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									Online Appendix for the following February 20 JACC article



TITLE: Endothelial Progenitor Cells in Cardiovascular Disorders




AUTHORS: Eduard Shantsila, MD, Haemostasis, Thrombosis & Vascular Biology Unit,
University Department of Medicine, City Hospital, Birmingham, United Kingdom, Timothy
Watson, MRCP, Haemostasis, Thrombosis & Vascular Biology Unit, University Department
of Medicine, City Hospital, Birmingham, United Kingdom, Gregory Y.H. Lip, MD, FRCP,
Haemostasis, Thrombosis & Vascular Biology Unit, University Department of Medicine, City
Hospital, Birmingham, United Kingdom




APPENDIX




SEARCH STRATEGY


We performed a comprehensive literature search using electronic bibliographic databases (i.e.,

MEDLINE, EMBASE, DARE, COCHRANE DATABASE), scanning reference lists from

included articles and hand searching abstracts from national and international cardiovascular

meetings. For the search, we used the term ―endothelial progenitor cell(s).‖ Bibliographies of

all selected articles and review articles were reviewed for other relevant articles. Finally, the

supplements of major journals were hand searched to identify relevant abstracts that had not

been published as peer-reviewed articles. Where necessary, study authors were contacted to
obtain further data.




ENDOTHELIAL PROGENITOR CELLS: PATHOPHYSIOLOGICAL

CONSIDERATIONS—DEFINITION AND LINKS TO ANGIOGENESIS




Endothelial Markers




In 1997, Asahara et al. (1) first reported the isolation of endothelial precursor cells (EPCs)

from peripheral blood because they had found that CD34+ hematopoietic progenitor cells can

differentiate to cells with endothelial characteristics. The EPCs were defined as cells positive

for both hematopoietic stem cell and endothelial cell markers, such as CD34 and vascular

endothelial growth factor (VEGF) receptor-2, respectively. The latter VEGF receptor-2 is

often referred to as kinase insert domain receptor (KDR).




The putative CD34+ EPC is able to proliferate and differentiate to mature endothelial cells

with expression of different endothelial markers (Figure) such as KDR (2,3), platelet-

endothelial cell adhesion molecule (CD31) (2,4), von Willebrand factor (2,3,5), VE-cadherin

(2,3), caveolin-1 (4,6), and endothelial nitric oxide synthase (4,6). While in vitro, EPCs can

form vascular-like structures (3,6), and in vivo, incorporate into neovessels at sites of tissue
ischemia (3,5,7). Of note, CD34 antigen density is highest on early progenitors and decreases

progressively as cells mature (8); however, CD34 is expressed not only on EPCs but on

mature endothelial cells, albeit at a lower density (9). Therefore, an early hematopoietic stem

cells marker, CD133, was adopted as an alternative additional marker to indicate a ―true‖ EPC

(10,12).


FIGURE
Potential Origin and Differentiation of Endothelial Progenitor Cells




                                                        BONE MARROW




                                          Hematopoietic stem cells              Mesenchymal stem
                                          CD34+ CD133++ CD45+                    cells CD34- c-kit-   Side population
                                                                                                      cells


                                          Myeloid Precursors
                                              CD14+ CD45+                                             Tissue-resident
                                                                                                      stem cells
            “Early” EPCs                                                                              c-kit+
             CD34++ CD133++
             KDR+                                                        Macrophages
                                                      Monocytes          CD14+++ CD45+
                                                            ++       +
                     “More mature” EPCs               CD14       CD45
                              +   +   +
                      CD34 CD133 KDR



                       BLOOD VESSEL
                                                                 Mature EPCs
                                                                 CD133- CD34low
                                                                 KDR+ CD31+
                                                                 VE-Cadherin+
                                                                 vWF+
                                                        Are these cells the same?




The marker CD133 (also known as prominin or AC133) is a 120-kDa transmembrane

polypeptide with an (as yet) unknown biological function. It is expressed on hematopoietic

stem and progenitor cells from human bone marrow, fetal liver, and peripheral blood (11). As

progenitors develop to more mature endothelium-like cells, CD133 is rapidly downregulated
(10). The CD133+ cells are able to form both early and late outgrowing colonies in vitro (10).

Thus, CD133 might provide a more reliable means of defining and tracking human

angioblast-like EPCs and distinguishing these from mature endothelial or monocytic cells.

The combination of CD34, CD133, and KDR is commonly used for this purpose, and this

represents a rare subset of peripheral blood cells. Interestingly, the CD34−/133+

subpopulation of endothelial progenitors was recently found to be a possible precursor of

classic CD34+/133+ EPCs, but to possess even more potent angioregenerative properties in

vivo than on the latter (13).




Hematopoietic Markers


Hematopoietic     cell   markers   such   as   CD34,   CD133,    and   CD117     (c-kit)   and

monocytic/macrophagic cell markers such as CD11 and CD14 are expressed by early

immature EPCs, and are subsequently lost in the more differentiated state (10,11).

Paradoxically, expression of endothelial markers progressively increases with EPC maturation

(3). Subtypes of these cells that do not express VE-cadherin and von Willebrand factor seem

to be an early subpopulation of EPCs localized predominantly in the bone marrow or detected

immediately after their migration into the systemic circulation (14). More mature circulating

CD34-positive EPCs also present CD31, CD146, VE-cadherin, and endothelial nitric oxide

synthase, as well as begin to express von Willebrand factor (10,11). Thus, the surface marker

profile of EPCs seems to depend predominantly on their stage of differentiation (15). The

current most detailed phenotypic description of circulating EPCs proposes the co-expression

of several common hematopoietic and endothelial antigens: CD34, CD133, CD31, CD38,
CD45, KDR, VE-cadherin, c-kit, and Flt-1 (16).




Cultivation of peripheral blood mononuclear cells (MNCs) in medium favoring endothelial

growth is another approach widely used for definition and quantitative analysis of EPCs.

Adherent cells grow colonies and have been shown to possess endothelial characteristics, such

as expression of von Willebrand factor and staining for Dil-acetylated low-density lipoprotein

and Fluorescein isothiocyanate (FITC)-conjugated BS-lectin (17–20). Despite the relatively

low numbers of CD34+ of circulating endothelial precursors in peripheral blood (100 to

500/ml), relatively large numbers of adherent cells are found during culture (approximately

100,000 from 1 mL blood). This raises some controversy with respect to the identification and

the origin of isolated EPCs, as these cells seem to reflect a functional subpopulation within

the blood MNCs that have the potential to differentiate into an endothelial phenotype in vivo

(18,21–23,24).




There are at least 2 morphologically and functionally distinct endothelial cell populations can

be grown from circulating MNCs (2). The early spindle-like outgrowth cells possess a

relatively low proliferative capacity and low ability to express mature endothelial proteins (3).

These cells presumably represent cells of different lineage, which include a subset of

CD14+/CD34− monocytic cells, which have the potential to differentiate (transdifferentiate)

into endothelial-like cells under certain environmental condition in the presence of special

growth factors (e.g., VEGF, fibroblast growth factor, and so on) (22). Late ―outgrowth cells‖
show a high proliferative potential and originate predominantly from bone marrow donors and

are considered as circulating angioblasts (2).




It is important to appreciate that although monocyte-derived EPCs have a lower in vitro

proliferation potential than hematopoietic stem cells or cord-blood-derived EPCs (25), the

different progenitor types seem to have a similar ability to enhance neovascularization in

experimental models (3,26,27). One may speculate that proliferation capacity is not the

decisive factor and that the reduced proliferation of the monocyte-derived EPCs is likely to be

attributable to increased release of growth factors, which may act in a paracrine manner to

support angiogenesis and arteriogenesis (28).




The expression of common markers by hematopoietic and endothelial progenitor cells in

embryonic development and transdifferentiation potential of monocytes into cells with

endothelial characteristics would suggest a possible common origin from a bone marrow

precursor, perhaps a putative hemangioblast (29). Bone marrow also contains mesenchymal

cells, which have been shown to differentiate into endothelial cells (30), improve

vascularization in vivo (31,32), and contribute to tissue repair (33). Likewise, other bone-

marrow-derived EPCs mesenchymal stem cells release a variety of angiogenic growth factors

(34). In addition to bone-marrow-derived cells, other cell populations, such as fat tissue

(35,36), cardiac tissue (37), neural stem cells (38), and fetal liver cells (39), can give rise to

endothelial cells, suggesting that tissue-resident stem/progenitor cells can contribute to
vascular growth in the adult.




In summary, a universal single or complex EPC marker still remains to be identified, showing

the heterogeneous nature of endothelial precursors. As a result, both different surface markers

and culture properties have been used by research workers to define EPCs.




ANGIOGENIC CYTOKINES AND CHEMOKINES: THE LINK TO EPCs




EPCs have been linked to angiogenic cytokines and chemokines. For example, VEGF is one

of the key angiogenic factors involved in the earliest stages of vasculogenesis and

angiogenesis (40–42), and is the primary determinant of hemangioblast differentiation into

angioblasts (EPCs) and hematopoietic stem cells (43). Asahara et al. first showed the effects

of VEGF on adult endothelial progenitors, which included enhanced EPC mobilization from

bone marrow, proliferation, differentiation, and incorporation of bone-marrow-derived EPCs

into the neovasculature (44). This physiological pathway may be another target of

cardiovascular risk factors, such as oxidized low-density lipoprotein; the latter inhibits VEGF-

induced EPC differentiation (45). For patients with inoperable CAD (46) or critical limb

ischemia (47), VEGF gene transfer results in mobilization of EPCs, which could potentially

be involved in the success of such therapy (46). Interestingly, the dose of EPCs required to

obtain clinical improvement in murine hind limb ischemia reduced by as much as 30-fold
when VEGF gene transfer was simultaneously used (48). Furthermore, combination of VEGF

gene therapy with cytokine (granulocyte colony-stimulating factor [G-CSF] and stem cell

factor) administration led to enhanced neovascularization, bone marrow cell mobilization, and

incorporation into the neovasculature, as well as improvements in cardiac performance, at

least in animal models of cardiac ischemia (49).




However, intramyocardial injection of VEGF-A plasmid followed by G-CSF in patients with

severe chronic ischemic heart disease failed to induce angiogenesis, as well as to show any

improvement in cardiac perfusion or function (50). This might be explained partly by the low

VEGF-A165 plasmid dose chosen (probably for safety reasons) because no significant

increase in CD34+ cells was observed. In another rodent study, VEGF gene transfer was

associated with enhanced angiogenesis and mobilization of bone marrow cells and the

recruitment of cultured MNCs to the sites of neovascularization (51).




Both G-CSF and granulocyte-macrophage colony-stimulating factor, which are already

widely used clinically in oncology and in transplant donors, were considered attractive

candidates for stimulating arteriogenesis. Pre-clinical studies uniformly report positive results

of their infusion alone (52) or in combination with bone marrow MNC transplantation (53) or

cytokines to mobilize EPCs in different models of ischemia (54–56). However, 3 clinical

trials of G-CSF and granulocyte-macrophage colony-stimulating factor treatment to stimulate

neovasculogenesis were stopped early because of serious safety concerns (57–59). For
example, the MAGIC cell-randomized clinical trial of intracoronary administration of

peripheral blood leucocytes with subcutaneous infusion of G-CSF in patients after myocardial

infarction was stopped because of a high rate of in-stent restenosis despite good

periprocedural results and short-term safety (59). In the study by Zbinden et al. (57), an acute

occlusion of a coronary artery developed in 2 of 7 patients with stable angina undergoing

percutaneous coronary intervention within 12 days of treatment with granulocyte-macrophage

colony-stimulating factor. In the study by Hill et al. (58), G-CSF increased the number of

circulating CD34+/CD133+ progenitors in patients with severe CAD, but also increased C-

reactive protein levels and white cell counts. At 1 month after treatment, there was no

improvement in either cardiac contractility or exercise duration, and a trend toward a greater

number of ischemic segments was seen. Worryingly, 2 of 16 patients included in the study

experienced myocardial infarction, which was fatal in 1 patient.




Although in 1 study, treatment with G-CSF in patients with myocardial infarction subjected to

primary PCI stenting with abciximab not only mediated mobilization of CD34+ progenitors,

but significantly improved left ventricular function and geometry without signs of accelerated

restenosis or other serious complications (60), it was proposed to restrict ongoing trials using

G-CSF or granulocyte-macrophage colony-stimulating factor to patients with no other

therapeutic options, such as those with refractory angina or critical limb ischemia (61). The

mechanisms of the reported complications are unclear, but may relate to the proinflammatory

and procoagulant effects of G-CSF (62), possibly leading to vascular smooth muscle cell

proliferation. Indeed, recently G-CSF was shown to induce neointimal overgrowth in a rabbit
iliac artery balloon injury model after bare-metal stenting, possibly as a result of concomitant

mobilization of smooth muscle progenitors. Implantation of paclitaxel-eluting stents

substantially reduced neointimal overgrowth, probably by preferential inhibition of

proliferation of smooth muscle lineage cells rather than EPCs, and G-CSF treatment in this

group significantly accelerated endothelial recovery (63). A further clinical trial by

Zohlnhufer et al. (64) has failed to reignite interest in the potential of G-CSF to induce

neoangiogenesis. In this study, a cohort of patients with acute myocardial infarction

undergoing percutaneous coronary intervention within 12 h of symptom onset were

randomized to a 5-day course of G-CSF or placebo. The CD34 cell counts were quantified by

flow cytometry up to 1 week after randomization. Although CD34+ cells did increase in the

G-CSF group, there was notably no difference in infarct size as assessed by technetium

Tc99m sestamibi scintigraphy 4 to 6 months compared with baseline. Importantly though, the

previously noted excess of restenosis did not feature strongly in this study.




A positive impact on the EPC characteristics and potential proangiogenic properties has been

shown in the experimental studies for a number of cytokines/chemokines such as stromal cell-

derived factor-1-alpha (65), stem cell factor (55), hepatocyte grow factor (66), transforming

growth factor-beta1 (67), hemangiopoietin (68), and secretoneurin (69). For example, stromal

cell-derived factor-1alpha was shown to play an important role in the mobilization of

CD34+CXCR4+ progenitor cells during cardioplegia and cardiopulmonary bypass (70).

Members of the platelet-derived growth factor (PDGF) family are involved in vascular

physiology, and may be possible promoters of angiogenesis. Secreted by ECs, PDGF-BB
plays an important role in the maturation of blood vessels via recruiting mural cells (71), as

well as in the promotion of angiogenesis indirectly by producing VEGF (72). Also, PDGF-BB

was shown to induce differentiation of bone marrow EPCs into smooth muscle cells (73).

When administered alone, PDGF-BB reduces EC survival and causes destabilization of

vessels as a result of impaired mural cell coverage. Both PDGF-BB and PDGF-AB show

positive vascular effects only when coadministered with other cytokines or bone marrow cells

(73–75). Recently, Li et al. (76) showed multiple proangiogenic properties of PDGF-CC, a

novel member of PDGF family: mobilization, differentiation of EPCs and their homing to the

sites of ischemia, migration of mature endothelial cells and microvessel sprouting, and release

of VEGF. Moreover, PDGF-CC can induce differentiation of progenitors into endothelial

cells and smooth-muscle cells, which represent another essential component of blood vessels

(76). Given its multiple angiogenic actions, PDGF-CC is considered to be an attractive

candidate for combination therapy with other growth factors (77).




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