Bone marrow-derived mesenchymal stem cells enhance angiogenesis via their α6β1 integrin receptor

Abstract

Bone marrow-derived mesenchymal stem cells (BMSCs) facilitate the angiogenic response of endothelial cells (ECs) within three-dimensional (3D) matrices in vivo and in engineered tissues in vitro in part through paracrine mediators and by acting as stabilizing pericytes. However, the molecular interactions between BMSCs and nascent tubules during the process of angiogenesis are not fully understood. In this study, we have used a tractable 3D co-culture model to explore the functional role of the α6β1 integrin adhesion receptor on BMSCs in sprouting angiogenesis. We report that knockdown of the α6 integrin subunit in BMSCs significantly reduces capillary sprouting, and causes their failure to associate with the nascent vessels. Furthermore, we demonstrate that the BMSCs with attenuated α6 integrin proliferate at a significantly lower rate relative to either control cells expressing non-targeting shRNA or wild type BMSCs; however, despite adding more cells to compensate for this deficit in proliferation, deficient sprouting persists. Collectively, our findings demonstrate that the α6 integrin subunit in BMSCs is important for their ability to stimulate vessel morphogenesis. This conclusion may have important implications in the optimization of cell-based strategies to promote angiogenesis.

Locally controlling mesenchymal stem cell morphogenesis by 3D PDGF-BB gradients towards the establishment of an in vitro perivascular niche

“…A further limitation of the current study is that in this simplified model the direct contact of MSCs with the vascular basement membrane, which is a known regulator of various stem cells, is not reproduced. 45,46 Together, these observations indicate that our in vitro model recapitulates some of the dynamics that are assumed to be present during vessel formation, including the diffusion of trace amounts of PDGF from the site of production before the capturing by the glycosaminoglycan components of the ECM. Enzymatic remodeling of the ECM by mobilized cells is also represented by the slow MMP-dependent degradation of the PEG-matrix and the consequent release of PDGF.…”

Vascular Network Formation by Human Microvascular Endothelial Cells in Modular Fibrin Microtissues

“…These heterotypic interactions were presumably enhanced in the cultures with a greater proportion of FB. In addition, the observed effects could be ECM-mediated, for example through interactions of pericytes with the ECM, which has been shown to regulate vessel formation 67 .…”

Vasculogenesis and angiogenesis in modular collagen–fibrin microtissues

“…The initiation and progression of angiogenesis is often simulated using a “bead assay” in which endothelial cells are coated onto the outside of polystyrene microspheres, which are then embedded in a surrounding protein matrix (often the clotting protein fibrin) [9]. The endothelial cells can extend and migrate from the surface of the microsphere, and in some cases these studies are performed in the presence of stromal cell populations either directly in or on top of the surrounding gel construct [10]. It has been shown that endothelial networks and vascular structures are stimulated by a variety of stromal cell types, including human lung fibroblasts [11], marrow-derived mesenchymal stem cells [12, 13], adipose-derived mesenchymal stem cells [14], and smooth muscle cells [15].…”