Endothelial progenitor cells and integrins: adhesive needs

Abstract

In the last decade there have been multiple studies concerning the contribution of endothelial progenitor cells (EPCs) to new vessel formation in different physiological and pathological settings. The process by which EPCs contribute to new vessel formation in adults is termed postnatal vasculogenesis and occurs via four inter-related steps. They must respond to chemoattractant signals and mobilize from the bone marrow to the peripheral blood; home in on sites of new vessel formation; invade and migrate at the same sites; and differentiate into mature endothelial cells (ECs) and/or regulate pre-existing ECs via paracrine or juxtacrine signals. During these four steps, EPCs interact with different physiological compartments, namely bone marrow, peripheral blood, blood vessels and homing tissues. The success of each step depends on the ability of EPCs to interact, adapt and respond to multiple molecular cues. The present review summarizes the interactions between integrins expressed by EPCs and their ligands: extracellular matrix components and cell surface proteins present at sites of postnatal vasculogenesis. The data summarized here indicate that integrins represent a major molecular determinant of EPC function, with different integrin subunits regulating different steps of EPC biology. Specifically, integrin α4β1 is a key regulator of EPC retention and/or mobilization from the bone marrow, while integrins α5β1, α6β1, αvβ3 and αvβ5 are major determinants of EPC homing, invasion, differentiation and paracrine factor production. β2 integrins are the major regulators of EPC transendothelial migration. The relevance of integrins in EPC biology is also demonstrated by many studies that use extracellular matrix-based scaffolds as a clinical tool to improve the vasculogenic functions of EPCs. We propose that targeted and tissue-specific manipulation of EPC integrin-mediated interactions may be crucial to further improve the usage of this cell population as a relevant clinical agent.

The Secretome of Hydrogel-Coembedded Endothelial Progenitor Cells and Mesenchymal Stem Cells Instructs Macrophage Polarization in Endotoxemia

“…In addition, the inclusion of ProNectin into the composition of our HA-hydrogels provides an RGD sequence (an arginine-glycineaspartic acid-conserved motif) for integrins on the surface of stem cells to bind to [47,48]. When stem cell integrins bind to the RGD sequence, cytoskeleton properties are altered and the cell's release of anti-inflammatory and proregenerative factors are stimulated [13]. Activation of the EPC surface integrin a4b1 plays a critical role in stimulating the release of anti-inflammatory and proregenerative factors from EPCs, thereby enhancing the cell's ability to mediate tissue repair after injury [13].…”

“…When stem cell integrins bind to the RGD sequence, cytoskeleton properties are altered and the cell's release of anti-inflammatory and proregenerative factors are stimulated [13]. Activation of the EPC surface integrin a4b1 plays a critical role in stimulating the release of anti-inflammatory and proregenerative factors from EPCs, thereby enhancing the cell's ability to mediate tissue repair after injury [13]. Therefore, activation of critical integrins and cytoskeleton properties induced in HA-hydrogelimmobilized stem cells, along with the improved viability of embedded stem cells during exposure to endotoxins, seems to be responsible for the superior therapeutic benefits associated with stem cell delivery by HA-hydrogels compared with conventional i.v.…”

“…Although this technique of cell therapy enhances the risk of potential embolism, the delivered cells are also subject to programmed cell death (anoikis) and are rapidly cleared from the systemic circulation before they can elicit their therapeutic benefits to target tissues [12]. Insufficient homing is a major limitation of systemically delivered stem cell-based therapies and is caused in part by inadequate expression and activation of cell surface adhesion receptors, including integrins, an effect that also inhibits their anti-inflammatory and proregenerative activities [13]. Additionally, i.v.…”

Collagen regulates the ability of endothelial progenitor cells to protect hypoxic myocardium through a mechanism involving miR‐377/VE‐PTP axis

“…The mechanisms mediating the effect of collagen on EPCs are not definitively resolved, however they might involve integrin‐mediated signalling. Integrins have been indicated as major determinants of EPC homing, invasion, differentiation and paracrine factor production 31. Furthermore, it has been shown that EPCs overexpressing integrin β 1 stimulated angiogenesis in ischaemic mouse hindlimbs, in which extracellular matrix proteins such as collagen I and fibronectin were up‐regulated 32…”

Endothelial progenitor cells in diabetes complications

“…В ответ на повреждение или ишемию периферических тканей происходят выход ЭПК из КМ в кровь и их миграция в область поврежде-ния. Поступление ЭПК в зону повреждения представляет собой сложный скоординированный многоступенчатый процесс, включающий в себя мобилизацию, хемотаксис, адгезию, трансэндотелиальную миграцию и дифферен-цировку клеток с участием факторов роста, хемокинов и молекул адгезии [17]. Основными факторами мобили-зации ЭПК являются: SDF-1 (хемокинстромальный фак-тор-1), VEGF (фактор роста эндотелия сосудов), HIF-1α (фактор, индуцированный гипоксией 1α), эритропоэтин, эстрогены и гранулоцитарный колониестимулирующий фактор (Г-КСФ) [18].…”