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Transmigration of CD34+ Cells Across Specialized and
Nonspecialized Endothelium Requires Prior Activation by Growth
Factors and Is Mediated by PECAM-1 (CD31)
Kwee L. Yong,
Mike Watts,
N. Shaun Thomas,
Angela Sullivan,
Stuart Ings, and
David C. Linch
From the Department of Haematology, Royal Free Hospital School of
Medicine, London, UK and the Department of Haematology, University
College Medical School, London, UK.
The transmigration of hematopoietic progenitor cells (HPCs) across
vascular endothelium is a critical step in the homing of transplanted
stem cells, but the molecular basis for this is unknown. We used
mobilized peripheral blood CD34+ selected cells and
cultured bone marrow microvascular (BMECs) and human umbilical vein
endothelial cells (HUVECs) to investigate the adhesion and
transendothelial migration of HPCs. Colony-forming cells (CFCs) in
freshly isolated CD34+ cells showed high levels of
adhesion to both forms of endothelium (28% ± 4% and 38% ± 6% of
granulocyte-macrophage colony-forming cells [GM-CFCs] adhering to
HUVECs and BMECs, respectively), but were unable to migrate to any
significant extent across either (1.0% ± 0.3% and 1.1% ± 0.6%
of GM-CFCs migrating across HUVECs and BMECs, respectively). Greater
than 95% of peripheral blood CD34+ cells are in
G0/G1 of the cell cycle, but after 48 to 72 hours of stimulation with growth factors (interleukin-3 [IL-3] 12 ng/mL, stem cell factor 10 ng/mL, and IL-6 10 ng/mL), 28% ± 5% of
cells were in S+G2/M. Growth factor stimulation had no
effect on the adhesion of mobilized CFCs but resulted in enhanced
migration of these cells (9.8% ± 1.6% and 12.6% ± 3.1% of
GM-CFCs migrating across HUVECs and BMECs, respectively; P < .01, n = 6). Assessment of cell proliferation by the
3H-thymidine suicide method showed that, whereas 11.7% ± 3.3% of proliferating CFCs transmigrated across endothelium, only
1.3% ± 0.3% of nonproliferating CFCs did so (P < .05, n
= 5). Transmigration of growth factor-activated CFCs was inhibited by
anti-CD18 monoclonal antibody (MoAb; 50% ± 18% inhibition) and by
anti-platelet endothelial cell adhesion molecule-1 (PECAM-1) MoAb
(70.8% ± 7.1% inhibition; P < .05, n = 3). IL-1
stimulation of HUVECs had no significant effect on CD34+
cell transmigration, but caused marked enhancement of neutrophil migration. Stem cell homing may depend, in part, on the ability of
local cytokines to upregulate the transmigratory ability of these
cells. The transmigration of HPCs shares at least some molecular pathways with that of mature cells (CD18 and PECAM-1), but
is differently affected by endothelial activation.
Blood, Vol. 91 No. 4 (February 15), 1998:
pp. 1196-1205
© 1998 by The American Society of Hematology.
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