Submitted March 1, 2006
Accepted March 20, 2006
Endothelial progenitor cells from infantile hemangioma
and from umbilical cord blood display unique cellular
responses to endostatin
Zia A Khan, Juan M Melero-Martin, Xiao Wu, Sailaja Paruchuri, Elisa Boscolo, John B Mulliken, and Joyce Bischoff*
Vascular Biology Program and Department of Surgery,Children's Hospital Boston,Harvard Medical School
University of Padua
Division of Plastic Surgery, Children's Hospital Boston, MA, USA
* Corresponding author; email: joyce.bischoff{at}childrens.harvard.edu.
Infantile hemangiomas are composed of endothelial cells
(ECs), endothelial progenitor cells (EPCs), as well as
perivascular and hematopoietic cells. Our hypothesis is
that hemangioma-derived EPCs (hemEPCs) differentiate
into the mature ECs that comprise the major compartment
of the tumor. To test this, we isolated EPCs
(CD133+/Ulex europeus-I+) and mature ECs (CD133-/Ulex
europeus-I+) from proliferating hemangiomas and used a
previously described property of hemangioma-derived ECs
(hemECs), enhanced migratory activity in response to the
angiogenesis inhibitor endostatin, to determine if
hemEPCs share this abnormal behavior. Umbilical cord
blood-derived EPCs (cbEPCs) were analyzed in parallel as
a normal control. Our results show that hemEPCs, hemECs,
and cbEPCs exhibit increased adhesion, migration and
proliferation in response to endostatin. This angiogenic
response to endostatin was consistently expressed by
hemEPCs over several weeks in culture, whereas hemECs
and cbEPCs shifted towards the mature endothelial
response to endostatin. Similar mRNA expression
patterns among hemEPCs, hemECs, and cbEPCs, revealed by
microarray analyses, provided further indication of an
EPC phenotype. This is the first demonstration that
human EPCs, isolated from blood or from a proliferating
hemangioma, are stimulated by an angiogenesis inhibitor.
These findings suggest that EPCs respond differently
from mature ECs when exposed to angiogenic or anti-
angiogenic signals.
