Cells in Regulating Hematopoietic Stem Cell Fate

“…BM ECs regulate HSC fate, in part, via the elaboration of paracrine factors . Commensurate with these observations, recent studies have suggested that ECs also regulate the self‐renewal and regeneration of stem cells in nonhematopoietic organs, including the liver, brain, lung, and skin , . In the present study, we describe the hematopoietic‐specific activities of BM ECs and highlight the potential for EC‐derived paracrine mechanisms to be translated into regenerative therapies for patients.…”

Angiocrine functions of organ-specific endothelial cells

“…The progenitors of airway basal cells 91 could also proliferate in response to angiocrine MMP-14 induction. FGF-2 and FGF-5 derived from cultured human basal cells stimulate the FGFR-1-dependent production of MMP-14 by pulmonary capillary ECs, which in turn supports the expansion and differentiation of basal cells 92 . Therefore, selective angiocrine upregulation of MMP-14 in pulmonary capillary ECs ignites the propagation of alveolar epithelial cells and basal cell progenitors.…”

Transcription factor KLF6 upregulates expression of metalloprotease MMP14 and subsequent release of soluble endoglin during vascular injury

“…Among these, MMP14 is a membrane-type MMP (MT-MMP) belonging to the collagenase type I class. In the vascular setting, MMP14 is involved in: (i) capillary tube formation of human ECs using 3D collagen matrices [ 10 , 16 ]; (ii) the inflammatory response of ECs [ 17 ]; (iii) the atherosclerotic plaque vulnerability [ 18 – 20 ]; and (iv) the cross-talk between human airway basal cells and ECs [ 21 ]. Interestingly, MMP14 is upregulated in wound-derived blood vessels compared with vessels from intact human skin [ 22 ].…”