From www.bloodjournal.org at EMORY UNIV HOSPITAL on April 7, 2008. For personal use only.

2007 109: 4118-

doi:10.1182/blood-2007-03-075762

Inflamed endothelium: an EPC adhesion kit

Elaine W. Raines

Updated information and services can be found at:

http://bloodjournal.hematologylibrary.org/cgi/content/full/109/10/4118
Information about reproducing this article in parts or in its entirety may be found online at:
http://bloodjournal.hematologylibrary.org/misc/rights.dtl#repub_requests

Information about ordering reprints may be found online at:

http://bloodjournal.hematologylibrary.org/misc/rights.dtl#reprints

Information about subscriptions and ASH membership may be found online at:
http://bloodjournal.hematologylibrary.org/subscriptions/index.dtl

Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published

semimonthly by the American Society of Hematology, 1900 M St, NW, Suite
200, Washington DC 20036.
Copyright 2007 by The American Society of Hematology; all rights reserved.
 From www.bloodjournal.org at EMORY UNIV HOSPITAL on April 7, 2008. For personal use only.
HEMOSTASIS
Comment on Dentelli et al, page 4264
Inflamed endothelium: an EPC adhesion kit
----------------------------------------------------------------------------------------------------------------
Elaine W. Raines UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE
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.
hile there is consensus that recruitment
W of bone marrow derived endothelial
progenitor cells (EPCs) to inflamed endothe-
lium can promote repair and neovasculariza-
tion, the mechanism of EPC homing to isch-
emic or injured sites is less well defined.1
Dissection of the mechanisms responsible for
EPC adhesion and homing will allow develop-
ment of strategies to improve retention and
survival of EPCs, and will be critical for real-
ization of the therapeutic potential of EPCs for
rescue of ischemia and repair of blood vessels.1
In this issue of Blood, Dentelli and col-
leagues demonstrate that EPC adhesion to
endothelial cells in vitro requires cytokine
activation, and is associated with up-regula-
tion 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 adhe-
sion molecules implicated in EPC homing
ICAM 1, E-selectin, or VCAM 1. Surpris-
ingly, EPC adhesion requires c-Kit tyrosine
kinase activity and signaling. The authors fur-
ther demonstrate c-Kit enhancement of EPC
4118
accumulation in vivo by implantation of endo-
thelial 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 con-
tribute 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 en-
hanced EPC adhesion? One possibility is that
c-Kit activation by soluble KitL has been
shown to modulate 41 and 51 integrin
avidity.3 Is endothelial mbKitL modulating
EPC 1 integrin avidity or possibly other inte-
grin signaling? Recently, 2 studies have shown
integrin activation can enhance EPC adhesion
and recruitment. 2 integrin activation on
EPCs increases their incorporation into isch-
emic 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
1 and 2 integrins on EPCs.5 Thus, it is pos-
sible that c-Kit signaling cross-talk with mul-
tiple integrins may contribute to its regulation
of EPC adhesion. Consistent with this possi-
bility, the Dentelli et al study shows that c-Kit
blockade inhibits EPC adhesion more than
antibodies to either of the 1 or 2 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 pro-
posed 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 con-
tribution of c-Kit signaling is warranted at
possibly multiple steps.
Conflict-of-interest disclosure: The author
declares no competing financial interests.
REFERENCES
1. Urbich C, Dimmeler S. Endothelial progenitor cells:
characterization and role in vascular biology. Circ Res.
2004;95:343-353.
2. Ashman LK. The biology of stem cell factor and its re-
ceptor C-kit. Int J Biochem Cell Biol. 1999;31:1037-1051.
3. Kovach NL, Lin N, Yednock T, Harlan JM, Broudy
VC. Stem cell factor modulates avidity of alpha 4 beta 1 and
alpha 5 beta 1 integrins expressed on hematopoietic cell
lines. Blood. 1995;85:159-167.
4. Chavakis E, Aicher A, Heeschen C, et al. Role of beta2-
integrins for homing and neovascularization capacity of
endothelial progenitor cells. J Exp Med. 2005;201:63-72.
5. Chavakis E, Hain A, Vinci M, et al. High-mobility group
box 1 activates integrin-dependent homing of endothelial
progenitor cells. Circ Res. 2007;100:204-212.
15 MAY 2007 I VOLUME 109, NUMBER 10 blood