Human endothelial colony-forming cells serve as trophic mediators for mesenchymal stem cell engraftment via paracrine signaling

Abstract

Endothelial colony-forming cells (ECFCs) are endothelial precursors that circulate in peripheral blood. Studies have demonstrated that human ECFCs have robust vasculogenic properties. However, whether ECFCs can exert trophic functions in support of specific stem cells in vivo remains largely unknown. Here, we sought to determine whether human ECFCs can function as paracrine mediators before the establishment of blood perfusion. We used two xenograft models of human mesenchymal stem cell (MSC) transplantation and studied how the presence of ECFCs modulates MSC engraftment and regenerative capacity in vivo. Human MSCs were isolated from white adipose tissue and bone marrow aspirates and were s.c. implanted into immunodeficient mice in the presence or absence of cord blood-derived ECFCs. MSC engraftment was regulated by ECFC-derived paracrine factors via platelet-derived growth factor BB (PDGF-BB)/platelet-derived growth factor receptor (PDGFR)-β signaling. Cotransplanting ECFCs significantly enhanced MSC engraftment by reducing early apoptosis and preserving stemness-related properties of PDGFR-β + MSCs, including the ability to repopulate secondary grafts. MSC engraftment was negligible in the absence of ECFCs and completely impaired in the presence of Tyrphostin AG1296, an inhibitor of PDGFR kinase. Additionally, transplanted MSCs displayed fate-restricted potential in vivo, with adipose tissue-derived and bone marrow-derived MSCs contributing exclusive differentiation along adipogenic and osteogenic lineages, respectively. This work demonstrates that blood-derived ECFCs can serve as paracrine mediators and regulate the regenerative potential of MSCs via PDGF-BB/PDGFR-β signaling. Our data suggest the systematic use of ECFCs as a means to improve MSC transplantation.vasculogenesis | adipogenesis | osteogenesis | angiocrine factors

CD44 expression in endothelial colony-forming cells regulates neurovascular trophic effect

“…The observation that ECFCs home to the lens and vitreous confirms suggestions made by others that ECFCs function largely in a paracrine manner (10,11). To confirm this, we analyzed gene expression for 84 angiogenic growth factors in CD44 hi and CD44 lo ECFCs grown in monolayer culture.…”

“…They have been reported to home to the site of tissue ischemia after intravenous injection, where they improve circulation in a model of myocardial infarction (4), stroke (5), ischemic retinopathy (6,7), and ischemic limb injury (8,9). Although a paracrine trophic rescue effect of ECFCs has been postulated (10,11), factors that may mediate this effect remain poorly characterized.…”

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

“…48 This finding correlates well with studies showing the perivascular location of neuronal stem cells 46,49 and the critical function of vascular basal membrane laminin to control MSC function by a 6 b 1 integrin and PDGF-BB signaling. 48,50 The integration of endothelial cells with herein described perivascular niche model consisting of MSCs which are exposed to stable growth factor gradients might provide a promising platform for the studying of stem cells in their perivascular niche while varying individual cellular, matrix associated or soluble bio-molecular factors.…”

Endothelial cell regulation of salivary gland epithelial patterning

“…For example, endothelial-produced factors are known to recruit and support stromal pericytes, which are important for organogenesis. Additionally, endothelial progenitor cell-produced platelet-derived growth factor (PDGF)-BB was identified in recruitment and sustaining the function of the PDGFRβ + mesenchymal stem cells (MSCs) after therapeutic engraftment during MSC cell therapy (Lin et al, 2014). Although IGFBP2 is known to be one of many angiocrine factors produced by endothelial cells in an organ-specific manner (Mouhieddine et al, 1996;Besnard et al, 2001;Bridgewater and Matsell, 2003;Huynh et al, 2011;Perri et al, 2014), in the salivary gland, IGFBP2 and IGFBP 3 appear to be produced primarily by CD31 − mesenchyme cells.…”