Circulating Endothelial Progenitor Cells in Crohn’s Disease: An EPiC in the Making?
Circulating Endothelial Progenitor Cells in Crohn's Disease: An EPiC in the Making?
Catharine Dietrich 0
Shree Ram Singh 0
0 Stem Cell Regulation and Animal Aging Section, Basic Research Laboratory, National Cancer Institute, NIH , Frederick, MD 21702 , USA
The inflammatory bowel diseases (IBDs), divided into
Crohn’s disease (CD) and ulcerative colitis (UC), are
characterized by chronic inflammation of the entire
gastrointestinal tract (CD) or colon (UC) associated with
unrestrained immune response with activation of CD4? T
cells, expansion of the intestinal microvasculature, and
endothelial impairment [1, 2]. Approximately 565,000
residents of the USA are diagnosed with CD each year.
Although the exact causes of CD remain unclear, it has
been suggested that autoimmune components, immune
deficiency, genetic susceptibility, dietary factors, bacteria,
and fungi may in part contribute to disease pathogenesis
[3–5]. Since current conventional therapies available for
CD only control the inflammatory process in order to avoid
structural damage to the intestine, new strategies targeted
at underlying disease etiology are needed in order to repair
damaged intestinal tissue and the immune system.
In recent years, advances in the understanding of the cell
populations involved in pathogenic processes and of the
regenerative and immunomodulatory potential of stem
cells have opened up a new direction in IBD therapy. In
this context, hematopoietic stem cells (HSCs),
mesenchymal stem cells (MSCs), endothelial progenitor cells
(EPCs), resident stem cells of intestine, and induced
pluripotent stem cells (iPSCs) could be helpful in IBD
therapy. Studies in the last several years suggest that
endothelial impairment substantially contributes to the
onset and progression of and recovery from inflammatory
conditions . EPCs, derived from bone marrow
hematopoietic stem cells, (HSCs) have the capability to
migrate to the site of endothelial damage through the
peripheral circulation and have been used to treat several
inflammatory diseases, ischemic limb disease, peripheral
vascular disease, and coronary heart disease [6–8].
Despite these successes, the effectiveness of circulating
EPCs in the amelioration of CD remains speculative
[1, 9, 10]. Garolla et al.  reported a lower number of
circulating EPCs in CD patients compared to controls,
demonstrating that apoptosis is the principal pathway for
EPC reduction. Contrary to the previous study, Masuda
et al.  reported no significant reduction in the number of
circulating EPCs among CD patients as compared to
controls. Furthermore, Marlicz et al.  described
significantly elevated numbers of circulating EPCs in CD
patients. Therefore, it is essential to clarify the importance
of circulating EPCs toward CD pathophysiology by
performing careful studies.
In this issue of Digestive Diseases and Sciences, Boltin
et al., in an effort to resolve the issue related to the number
of circulating EPCs in context of CD , studied 32 CD
patients and 51 healthy controls, recruiting CD patients of
varying ancestry, assessing disease activity using the
Crohn’s disease activity index (CDAI). Among these
patients, twenty-eight were being treated with biological
therapy (infliximab) and twenty-one were receiving
immunomodulators. Boltin et al.  isolated the
peripheral blood mononuclear cells and evaluated the EPC
numbers by fluorescent cell sorting (FACS) analysis
employing antibodies to the biomarkers cluster of
differentiation (CD)34, vascular endothelial growth factor
(VEGF) receptor-2, CD133, and CD45. They reported a
significant increase in the percentage of EPCs of the
peripheral white blood cells in CD patients as compared to
healthy controls. Nevertheless, they could not significantly
correlate EPC percentages and other factors such as age,
gender, CDAI, disease duration, duration of biological
therapy, or smoking.
Boltin et al.’s  findings mark an important step
toward addressing the current controversies in CD
research. Their results are consistent with accumulating
evidence that EPCs do in fact participate in the
regeneration of damaged epithelium. Actually, in a recent EPC
transplantation study using fetal sheep, Wood et al. 
demonstrated that EPCs can migrate to the intestinal
mucosa and participate in vasculogenesis. Given this
observation, why were circulating EPC numbers in CD
patients reported to be unchanged or even reduced in
previous studies? Boltin et al.  reasoned that in their study,
a high percentage of patients were receiving biological
therapy that in turn could assist in recruiting EPCs to the
endothelial repair site. In fact, Galiano et al.  reported
that a local elevated level of VEGF and SDF-1 in ischemic
foci may help in EPC recruitment from the circulation to
the site of injury to assist diabetic wound healing.
Therefore, it is highly likely that an increase in peripheral EPCs
may be a sign of treatment feedback, though the authors
could not support this association in their study . The
present study  presents a major advantage over
previous studies in terms of clinical variables and number of
patients. Nevertheless, there are also several limitations
suggested by authors  including lack of endoscopic and
laboratory measures of disease activity, measuring EPC
abundance in tissues, and lack of clinical and demographic
In this article, authors only presented data on the
circulating numbers of EPCs in CD patients using flow
cytometry; therefore, in future experiments employing
large sample of patients, histologic sections by
immunohistochemistry to show increased numbers of EPC in and
around the gut lesions, especially near newly formed blood
vessels, are needed. Exclusive EPC markers will be needed
to distinguish EPCs from native endothelial cells.
Proliferative ability, survival, and migration efficiency of early
and mature EPCs should be tested in order to measure their
functionality. Furthermore, evaluation of the mobilization
and recruitment of EPCs using CD tissue microarrays
or RNA-Seq would be needed in order to unravel novel
regulators. Once this new information is available,
knowledge of the mechanisms by which EPCs can
mobilize and repair endothelial damage in response to chronic
inflammation in CD patients, and the signaling pathways
involved in the regulation of endothelial repair should
increase. From a therapeutic standpoint, trials of EPC
transplantation in CD patients could help ascertain if this
intervention enhances the regeneration process of intestinal
Enhanced understanding of the etiology of CD and the
mechanisms of endothelial damage and repair will provide
useful insights into the CD pathogenesis, which in turn will
inform the design of novel therapeutic strategies in its
Compliance with ethical standards
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