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Posts Tagged ‘Werner’


Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs

Author and Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 1/25/2018

The secret to building a strong heart lies in blood vessels, Stanford researcher find

Curiously, blood flow through those missing vessels – and the oxygen it provides – is only part of the story. In a follow-up experiment, the researchers grew heart muscles in a dish along with endothelial cells that had not yet formed into blood vessels. The team found that when those endothelial cells produced no Ino80, the heart muscle didn’t develop properly. Apparently, Red-Horse said, “endothelial cells are producing something that’s a growth factor” for cardiac muscle cells. “The next step is to identify that factor.”

https://news.stanford.edu/2018/01/25/secret-building-strong-heart-blood-vessels/

This is a post in Clinical Cardiology Frontiers:

  • Resident-Cell-based Therapy and
  • Molecular Cardiology

An Overview of the State of  Science on Circulating Endothelial Progenitor Cells (cEPCs) and Cardiovascular Outcomes: Exploring Pharmaco-therapy targeted at Endogenous augmentation of cEPCs

 

Werner (2005) reported that after 12 months a total of 43 participants died, 23 from cardiovascular(CV) causes. A first major cardiovascular event occurred in 214 patients in 519 patients with coronary artery disease as confirmed on angiography. Endothelial progenitor cells (EPCs) derived from bone marrow are believed to support the integrity of the vascular endothelium. His study identified that the number and function of endothelial progenitor cells correlate inversely with cardiovascular risk factors, but the prognostic value associated with circulating endothelial progenitor cells has not been defined. The level of circulating CD34+KDR+endothelial progenitor cells predicts the occurrence of cardiovascular events and death from cardiovascular causes and may help to identify patients at increased cardiovascular risk. The number of endothelial progenitor cells positive for CD34 and kinase insert domain receptor (KDR) was determined with the use of flow cytometry, they evaluated the association between baseline levels of endothelial progenitor cells and death from cardiovascular causes, the occurrence of a first major cardiovascular event (myocardial infarction, hospitalization, revascularization, or death from cardiovascular causes), revascularization, hospitalization, and death from all causes (italics added).

Werner (2005) reported that after 12 months a total of 43 participants died, 23 from cardiovascular(CV) causes. A first major cardiovascular event occurred in 214 patients in 519 patients with coronary artery disease as confirmed on angiography. Endothelial progenitor cells (EPCs) derived from bone marrow are believed to support the integrity of the vascular endothelium. His study identified that the number and function of endothelial progenitor cells correlate inversely with cardiovascular risk factors, but the prognostic value associated with circulating endothelial progenitor cells has not been defined. The level of circulating CD34+KDR+endothelial progenitor cells predicts the occurrence of cardiovascular events and death from cardiovascular causes and may help to identify patients at increased cardiovascular risk. The number of endothelial progenitor cells positive for CD34 and kinase insert domain receptor (KDR) was determined with the use of flow cytometry, they evaluated the association between baseline levels of endothelial progenitor cells and death from cardiovascular causes, the occurrence of a first major cardiovascular event (myocardial infarction, hospitalization, revascularization, or death from cardiovascular causes), revascularization, hospitalization, and death from all causes (italics added).

In light of the inverse correlation found between CV risk and enumeration and function of cEPCs, this study proposes a pharmaco-therapeutic method to enhance the cell count by a method of endogenous augmentation as presented in Part II and called ElectEagle.

 

Phenotypic Identification of Circulating Endothelial Progenitor Cells (cEPCs)

 

In the current state of science on cEPCs, the definition of these cells is ambiguous, as found in Fadini et al. (2004) letter to the Editors of Heart. On this subject, additional five letters were addressed to NEJM Editor in 2005, in reference to Werner et al. (2005) article Correspondence titled: Circulation Endothelial Progenitor Cells. Werner et al. (2005) was in fact the stimulant for this project which takes his result as a starting point and carries the research into pharmaco-therapy and device design for diagnostic based on a quantitative model derived from Werner’s data.

In the article in Heart, peripheral blood CD34+ cells are defined as endothelial progenitor cells. In Fadini’s concern he notes that cEPCs represent a subset of peripheral blood mononuclear cells (PBMNCs) expressing immature surface markers common to hematopoietic stem cells and endothelial lineage markers. By contrast CD34 represents a marker of immature staminal cells that may be used to characterize EPCs together with other surface antigens, but that identifies not only EPCs. Peripheral blood CD34+ cells form a very heterogeneous pool containing also CD45+ cells (lymphatic precursors), CD14+ cells (monocyte/macrophage lineage precursors) and other non-hematopoietic cells not belonging to the endothelial lineage.

Fadini’s concern is supported by George et al. (2006), who concluded that current methods for quantitatively assessing numbers of circulating EPC are not correlated. George’s findings may suggest that CD34/KDR is more appropriate for the definition of circulating EPC, whereas CFU (colony forming Unit) numbers are more likely to reflect their ability to proliferate. Fadini’s research supports the percentage of EPCs among the CD34+ pool vary widely from patient to patient and, in the same patient, under different pathophysiological conditions, indicating possible peripheral differentiation rather than bone-marrow mobilization. His observation is supported by Lapidot & Petit (2002) and Hur et al., (2004).

Furthermore, CD133 is considered the best surface marker to define, identify and isolate circulating EPCs. Even if the exact phenotype of EPCs has not been clearly established, additional markers reflecting endothelial commitment, including Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2 or KDR), Platelet-Endothelial Cells Adhesion Molecule-1 (PECAM-1 or CD31), Vascular Endothelial-Cadherin, von Willebrand Factor, c-kit, Tie-2 and VEGFR-1, are required. Using flow cytometry less than 0,001% of PBMNCs is identified as EPCs, but two or three markers are needed to avoid unspecific count. Thus minimal requirement to identify EPCs should be the parallel use of CD34 (or CD133) and KDR expression, as supported by George (2006).

Thus, he suggests that PBMNCs-derived CD34+ cells may not be used to identify EPCs. Fadini suggests that if we consider that EPCs or CD34+ cells stimulate angiogenesis in a paracrine way by means of producing growth factors, then, it would be more appropriate to call them “Circulating Angiogenic Cells” (CACs) as already proposed. EPCs reduction and endothelial dysfunction as observed by circulating cells and vascular wall cells of diabetic patients are exposed to high oxidative stress, thus increased apoptosis or reduced peripheral differentiation are likely to explain low EPCs counts. Several other clinical conditions characterized by poor endothelial function, like diabetes mellitus, obesity, hypertension, autoimmune disorders (such as Systemic Lupus Erythematosus), chronic renal diseases, etc., all are likely to be influenced by EPCs reduction (Fadini, 2004).

The five letters to NEJM Editor, Kim et al (2005) are of great scientific merit and of great interest to this project. We are developing new intellectual property (IP) in several forms in Part II and Part III. The IP in Part III is actually using Werner et al. (2005a) data, for our method called ElectEagle. Therefore, here, Werner’s (2005b) points will be considered as his reply to the five letter correspondence and no discussion of the content of the five letters is presented.

  •           Werner & Nickenig (2005b) disagree with Bertolini et al. that CD34+KDR+ cells are mature circulating endothelial cells. Endothelial cells are predominantly identified by the presence of CD146 (and results of Boos et al., as described in their letter).
  •           In Werner et al (2005a), CD146+ circulating endothelial cells were not predictive of cardiovascular outcomes, which indicates that CD34+KDR+ cells differ substantially from circulating endothelial cells (unpublished data). It is an accepted standard to identify circulating endothelial progenitor cells by the presence of CD34 and KDR.
  •           To confirm the results, Werner et al (2005a) measured CD133+ endothelial progenitor cells and obtained similar results, which appear in the online Supplementary Appendix to our article.
  •           Drs. Ott and Taylor suggest calculating the absolute number of endothelial progenitor cells with the use of peripheral-blood mononuclear cells or lymphocytes. However, absolute cell counts measured by flow cytometry can be determined only with the use of enumeration systems (e.g., flow count beads).
  •           At present, we cannot think of a major advantage to measuring the absolute number of endothelial progenitor cells. The method provided allows a single measurement that is easy to perform, highly predictive, and transferable to other laboratories.
  •           Dr. Kim and Dr. Leu and colleagues address  the role of endothelial progenitor cells in acute coronary syndromes and acute myocardial infarction. Only one study has investigated the mobilization of CD34+KDR+ endothelial progenitor cells in myocardial infarction, whereas other studies have measured CD34+ cells or non–endothelial progenitor cell subfractions.
  •           None of the studies have systematically looked at the time course directly after acute myocardial infarction, owing to the fact that the exact onset of myocardial infarction is difficult to determine. Treatment of myocardial infarction requires the administration of multiple drugs that may influence the number of endothelial progenitor cells. Therefore, current data on progenitor cells in myocardial infarction are questionable.
  •           In order to elucidate the mobilization of endothelial progenitor cells after myocardial infarction, Werner et al (2005a) measured the number of CD34+KDR+ cells in patients undergoing transcoronary ablation of septal hypertrophy (unpublished data). Preliminary results indicate that directly after myocardial infarction, the number of endothelial progenitor cells decreases as a result of consumption of cells within the ischemic region. The increase in cells described previously may be due to medical treatment.
  •           No patient who was included in the study had had a recent ischemic event, so misclassification of patients was not an issue.
  •           Werner et al. (2005a) did not find an association between high sensitivity CRP measures and the number of endothelial progenitor cells. To their knowledge, there are no data available on the association between endothelial progenitor cells and inflammatory markers in a similar population of patients. Data that are available come from in vitro, animal, and small-scale studies investigating the role of endothelial progenitor cells in acute coronary syndromes. Since their study population consisted mainly of patients with stable coronary artery disease, this may explain the lack of an association.

Circulating Endothelial Cells (cECs) and Circulating Endothelial Progenitor Cells (cEPCs)

Vascular endothelial cells (EC) respond to numerous pathophysiological stimuli such as growth factors, cytokines, lipoproteins, and oxidative stress. Prolonged or unregulated activation of these cells often results in a loss of EC integrity and, thus, dysfunction—a process that can be assessed by the use of specific plasma markers such as von Willebrand factor (vWf), tissue plasminogen activator, soluble EC protein C receptor, soluble E selectin, and soluble thrombomodulin, as well as physiological techniques such as flow-mediated dilatation (FMD). Indeed, endothelial perturbation in cancer may well contribute to an increased risk of thrombosis in these patients. (Goon et al., 2006)

The presence of circulating endothelial cells (cECs) has recently been recognized as a useful marker of vascular damage. Usually absent in the blood of healthy individuals, cECs counts are elevated in diseases hallmarked by the presence of vascular insult, such as sickle cell anemia, acute myocardial infarction, Cytomegalovirus (CMV) infection, endotoxemia, and neoplastic processes. Current opinion suggests toxemia, that cECs are cells driven from the intima after vascular insult, and are thus the consequence—rather than the initiator—of a particular pathology (Goon et al., 2006).

A related circulating cell population are endothelial progenitor cells (cEPCs), which originate from the bone marrow, rather than from vessel walls. Seen in small numbers in healthy individuals, their numbers tend to increase following vascular injury. So far, experiments have established the ability of EPCs to form colonies in vitro, suggesting a role in both angio-genesis and in the, maintenance of existing vessel walls.

CEC are generally accepted as cells expressing endothelial markers [e.g., vWf, CD146, and vascular endothelial cadherin (VE-cadherin)] in the absence of hematopoietic (CD45 and CD14) and progenitor (CD133) markers. Interestingly, the progenitor marker CD34 is also present on mature cECs. Although CD146 is widely regarded as the principal marker for cECs (mature cell form), it has also been described in trophoblasts, mesenchymal stem cells, periodontal and malignant (prostatic cancer and melanoma) tissues, and activated lymphocytes (Goon et al., 2006).

Optimal Method for cECs and cEPCs Quantification (Cell Count) Remains Unknown

Together with EPCs, cECs only represent between 0.01% and 0.0001% of mononuclear cells in normal peripheral blood (Khan et al. (2005), making it very difficult to accurately quantify their numbers. To do this, it is often necessary to employ cell enrichment techniques combined with specific cell marker labeling.  The immunobead capture method (immunomagnetic beads bearing CD146 antibodies) developed by George et al. (1992) is the most widely used. Immunobeads have been successfully employed by other investigators, albeit with modifications [e.g., addition of EDTA and albumin to minimize cECs autoaggregation; drying cECs on a glass slide before counting (this enables storage at room temperature and secondary labeling); use of UEA-1 (an EC-specific stain); addition of an Fc receptor blocking agent, and double labeling for further analyses (e.g., for CD31 and CD34)]. After cell separation, either fluorescence microscopy, immunocyto-chemistry, or flow cytometry is used to confirm the endothelial chemistry, phenotype of the cells. Other methods used to concentrate mononuclear cell suspensions include standard and density (Lymphoprep, Axis-Shield, Oslo, Norway; Percoll, Sigma, St. Louis, MO; Ficoll, Sigma) centrifugation and mononuclear cell culturing on fibronectin-coated plates. The main alter- alternative to the immunobead method is flow cytometry” (Goon, 2006).

Werner et al. (2005a) used the following method for Flow Cytometry — For fluorescence-activated cell-sorting analysis, mononuclear cells were resuspended in 100 µl of a fluorescence-activated cell-sorting buffer containing phosphate-buffered saline, 0.1 percent bovine albumin, and aprotinin (20 µl per milliliter). Immunofluorescent cell staining was performed with the use of the fluorescent conjugated antibody CD34–fluorescein isothiocyanate (FITC) (10 µl; Becton Dickinson), KDR (kinase insert domain receptor), and CD133–phycoerythrin (PE) (10 µl; Miltenyi). For the identification of KDR+ cells, indirect immunolabeling was performed with the use of a biotinylated goat mononuclear antibody against the extracellular domain of human KDR (R&D Systems). IgG2a–FITC–PE antibody (Becton Dickinson) served as a negative control. For staining of KDR, extensive blocking was required with the use of human immunoglobulin (polyglobulin, 10 percent; Bayer) and goat serum (Sigma-Aldrich). Cell fluorescence was measured immediately after staining, and data were analyzed with the use of CellQuest software (FACS Calibur, Becton Dickinson). Units of all measured components are absolute cell counts obtained after the measurement of 10,000 events in the lymphocyte gate. To assess the reproducibility of the measurements, two separate blood samples were obtained, on days 0 and 7, from 10 subjects. The intraclass correlation between the two probes was 0.94. Probes were measured at the same time of day, with identical instrument settings, by two investigators. For each patient, a corresponding negative control with IgG2a–FITC–PE antibody was obtained.

Colony-Forming Units of Endothelial Cells (Werner et al. 2005a)

In an endothelial basal medium (CellSystems) with supplements, 1×107 mononuclear cells were seeded on human fibronectin–coated plates (Sigma-Aldrich). After 48 hours, 1×106 nonadherent cells were transferred into new fibronectin-coated wells to avoid contamination with mature endothelial cells and nonprogenitor cells.22 After seven days in vitro, endothelial colony-forming units in at least three wells were counted by two independent investigators. Colony-forming units of endothelial cells are expressed as absolute numbers of colonies per well. (Werner, et al. 2005)

George et al. (2006) reports using the following method while performing an analysis of several methods used for cEPCs assessment and correlated them with humoral factors known to influence their numbers:

Peripheral blood mononuclear cells were obtained and stained for FACS analysis with antibodies to CD34, CD45, CD133, and KDR and the remaining cells grown under endothelial cell conditions for assessment of colony-forming unit (CFU) numbers and adhesive properties. Levels of circulating vascular endothelial growth factor (VEGF), erythropoietin (EPO), and C-reactive protein (CRP) were determined and correlated with each of the EPC markers.

Pathophysiology of cECs

The endothelium can be viewed as a membrane-like layer lining the circulatory system, its primary function being the maintenance of vessel wall permeability and integrity. The EC layer is relatively quiescent, with an estimated cell turnover period of between 47 and 23,000 days, as shown by labeling studies. Proliferation seems to occur mainly at sites of vasculature branching and turbulent flow. cECs are thought to have ‘‘sloughed off’’ vessel walls, indicating severe endothelial damage. Thus, unsurprisingly, cECs have been shown to correlate with various endothelial dysfunction and inflammatory markers.

Although not fully understood, it would appear that cECs detachment from the endothelium involves multiple factors, such as mechanical injury, alteration of endothelial cellular adhesion molecules (such as integrin alphaVbeta3), defective binding to anchoring matrix proteins (such as fibronectin, laminin, or type IV collagen), and cellular apoptosis with decreased survival of cytoskeletal proteins. The net effect is a reduced interaction between the EC and basement membrane proteins, with subsequent cellular detachment (Goon et al. 2006).

 

Pathophysiology of cEPCs

In Science 1997, Asahara et al. was the first to isolate EPC in human peripheral blood, using anti-CD34 monoclonal antibodies. With the use of CD133, an antigen specifically identifying primitive stem cells, a novel means to precisely delineate mature (cECs) from immature (cEPCs) EC forms was possible (Asahara et al. 1997), although this antigen is only present in human EPCs and cannot be applied to mouse EPCs (Rafii et al. 2003). To detect cEPCs in peripheral blood, Flow Cytometry and culture have become the principal methods employed. Other markers used include vWf, VE-cadherin, vascular endothelial growth factor receptor-2 (VEGFR-KDR) and binding by lectins and acetylated low-density lipoproteins (Peichev et al. 2000, Rafii et al. 2003).

cEPCs are potentially crucial for neovascularization and may be recruited from the bone marrow after tissue ischemia, vascular insult, or tumor growth (Rafii et al. 2003). They possess the ability to migrate, colonize, proliferate, and, ultimately, differentiate into endothelial lineage cells. These cells have yet to acquire mature ECs characteristics while appearing to contribute to vascular homeostasis.

cEPCs have been isolated previously from human umbilical cord blood, adult bone marrow, human fetal liver cells, and cytokine-mobilized peripheral blood, and an increase in cEPCs follows in vivo administration of the angiogenic growth factor VEGF. When incubated with VEGF, fibroblast growth factor-2 (FGF-2), and insulin-like growth factor, CD133+ cells differentiated into mature-type adherent EC, expressing endothelial-specific cell markers (vWf and VE-VE cadherin) and abolishing CD133 expression (Goon, 2006). Generation of endothelial outgrowths that are positive for CD146, vWf (mature endothelial growth markers), and CD36 (a representative scavenger receptor marker as well as a microvascular marker) markers from circulating mononuclear cells (of donor genotype in bone marrow transplant patients), strongly suggests the viability and proliferative potential of cEPCs.

cEPCs recruitment and mobilization have been positively correlated with increased levels of angiogenic growth factors such as VEGF which induces the proliferation, differentiation, and chemotaxis of cEPCs, and is essential for hematopoiesis, angiogenesis, and, ultimately, survival.  cEPCs influence cells mainly by interactions with VEGFR-1 and VEGFR-2, both being receptors expressed on hematopoietic stem cells (HSC) and cEPCs. In another study, granulocyte colony-colony stimulating factor also increased the number of CD34 stimulating CD34+ cells, potentially stimulating neovascularization in areas of is- ischemic myocardium Other angiogenic growth factors stimulating cEPCs mobilization include angiopoietin-1, FGF, SDF-1, PlGF, and (in mice) macrophage colony-stimulating factor. After mobilization, cEPCs appear to “home in” and become incorporated into sites of vascular injury and ischemia, with evidence of improvement in the function and viability of tissue (e.g., after acute myocardial infarction) (Kocher et al. 2001).

Chemotactic agents responsible for this process include VEGF and SDF-1, but others may also be involved. In the clinical setting, moderate exercise of patients with stable coronary artery diseases leads to a significant increase in cEPCs (Laufs et al. 2004). Furthermore, cEPCs and HSC introduced into the circulation of acute and chronic cardiovascular disease patients through injection have shown vascular encouraging preliminary results, with evidence of improved cardiovascular function and tissue perfusion Tse et al. (2003); as of yet, there are no randomized control trial!

Recent reports suggest that cECs and cEPCs enumeration can be used to monitor antiangiogenesis drug therapy with some success. This exciting prospect needs to be fully corroborated in a clinical setting. In addition, cECs and cEPCs monitoring would need to be efficient, specific, robust, and reproducible. Therefore, it is vital to reach a general consensus regarding definitions and techniques for cECs and cEPCs quantification, in order to validate further reports that have implications for future clinical trials involving these markers (Goon, 2006).

In 2002, matrix metalloproteinase-9 (MMP-9) was identified as the molecular key to the release of EPCs from the bone-marrow compartment via cleavage of membrane kit ligand (Heissig et al., 2002). MMP-9 activity has also been shown to be upregulated by SDF-1alpha, VEGF, and hypoxia. Hypoxia is a potent stimulus for neovascularization, ischemia-induced growth, EPC trafficking and upregulation, vascular malformations and malignant endothelial cell tumors. This include activation of two upstream mediators of vasculogenesis, SDF-1 alpha and MMP-9, during the proliferative phase via EPC mediated vasculogenesis when these stem cells may rapidly proliferate in the ischemic tissue resulting in growth.

How a mobilized population of progenitor cells homes to ischemic tissue under repair was examined using bone-marrow transplantation studies. Following this procedure, reconstitution is regulated by chemokine ligand-receptor pair, stromal-cell derived factor 1 (SDF-1) and CXCR4 (Lapidot & Petit, 2002 reporting their discovery of 1999). EPCs express CXCR4, CXCR4/SDF-1 signal for EPC homing to peripheral sites of neovascularization. EPC SDF-1alpha expression was increased in proportion to reduced oxygen tension and this correlated with EPC localization in the most ischemic tissue sections (Kleinman, et al. 2005).

Table 1: Humoral factors known to influence eCPCs numbers

CD34 CD45 CD133 KDR CD34/KDRMost appropriate Definition of cEPCs CD34/CD133/KDR CD34/CD133 Adhesive properpies
VEGF level corr Positive correlation
EPO
CRP
CFU Colony forming unit numbersReflects cEPCs ability to proliferate No corr No corr Negative correlation Positive correlation
Adhesive properties No corr No corr No corr No corr
CD34
CD45
CD133
KDR
CD34/CD133/KDR Positive correlation
CD34/CD133 No corr

 SOURCE:

Table 1 is constructed from data in George et al. (2005),(2006) who concluded that current methods for quantitatively assessing numbers of circulating EPC are not correlated. VEGF serum levels are associated only with CD34/KDR and CD34/ CD133/KDR, whereas CFU numbers correlate with EPC functional properties. These findings may suggest that CD34/KDR is more appropriate for the definition of circulating EPC, whereas CFU numbers are more likely to reflect their ability to proliferate.

 

Trans-Endothelium Cell Migration

Lapidot and Petit in a recent review of the stem cell mobilization research field concluded that the following are the seminal processes at work in the facilitation of transendothelium cell migration. These processes could mediate stem cell release and remodeling of the bone marrow microenvironment, followed by stem cell migration via the circulation, homing back to the bone marrow and repopulation of damaged/restructured sites in an organ as part of the continuous replenishment of the blood with new immature and maturing cells while maintaining undifferentiated stem cells (Lapidot and Petit, 2002).

  •       Regulation of hematopoietic stem cell release, migration, and homing to the bone marrow, as well as the mechanism of different mobilization pathways, involve a complex interplay between adhesion molecules, chemokines, cytokines, proteolytic enzymes, stromal cells, and hematopoietic cells, the mechanism is not fully understood;
  •       The chemokine, stromal derived factor-1 (SDF-1)and its receptor CXCR4 play a major role in stem cell mobilization, including granulocyte colony-stimulating factor (G-CSF) and G-CSF with the chemotherapeutic agents cyclophosphamide Cy-induced mobilization, as well as in stem cell homing to the bone marrow and anchorage (i.e., activation of adhesion interactions in order to retain stem cells within the organ).
  •       They suggested that in addition to SDF-1 degradation and inactivation within the bone marrow by proteolytic enzymes such as neutrophil elastase, which is essential for optimal stem cell mobilization, interactions between this chemokine and its receptor are also needed for stem cell release and mobilization. For example, they suggested that IL-8, which is secreted in response to SDF-1 stimulation, and MMP-2 and MMP-9, which are mostly secreted by neutrophils but are also secreted by immature human CD34+ progenitor cells in response to stimulation with this chemokine, can also lead to migration away from the bone marrow across the endothelium into the circulation also in the absence of or against a gradient of SDF-1 under shear flow forces within the extravascular space of the bone marrow (Cinamon et al., 2001).
  •        They suggest that in order to maintain stem cells in the circulation low levels of surface CXCR4 are required and may be achieved by factors in the blood plasma such as proteolytic enzymes that can also cleave CXCR4 in addition to SDF-1 . Valenzuela-Fernandez (2002). Furthermore, increase in the levels of CXCR4 expression on the surface of stem cells in the circulation will mediate their homing and reengraftment of the bone marrow as part of homeostatic regulation of leukocyte trafficking as well as steady-state hematopoiesis and stem cell self-renewal, which go hand in hand with bone destruction and bone remodeling. However, this hypothesis is also an oversimplification of a much more complex and dynamic situation with physiological steady-state homeostatic as well as stress-induced mobilization situations in which the mechanisms and mode of regulation are still poorly understood.
  •        A significant number of studies in the past few years have revealed insights into regulation of hematopoietic stem cell release, migration, and homing as well as the mechanism of different mobilization pathways. However, the exact sequence of events involving many different molecules is still not clear. More importantly, in addition to results from clinical mobilization protocols using Cy and G-CSF, which demonstrate a role for SDF-1 and CXCR4 interactions in immature human CD34+ cell mobilization, two recent reports also demonstrate a role for these interactions in autologous and allogenic CD34+ cell homing and repopulation.
  •        Taken together, these results suggest that stem cell homing and release or mobilization are mirror images utilizing a similar mechanism and suggest manipulation of SDF-1/CXCR4 interactions in order to improve stem cell mobilization or to target migration of transplanted cells to specific organs. These results strongly support the idea that increasing the migration potential of immature human CD34+ cells prior to transplantation, either by short term stimulation with SCF and IL-6 and/or by cotransplantation with accessory cells. It could also increase homing and repopulation in transplanted patients, leading to improved treatment efficiencies and cure rates in clinical protocols.

 

Prospects and Limitations of Exogenous methods for cEPCs Augmentation

ElectEagle represents a conceptual formulation for several strategies to increase cEPCs number endogenously.

Additional posts on this Scientific Web Site on related topics are:

Lev-Ari, A., (2012S). Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs

https://pharmaceuticalintelligence.com/2012/08/27/endothelial-dysfunction-diminished-availability-of-cepcs-increasing-cvd-risk-for-macrovascular-disease-therapeutic-potential-of-cepcs/

Lev-Ari, A., (2012T). Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs

https://pharmaceuticalintelligence.com/2012/08/24/vascular-medicine-and-biology-classification-of-fast-acting-therapy-for-patients-at-high-risk-for-macrovascular-events-macrovascular-disease-therapeutic-potential-of-cepcs/

Below, this method is contrasted with exogenous methods involving the cell-based vascular therapy approaches currently applied for angiogenesis (mature cell-derived generation of new vessels), vasculogenesis (EPC-dependent generation of new vessels), neovascularization (ischemic tissue) and re-endothelialization (injured blood vessel.)  The majority of these methods are exogenous involving implantation or transplantation of various kinds: genetically engineered vein grafts, vascular bioprosthesis, retroviral transduction of genetic modifications to over-express a therapeutic gene(s).Despite the hurdles quoted below, the outlook for EPC-based therapy for cardiovascular disease is promising.Among the remaining outstanding issues in this fast growing research discipline, Dzau et al., chart a perspective for future research directions (Dzau et al. 2005)

“Despite the encouraging results regarding the therapeutic potential of EPCs, several issues currently stand in the way of their wide clinical application. Strategies need to be developed to enhance the number of EPCs to allow the harvesting of adequate number for therapeutic application. The limited ability to expand PB-MNC–derived EPCs in culture to yield sufficient number for clinical application indicates that alternative sources of cells (i.e., chord blood) or strategies to increase their number endogenously need to be explored. We believe that further characterization of the biology of EPCs, the nature of the mobilizing, migratory and homing signals, and the mechanisms of differentiation and incorporation into the target tissues need to be identified and further characterized. Strategies to improve retention and survival of the transplanted cells need to be developed as well. The issues of the timing of cell administration, the appropriate clinical condition, the optimal cell number, and, most importantly, the safety of cell transplantation must be defined. There is urgent need to standardize the protocols for isolation, cultivation, and therapeutic application for cell-based therapy. Finally, large-scale randomized, controlled, multi-centric trials will be essential to evaluate the long-term safety and efficacy of EPC therapy for treatment of tissue ischemia and vessel repair amid concerns of potential side effects such as neovascularization of occult neoplasias and the development of age- and diabetes-related vasculopathies. Despite these hurdles, the outlook for EPC-based therapies for tissue ischemia and blood vessel repair appears promising. Genetic engineering of EPC may provide an important strategy to enhance EPC mobilization, survival, engraftment, and function, thereby rendering these cells efficient therapeutic modalities for cardiovascular diseases.” (italics added).

In the Brief Review in Hypertension, Dzau et al., list several serious potential problems with therapeutic use of EPCs (Dzau et al. 2005)

“Although the preclinical and clinical studies reviewed here generally lend support to the therapeutic potential of autologous EPCs in the treatment of tissue ischemia and repair of injured blood vessels, the clinical application of EPCs is limited by several factors. First, the scarcity of cEPCs makes it difficulty to expand sufficient number of cells for therapeutic application without incurring the risk of cell senescence and change in phenotype (Asahara, et al., 1997, 1999). Furthermore, EPCs from patients with cardiovascular diseases display varying degrees of functional impairment (Vasa et al., 2001a, 2001b), (Hill et al., 2003), (Heeschen et al., 2004), (George et al., 2003), (Loomans et al., 2004), (Tepper et al., 2002). Aging and diabetes markedly reduce the availability and impair the function of EPCs (Hill et al., 2003), (Loomans et al., 2004), (Tepper et al., 2002), (Schatteman et al., 2000), (Scheubel et al., 2003), (Edelberg et al., 2002). Because older and diabetic patients are the most vulnerable populations for cardiovascular diseases, this severely restricts the ability to treat with autologous EPCs the patients who theoretically need them most.

The purity and developmental stage of the cells used for transplantation are important factors. Yoon et al reported recently that injection of total bone marrow cells into the heart of infarcted rats could potentially lead to severe intramyocardial calcifications (Yoon et al., 2004). In contrast, animals receiving the same number of clonally expanded bone marrow cells did not show myocardial calcification. Thus, this finding brings attention to the potential risks of transplanting unselected bone marrow cells and cautions against their premature use in the clinical setting.

Exogenous mobilization of bone marrow with hematopoietic growth factors and other endothelial cell growth factors may recruit progenitor cells to sites of occult neoplasia, leading to vascularization of dormant tumors. In addition, mobilization could potentially accelerate progression of atherosclerotic plaque by recruiting inflammatory and vascular smooth muscle cell progenitor cells into the plaque, contributing to neointima hyperplasia and transplant arteriopathy (Caplice et al., 2003), (Sata et al., 2002). Increased rate of in-stent restenosis led recently to the cancellation of the MAGIC clinical trial using G-CSF for endogenous mobilization of progenitor cells in patients with myocardial infarction.120 Finally, there has been one study that has shown evidence that EPC may themselves contribute to allograft vasculopathy by promoting neovascularization of the plaque(Hu et al., 2003). However, another study failed to show evidence that EPCs contribute significantly to transplant arteriosclerosis (Hillebrands et al., 2003).”

In accordance with this account is the latest review of EPC as therapeutic vectors in CV disorders covering experimental models and human trials (Ben-Shoshan and George, 2006).

The conceptual formulation for several strategies to increase cEPCs number endogenously presented in this investigation is complementary to methods currently applied or are still in clinical trials, as reviewed by Dzau et al. (2005). However, our approach, ElectEagle, involves endogenous augmentation of cEPCs by development of a concept-based protocol for therapeutic treatment using three components:

  •                Inhibition of ET1, ETB
  •                Induction of NO production and stimulation of eNOS
  •                Treatment Regimen with PPAR-gamma agonists (TZD) 

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Endothelial Dysfunction, Diminished Availability of cEPCs,  Increasing  CVD Risk — Macrovascular Disease – Therapeutic Potential of cEPCs

Author and Investigator Initiated Study: Aviva Lev-Ari, PhD, RN

In normal conditions, the vascular endothelium produces and secretes substances that modulate vascular tone and protect the vessel wall from inflammatory cell infiltration, thrombus formation, and vascular smooth muscle cell proliferation (Rubanyi, 1993). Pathologic conditions such as hyperlipidemia, hyperglycemia, and hypertension impair the ability of the vascular endothelium to produce vasodilatory and anti-adhesion moieties and increase the production of vasoconstrictor, proadhesion, and pro-thrombotic molecules, leading to elevated vascular tone, enhanced cell adhesion, proliferation of media smooth muscle cells, and propensity toward thrombosis (Drexler & Hornig, 1999),(Endemann & Schiffrin, 2004). Endothelial cell loss and turnover are accelerated in the presence of hemodynamic and biochemical alterations and are a prominent feature of vascular injury resulting from percutaneous coronary intervention (Bennett & O’Sullivan, 2001).

The loss of endothelial function and integrity sets in motion the cascade of events that lead to atherosclerosis and restenosis after percutaneous revascularization (Ross, 1999),(Dzau et al., 2002). Processes of mobilization, growth, differentiation, recruitment, homing, replication and migration characterize cEPCs from the initial cell division of stem cells to cell apoptosis. What are the factors influencing cEPC mobilization, growth, differentiation, recruitment, mobilization, homing, replication and migration?

Physiological Factors

Chemokines

SCF-1, G-CSF, GM-CSF

Effect on cEPCs: recruitment, mobilization (Takahashi et al., 1999), (Kong et al., 2004a), (Kocher et al. 2001), (Shi et al., 1998), (Cho et al., 2003),(Orlic et al., 2001),(Bhattacharya et al., 2000), (Shi et al, 2002)

SDF-1

Effect on cEPCs: recruitment, mobilization, homing (Yamaguchi et al., 2003),(Powell et al., 2005),(Askari et al., 2003), (Hiasa et al., 2004),(George et al., 2003),(George et al., 2004),(Massa et al., 2005)

Cytokines / Growth Factors

FGF, VEGF, PIGF

Effect on cEPCs: mobilization, differentiation (Kalka et al., 2000a),(Ashara et al., 1997),(Kalka et al., 2000b)

                                  Angiopoietin, PDGF

Effect on cEPCs: differentiation

Hormones

Erythropoietin

Effect on cEPCs: mobilization, replication (Heeschen et al., 2003), (George, et. al., 2005).

Estrogen

Effect on cEPCs: mobilization (Strehlow et al., 2003), (Imanishi et al., 2005)

Signaling molecules

NO, Akt

Effect on cEPCs: mobilization, differentiation(Aicher et al., 2003).

 

Pharmacological Factors

3-HMC-CoA Inhibitors (statins)

Effect on cEPCs: mobilization, migration, homing (Werner et al., 2003),(Vasa et al., 2001a),(Walter et al., 2002),(Dimmeler et al., 2001),

(Llevadot et al., 2001),(Spyridopoulos et al., 2004)

             PPAR-gamma Agonists

Effect on cEPCs: mobilization, differentiation (Verma & Szmitko, 2006), (Andrew et al., 2004)

Physical Factors

 

            Exercise, hypoxia

Effect on cEPCs: mobilization (Laufs et al., 2003),(Kleinman et al., 2005),(Goon et al., 2006)

Pathological Factors

Coronary artery disease (CAD)

Effect on cEPCs: mobilization, homing (Kalka et al., 2000a),(Vasa et al., 2001b),(Heeschen et al., 2004)

Acute MI

Effect on cEPCs: mobilization, homing (Shintani et al., 2001),(Valgimigli et al., 2004),(Massa et al., 2005)

Peripheral limb ischemia

Effect on cEPCs: mobilization, homing (Takahashi et al., 1999),(Iwaguro et al., 2002),(Asahara et al., 1997),(Kalka et al., 2000b)

Vascular injury and inflammation

Effect on cEPCs: mobilization, homing (Ross, 1999),( Losordo et al., 2003), (Dimmeler & Zeiher, 2004),(Werner et al., 2003),(Verna et al, 2004).

EPC transplantation has been shown to induce new vessel formation in ischemic myocardium and hind limb (Kalka et al., 2000c),(Kawamoto et al, 2001),(Kocher, 2001) and to accelerate re-endothelialization of injured vessels and prosthetic vascular grafts in humans and in various animal models (Kocher, 2001),(Griese et al., 2003) demonstrating their therapeutic potential as a cell-based strategy for rescue and repair of ischemic tissues and injured blood vessels. Furthermore, EPCs are amenable to genetic manipulation, underscoring their usefulness as vectors for local delivery of therapeutic genes (Griese et al., 2003),(Kong et al., 2004b), (Iwaguro, 2002)

   Clinical Frontiers and Therapeutic Applications of cEPCs

  • Angiogenesis
  • Neovascularization of Artherosclerotic Plaque
  • Risk Factors impairing Collateral Development
  • Inhibitory Effects of Hypercholesterolemia
  • Bone Marrow Cells: Supporting cells in vascular growth processes
  • Inverse Relations: cEPCs and Risk of Macrovascular Events
  • New Stenting Technology:

 

  1.    Stents eluting Nitric Oxide (Verma and Marsden, 2005)
  2.    Stents coated with antiboby specific (anti-CD34) to the EPCs antigen cell     (Chadwick, 2006),(Aoki et al., 2005)
  3.    EPC-covered intravascular stents deployed for prevention of stent  thrombosis and restenosis as well as for rapid  formation of normal tissue architecture (Shirota et al., 2003).

 

  1. Table 1:            Alterations in number and function of cEPCs Disease Characterization and Suitability for ElectEagle an Endogenous Augmentation Method for cEPCs number (not for cEPCs function)

Disease Type

(Dzau et al., 2005)

Number

of

 cEPCs

Function

of

cEPCs

References

Disease Suitability for Endogenous Augmentation of cEPCs
Myocardial
     CAD

down

 down

(Kalka et al., 2000a),(Shintani et al., 2001),(Vasa et al., 2000b),(Hill et al., 2003),(Heeschen et al., 2004)

yes

     CHF

down

down

(Valgimigli et al.,2004),(Massa et al., 2005)

yes

     Unstable angina

down

unknown

(George et al., 2004)

yes

     MI

up

down

(Massa et al., 2005)

No

Vascular
     Atherosclerosis

down

down

(Vasa et al., 2001b),(Heeschen, 2004)(Lusis, 2000)

yes

     Acute Vascular injury and inflammation

up

unknown

(Fuujiyama et al.,2003)(Werner et al., 2003),(Walter et al., 2002),(Strehlow et al., 2003),(Shi et al., 1998),(Gill et al., 2001),

(Chu et al., 2003)

No

     PeripheralLimb ischemia

up

unknown

(Takahashi et al.,1999),(Iwaguro et al., 2002),(Asahara et al., 1997),(Asahara et al., 1999),(Kalka et al., 2000b)(Segal at al., 2006)

No

     Transplantarteriopathy

down

unknown

(Simper at al., 2003)

Yes

     In-stentrestenosis

down

unknown

(George et al., 2003)

yes

     Hypertension

unknown

unknown

No

     Hyperlipidemia

down

down

(Rauscher et al., 2003)

yes

Diabetes

down

down

(Loomans et al.,2004),(Tepper et al., 2002)

yes

Renal Failure
     Hemodialysis

down

down

(Choi et al., 2004)

yes

Source: original table created by Lev-Ari, A.

Based on Table 1, above, Lev-Ari, A. concluded that four Cardiovascualr diseases are NOT candidates for cEPCs therapeutic treatment

List of Disease unsuitable for ElectEagle an Endogenous Augmentation Method for  cEPCs includes:

  • Myocardial infarction
  • Acute Vascular injury and inflammation
  • Peripheral Limb ischemia
  • Hypertension

Table 2:           Therapeutic Angiogenesis Effects achieved by Cell-Based Therapy: Donor, Human; Recipient, Autologous;

Diagnosis, Myocardial Infarction

 

Therapeutic

Effect

Measured

Effect

Method of Delivery

Type and

Source of Cells

References

EjectionFruction

Up

(Stamm et al.,2003)

(Assmus et al., 2002),

(Britten et al., 2003),

(Schachinger et al., 2004),

(Wollert et al., 2004)

(Fernandez-Aviles

et al., 2004),

(Kang et al., 2004)

 

Infarct border

(Stamm et al., 2003)

CD133

(Stamm et al., 2003),

 

BM

(Stamm et al., 2003)

(Stamm et al., 2003)

Collateral flow (SPECT)

Up

(Stamm et al., 2003)

Infarct size

Down

(Strauer et al., 2002)

Intracoronary Balloon

Catheter

(Strauer et al., 2002)

BM

(Strauer et al., 2002)

(Strauer et al., 2002)

Wall motion

Up

(Strauer et al., 2002)

Contractility

Up

(Assmus et al., 2002),

(Britten et al., 2003),

(Schachinger et al., 2004),

(Wollert et al., 2004)

Intracoronary Balloon

Catheter

(Assmus et al., 2002),

(Britten et al., 2003),

(Schachinger et al., 2004),

(Wollert et al., 2004)

BM

PB

MNC

(Assmus et al., 2002),

(Britten et al., 2003),

(Schachinger et al., 2004),

(Wollert et al., 2004)

(Assmus et al., 2002),(Britten et al., 2003),(Schachinger et al., 2004),

(Wollert et al., 2004)

Myocardial perfusion

Up

(Assmus et al., 2002),

(Britten et al., 2003),

(Schachinger et al., 2004),

(Wollert et al., 2004)

Remodeling

Down

(Assmus et al., 2002),

(Britten et al., 2003),

(Schachinger et al., 2004),

(Wollert et al., 2004)

LV wall thickness

Up

(Fernandez-Aviles et al., 2004)

Intracoronary w/PCA

(Fernandez-Aviles et al., 2004)

CD34+

CD117+

AC133+

(Fernandez-Aviles et al., 2004)

End-systolic (ESV) volume

Down

(Fernandez-Aviles et al., 2004)

Exercise time

Up

(Kang et al., 2004)

Intracoronary

G-CSF

CD34+

(Kang et al., 2004)

 

Table 3:          

Therapeutic Angiogenesis Effects achieved by Cell-Based Therapy: Donor, Human; Recipient, Autologous;

Diagnosis, Myocardial Ischemia – Unstable Ischemia

 

Therapeutic

Effect

Measured

Effect

Method of Delivery

Type and

Source of Cells

References

Ejection Fruction

Up

(Perin et al., 2003),

(Tse et al., 2003)

Transendocardial with NOGA mapping

MNCs

(Perin et al., 2003),

(Tse et al., 2003)

BM

(Perin et al., 2003),

(Tse et al., 2003)

(Perin et al., 2003),

(Tse et al., 2003)

Anginal episodes

Down

(Perin et al., 2003),

(Tse et al., 2003)

Wall thickening

Up

(Perin et al., 2003),

(Tse et al., 2003)

Wall motion

Up

(Perin et al., 2003),

(Tse et al., 2003)

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