Inflamed endothelium: an EPC adhesion kit

Dentelli and colleagues implicate signaling by the hematopoietic growth factor receptor c-Kit as a new mechanism for adhesion of endothelial progenitor cells (EPCs) to sites of vascular injury.

While there is consensus that recruitment of bone marrow–derived endothelial progenitor cells (EPCs) to inflamed endothelium can promote repair and neovascularization, the mechanism of EPC homing to ischemic or injured sites is less well defined.¹  Dissection of the mechanisms responsible for EPC adhesion and homing will allow development of strategies to improve retention and survival of EPCs, and will be critical for realization of the therapeutic potential of EPCs for rescue of ischemia and repair of blood vessels.¹ 

In this issue of Blood, Dentelli and colleagues demonstrate that EPC adhesion to endothelial cells in vitro requires cytokine activation, and is associated with up-regulation of the membrane-bound (mb) form of the ligand (L) for the hematopoietic growth factor receptor c-Kit, mbKitL, or stem-cell factor. Specifically the authors establish that blockade or knockdown of either endothelial mbKitL or c-Kit on EPCs inhibits EPC adhesion by 70%, and the extent of this inhibition is greater than that observed with antagonists to other adhesion molecules implicated in EPC homing—ICAM 1, E-selectin, or VCAM 1. Surprisingly, EPC adhesion requires c-Kit tyrosine kinase activity and signaling. The authors further demonstrate c-Kit enhancement of EPC accumulation in vivo by implantation of endothelial cells engineered to express mbKitL in a severe combined immunodeficient (SCID) mouse model that also requires c-Kit kinase activity, and show mbKitL in endothelial cells from inflamed lesions of atherosclerosis. Taken together, the results of the study by Dentelli et al implicate EPCs' c-Kit signaling in their adhesion to inflamed vessels, including those in atherosclerosis.

While integrins have been shown to contribute to EPC adhesion and homing, c-Kit involvement is unique, as this receptor is best known for its signaling in hematopoietic cells and subsequent stimulation of proliferation, differentiation, and functional activation.²  How might c-Kit signaling be involved in enhanced EPC adhesion? One possibility is that c-Kit activation by soluble KitL has been shown to modulate α4β1 and α5β1 integrin avidity.³  Is endothelial mbKitL modulating EPC β1 integrin avidity or possibly other integrin signaling? Recently, 2 studies have shown integrin activation can enhance EPC adhesion and recruitment. β2 integrin activation on EPCs increases their incorporation into ischemic tissues,⁴  and enhanced EPC adhesion to endothelial cells following EPC stimulation with a nuclear protein released during tissue injury is mediated by increased affinity of both β1 and β2 integrins on EPCs.⁵  Thus, it is possible that c-Kit signaling cross-talk with multiple integrins may contribute to its regulation of EPC adhesion. Consistent with this possibility, the Dentelli et al study shows that c-Kit blockade inhibits EPC adhesion more than antibodies to either of the β1 or β2 integrin ligands, VCAM 1 or ICAM 1, respectively.

The dependence of EPC accumulation in vivo on c-Kit signaling may also reflect broader effects of c-Kit activation on EPC migration, invasion, differentiation, and/or survival.²  While a multistep process is proposed for homing of EPCs to ischemic and injured tissues,¹  evaluation of the contribution of different mediators to each step will be aided by use of uniform and characterized EPC populations. The work of Dentelli and colleagues suggests that evaluation of the contribution of c-Kit signaling is warranted at possibly multiple steps.