Huang et al., Autacoids 2011, S3 Autacoids 10.4172/2161 … · 2017. 8. 17. · Autacoids ISSN:2161-0479 Autacoids, an open access journal Review Article Open Access Autacoids Huang

ISSN:2161-0479 Autacoids, an open access journal Autacoids

Open AccessReview Article

AutacoidsHuang et al., Autacoids 2011, S3DOI: 10.4172/2161-0479.S3-001

Cardiac Cell Transplantation & Endothelial Dysfunction

Keywords: Stem cells; Progenitor cells; Angiogenesis; Endothelialcells; Ischemic Heart disease

IntroductionMore than 3 decades ago, Furchgott and Zawadski first reported

that the endothelium acted as not only a physical barrier between the blood and the interstitial space, but also an endocrine organ capable of releasing multiple substances [1]. Since that discovery, the importance of the endothelium in ischemic heart disease has been increasingly reported. Myriad molecules secreted by endothelial cells have been shown to participate in regulating vascular tone, platelet activity, the endogenous thrombolytic system, vascular inflammation, cell migration, and proliferation [2]. Endothelial dysfunction was first described in human hypertension in 1990 [3], where it was characterized by an altered balance in the release of relaxing and contracting factors; reduced production of endothelium-derived Nitric oxide (NO) and increased production of thromboxane A2, prostaglandin H2, and superoxide anion. This altered functional state leads to reduced endothelial-dependent vasodilatation and increased vasoconstrictor responses. When such an imbalance in endothelial function occurs, the dysfunction can become an important basis underlying the pathophysiological processes observed in numerous cardiovascular and endocrine/metabolic diseases.

Ischemic heart disease, often associated with sudden cardiac arrest, is the leading cause of mortality and morbidity worldwide [4]. In 2010, cardiovascular disease accounted for 34% of all deaths with an associated cost of $503.2 billion [5]. Currently, clinical management of ischemic heart disease relies upon restoration of blood flow through surgical interventions such as coronary artery bypass graft (CABG) and percutaneous Tran’s luminal coronary angioplasty (PTCA), and on pharmacological therapeutics that, in most cases, only minimally lead to endothelial repair. Therefore, these treatments have but a modest influence on ischemic heart failure. Hence there is a need for therapeutic interventions that can accelerate the repair of dysfunctional endothelium in the ischemic myocardium, promote the formation of collateral circulation, and provide sufficient oxygen to

the ischemic tissue, leading to improved heart function. A promising novel therapeutic option is the replacement of damaged endothelial cells. Endothelial dysfunction has been suggested to be an independent predictor of adverse cardiovascular event outcomes [6], emphasizing the important physiological role of this single layer of cells. In ischemic heart disease treatment, direct replacement of the damaged endothelial cells by stem/progenitor cells could allow re-endothelialization, as well as neo vascularization of ischemic tissues.

Development of the coronary circulation - origins of endothelial cells

During the heart’s development, the primordial heart assembles first as a tube that subsequently differentiates into a complex organ with four chambers each with muscular walls of varying thickness. As diffusion of respiratory gases, nutrients, and metabolites is limited to a few hundred microns, a dedicated coronary vascular system is essential if the heart tissue is to remain viable. The process of coronary vessel formation is highly regulated and can be divided into the following overlapping steps. The first, known as vasculogenesis, involves the de novo formation of vessels; this is followed by angiogenesis, the continued postnatal expansion during which extensive remodeling of primitive vascular clusters leads to the formation of the mature coronary circulation. Coronary vasculogenesis involves a mesenchymal process

*Corresponding author: Yigang Wang, MD, PhD, Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267-0529, Tel: 513-558-5798; Fax: 513-558-0807; E-mail: [email protected]

Received November 24, 2011; Accepted January 09, 2012; Published January 12, 2012

Citation: Huang W, Millard RW, Wang Y (2011) Stem Cell Therapy for Endothelial Dysfunction in the Coronary Circulation. Autacoids 1:101. doi:10.4172/2161-0479.S3-001

Copyright: © 2011 Huang W, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

AbstractThe endothelium is increasingly recognized as serving a critical role in maintaining circulatory homeostasis.

Endothelial dysfunction is evidenced as an attenuation or exaggeration of the normal dynamic vasomotor range. Circulating endothelial progenitor cells (EPCs) are responsible for the endothelial replenishment. When EPC recruitment is insufficient after endothelial injury, endothelial pathophysiological ensues. Impaired endothelial function is associated with myriad cardiovascular diseases including coronary artery disease, atherosclerosis, hypertension, chronic heart failure, peripheral artery disease, diabetes, and chronic renal failure. Therefore, correction of endothelial dysfunction presents a therapeutic opportunity that, if met, could reduce adverse cardiovascular events. EPCs play an important role in maintaining endothelial function and might affect the progression of ischemic heart disease. The mechanisms underlying the salutary effect of EPCs involve EPC-mediated paracrine effects, EPC differentiation into endothelial cells, and promoting the repair of damaged endothelium. The implementation of EPCs is emerging as a new promising cell-based therapy for restoration of angiogenic activity in cardiovascular disease, which might be particularly beneficial. The goal of this article is to review and critically evaluate the relevant literature describing putative role of EPCs in the treatment of ischemic heart disease, especially that of the coronary arterial system, that is rooted in endothelial dysfunction.

Stem Cell Therapy for Endothelial Dysfunction in the Coronary CirculationWei Huang1, Ronald W. Millard2 and Yigang Wang1*1Department of Pathology and Laboratory Medicine2Department of Pharmacology & Cell Biophysics, Cardiovascular Center of Excellence, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267, USA

Citation: Huang W, Millard RW, Wang Y (2011) Stem Cell Therapy for Endothelial Dysfunction in the Coronary Circulation. Autacoids S1:001. doi:10.4172/2161-0479.S3-001

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ISSN:2161-0479 Autacoids, an open access journal Autacoids Cardiac Cell Transplantation & Endothelial Dysfunction

that eventually connects formed tubes in myocardium to the aortic root [7]. It is widely accepted that development of the epicardium is highly associated with the development of the coronary vascular system. Most studies in heart development have demonstrated that pro-epicardial cells undergo an epithelial-to-mesenchymal transition (EMT) to generate the migratory epicardium derived cells (EPDCs), which can give rise to coronary smooth muscle cells (SMCs), pericytes, fibroblasts and cardiomyocytes [7,8]. Although studies have demonstrated the important role of EPDCs in endothelial progenitor cell differentiation, the explicit origin of coronary endothelial cells is disputed [9-11]. Bone marrow (BM) derived cells, spleen-derived mononuclear cells, cord blood derived mononuclear cells, fat tissue derived stem cells, adventitial stem cells, and skeletal muscle progenitor cells all contribute to the pool of endothelial cell lineage [12]. Regardless of their origin, EPCs migrate over and into the developing heart where they assemble into the ECs that form primitive vascular clusters.

Endothelial function and dysfunction in coronary artery disease

Endothelial function and myocardial remodeling are tightly linked, assuring appropriate dilatation of coronary vasculature is crucial during elevated myocardial metabolic demand conditions [13]. Endothelium-derived nitric oxide (NO), a vasodilator, is recognized as important for regulation of myocardial perfusion with oxygen [13,14]. Products of myocardial metabolism, especially adenosine, serve important roles in blood supply to tissue demand matching [13]. Nor epinephrine, released from cardiac adrenergic nerves, acts on beta-2 adrenergic receptors on coronary vascular smooth muscle to coordinate coronary vascular resistance inversely to myocardial metabolic demand [14]. In addition to mediating vascular tone, molecules secreted by vascular endothelium participate in the development of atherosclerosis though regulation of platelet activity, the endogenous thrombolytic system, vascular inflammation, cell migration and proliferation [2]. Under increased stress, the myocardium responds by activating multiple integrative mechanisms to limit cellular injury and to repair the damaged tissues. In response to ischemia, hypoxia inducible factor-1 (HIF-1) promotes secretion of multiple pro-angiogenic growth factors, including VEGF, FLK-1, FGF-1, FGF-2 and TGF-β [15,16]. These molecules are implicated in coronary vasculogenesis. However, this adaptive mechanism is insufficient to limit myocardial injury and typically does not provide sufficiently coordinated vasculogenesis to reduce the eventual infarct size [17]. Impaired endothelium-dependent coronary flow reserve (CFR), accompanied by insufficient myocardial perfusion, contributes to ischemic heart disease [18,19] and is suggested as an independent predictor of adverse cardiovascular events [6].

Assessment of coronary endothelial dysfunction

Better characterization of the condition known as endothelial dysfunction should provide more rational diagnostic and therapeutic interventions for patients with coronary artery disease. Usually, coronary flow reserve (CFR) and so-called fractional flow reserve (FFR) following brief coronary artery occlusion are used to assess endothelial function. The gold standard for the diagnosis of coronary endothelial dysfunction is coronary angiography, followed by pressure/flow assessment with a Doppler catheter in response to intracoronary acetylcholine [vasodilatation (viable endothelium)/vasoconstrictor (endothelial dysfunction) challenge test], and CRF or FFR testing in response to intracoronary adenosine of following brief coronary artery occlusion (smooth muscle vasodilatation evaluation) [20]. Additionally, biomarkers of endothelial dysfunction expressed in plasma, such as

ICAM-1, VCAM-1, and E-selectin, LOX-1, CD-40 ligand, CRP and ADMA, have been proposed [21].

During the past several decades, in vivo noninvasive diagnostic techniques have become increasingly popular, as discoveries of mechanisms underlying endothelial dysfunction in the laboratory have been translated to studies in patients. Cardiac magnetic resonance imaging (CMRI), a promising new technology without use of radiation, can be used to measure global and regional myocardial function, the ischemic region size, and scar tissue. Myriad parameters can be acquired in one imaging session [22]. Several other noninvasive techniques like positron emission tomography (PET) [23], myocardial perfusion scintigraphy-single photon emission computed tomography (SPECT) [24] and 2D Doppler echocardiography [25] using echo-contrast agents also can be used to assess coronary endothelial dysfunction.

Established drug therapy to mitigate endothelial dysfunction

Although the mechanisms underlying coronary endothelial dysfunction are often multi-faceted, treatment strategies are principally targeted at ameliorating an underlying pathology such as atherosclerosis or ischemia [26]. All pharmacological therapies are intended to restore or replace endothelial functions, reduce mortality and morbidity, and improve quality of life. As noted above, NO, released by endothelial cells, plays a crucial role in modulating myocardial perfusion by regulating the appropriate dilatation of proximal coronary vasculature in response to increases endothelial shear stress consequent to adenosine-mediated distal vasodilatation. Members of the “statin” drug class (HMG co-reductase inhibitors) have been shown to improve endothelial function by lipid-independent mechanisms, involving anti-inflammatory, antioxidant properties, and to independently restore vascular NO availability [27]. Through a different mechanism, aspirin, a non-selective cyclooxygenase inhibitor, can prevent platelet aggregation at dysfunctional endothelial loci. The therapeutic effects of other drugs like beta-blockers, or calcium channel blockers (CCBs) related to mitigating endothelial dysfunction is controversial. However, carvedilol, a newer generation of beta-blocker (an alpha-1 + beta-1 + beta-2 adrenergic receptor antagonist) can mitigate the adverse side effects, such as worsening of coronary spasm derived from beta-blockers alone [28].

Putative angiogenic growth factor therapy for ischemic heart disease

The hypoxic myocardial environments consequent to progressive coronary artery disease are the loci wherein angiogenesis can be expected to occur through the expression balance of pro-angiogenic and anti-angiogenic molecules. Therefore, to improve myocardial perfusion in coronary artery disease, pro-angiogenic growth factors as either delivered as purified protein or expressed through gene therapy have been tested [29,30]. The pro-angiogenic growth factors most commonly employed have been VEGF and FGF-2, heparin-binding endothelial cell mitogens. To date, the therapeutic value of FGF-2 and VEGF-2 remains controversial, despite a substantial number of clinical trials [31,32]. One of the major limitations of this pro-angiogenic therapy may be the lack of accompanying smooth muscle myogenesis. In addition to intrinsic hypoxia, shear stress, a more important extrinsic mediator is required for endothelium-mediated arteriogenesis. Without concomitant smooth muscle development, capillaries formed during vasculogenesis remain as endothelial tubes and decline with time even under shear stress conditions [8]. Other putative mediators or angiogenesis continue to be proposed. For example, caveolin-1, a contributor to eNOS mediated NO release during shear stress has


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been suggested as a putative therapeutic agent [33]. Additionally, the potential of thymosin β4 (Tβ4) to restore heart function after ischemia was first reported in 2004 [34]. Tβ4 was demonstrated to participate in coronary vasculogenesis, angiogenesis and arteriogenesis [35].

Endothelial progenitor cell-based therapy for endothelial dysfunction

Limited endothelial regeneration and impaired angiogenesis are involved in the progression of coronary artery disease and complications. Currently, the beneficial effects of pharmacological agents and growth factors on the pathogenesis of endothelial dysfunction are limited. However, a growing body of preclinical data suggests that a stem/progenitor cell-based approach may hold promise, as a treatment that can directly restore function to the endothelium and damaged tissue. Currently, there are seen to be two distinct categories of stem cells in animal models and humans: (1) embryonic stem cells; and (2) non-embryonic, “adult” or “somatic” stem/progenitor cells, which derive from any body tissue except for gametes. Several of these cell types have been shown to increase the functional recovery of the heart after ischemia by physically forming new blood vessels, or alternatively by providing pro-angiogenic and anti-apoptotic factors promoting tissue repair in a paracrine manner.

A promising new therapy for endothelial function is emerging from the discovery of EPCs. In the 1990’s, the discovery of circulating EPCs led to our current understanding of how bone marrow-derived cells contribute to physiological or pathological neovascularization [36,37]. A study performed by Fujiyama et al. [38] revealed that functional restoration of endothelium resulted from transplanted EPCs, which was confirmed by the release of NO, along with inhibited neointima deposition [38]. In addition to the role of mature ECs on neovascularization, Bruhl et al. revealed a relationship between the number of circulating EPCs and neovascularization in p21Cip1 (p21) knockout and heterozygous mice [39]. In heterozygous mice, the reduced p21 level speeds up cell cycle progression and proliferation, while inhibiting apoptosis in the mature EC and EPC pool, thereby leading to increased neovascularization. Also, EPCs can incorporate into the newly formed vessels as evidenced by the expression of an EC marker protein in vivo [40,41]. Circulating EPCs are comprised of two cell populations, hematopoietic EPCs and non-hematopoietic EPCs. Hematopoietic EPCs represent a pro-vasculogenic subpopulation of hematopoietic stem cells (HSCs) [42,43].

EPCs and HSCs can be identified and separated by different cell surface markers, including CD34, CD133, Flk-1/KDR, CXCR4, CD106 (Endoglin) in human samples and c-Kit, Sca-1, and CD34 together with Flk-1/VEGFR2 in mouse samples [44]. Different populations of progenitor cells express unique cell surface marker profiles that provide some insight into their capacity for angiogenesis. Because CD34 is not exclusively expressed on hematopoietic stem cells, CD133 can be better employed as an immature stem cell marker; higher vascular regeneration potential was demonstrated in CD133+/CD34- EPCs in comparison with CD133+/CD34+ EPCs [12]. Moreover, CD133+/VEGFR2+ cells are more like immature EPCs, whereas CD34+/VEGFR2+cells represent endothelial cells (ECs) [45]. The non-hematopoietic EPCs are not HSC-derived cells; the origin of these cells remains obscure.

In addition to direct restoration of endothelial function, the heterogeneous EPCs play an important role in maintaining circulatory homeostasis in the heart by release of multiple cytokines [46-48], including VEGF-A, VEGF-B, SDF-1, IGF-1, MMP-2, TIMP-1 and TIMP-2, thereby modulating angiogenesis, cardio myocyte apoptosis,

and fibrosis after ischemic events [46]. The effects of the angiogenic growth factors secreted by EPCs, which facilitate mature EC migration and improve angiogenesis in the ischemic tissues, can be attenuated by neutralizing antibodies to VEGF and SDF-1[46]. Furthermore, these factors were shown to have anti-apoptotic effects on cardiomyocytes through up-regulation of Bcl-2 [49].

Animal models of ischemic cardiovascular disease have been used to evaluate the therapeutic potential for induction of neovascularization by transplanted EPCs [50,51]. Cho et al. [52] demonstrated that direct intra myocardial delivery of human EPCs into mice not only promoted the secretion of various angiogenic and anti-apoptotic factors, such as VEGF-A, FGF-2, IGF-1, HGF, Ang-1 and SDF-1, but also promoted the secretion of host endogenous factors, which contributed to EPC-induced cardiac protection. Results of these pre-clinical studies have provided the foundation and rationale for clinical studies using autologous bone marrow-derived EPCs to restore heart function after ischemic vascular injury [53,54]. Furthermore, a strong correlation between cardiovascular risk factors and EPC number and function has been reported [6]. Regardless of whether the therapeutic effect on neovascularization in ischemic tissue is derived from the paracrine effect of transplanted EPCs or the response of the endogenous cells to the paracrine effect of EPCs, the beneficial effect of EPCs on impaired endothelial dysfunction and angiogenesis is clear. Thus transplanted EPCs have been shown to be effective, but before this therapy can reach the clinical mainstream, its safety must be confirmed. Xu et al. [55] reported a role of these cells in the development of atherosclerosis [55]. To this end, some putative vascular progenitor cells and pro-angiogenic cells [56] (e.g. cardio sphere-derived progenitor cells and heart-derived Lin-c-kit+ cells) have been employed in FDA-approved clinical trials.

Considering the limited proliferative and differentiation capacity of adult progenitor cells, technical improvement for intended efficacy should include (i) administration of specific growth factors or peptides to promote endogenous EPCs mobilization; (ii) intravenous delivery of EPCs; (iii) optimized in vitro expansion of EPCs derived from stem/progenitor cells.

Approaches to enhance EPCs migration and homing by selective growth factor expression

Although EPC number and function are known to be highly linked with cardiovascular risk factors, mechanisms underlying the decreased circulating EPCs in coronary artery disease remain unclear. Several reports have indicated that stoma-derived factor-1α (SDF-1α) and its G protein–coupled receptor CXCR4 are essential for promoting hematopoietic progenitor cell recruitment and angiogenesis [57,58]. Carr et al. [59] demonstrated that administration of SDF-1α could stimulate CXCR4 receptors expressed on EPCs and bone marrow stem cells (BMCs), and thereby act as a chemo tactic and pro-migratory factor. Our recent study reported that over expression of CXCR4 facilitated mobilization and engraftment of MSCs, leading to enhanced angiogenesis [60]. Other mobilizing factors, such as G-colony stimulating factor (GSF), VEGF and erythropoietin (Epo) were reported to enhance EPCs’ mobilization, proliferation and homing, which can activate the Akt protein signaling pathway and endothelial nitric oxide (eNOS) secretion [12]. In a phase I/II clinical trial, the salutary therapeutic angiogenic effects of GSF-mobilized CD34+ MSCs has been demonstrated in patients with intractable critical limb ischemia [61]. Moreover, the CXCR4 inhibitor AMD3100 is now FDA-approved to mobilize EPCs; an efficient therapeutic effect in human coronary artery disease (MI) has been proven [62].


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Differentiated ECs from stem/progenitor cells and their surface markers

One of the challenges to stem cell therapy is the limited supply of postnatal stem cell sources. Both ESCs and iPSCs have been used to generate unlimited numbers of genetically identical functional cells for therapy for ischemic disease, but using iPSCs for cell-based therapies and transplantation can obviate the ethical issues and potential for allogeneic immune responses to ESCs. Importantly, Yamanaka et al. have recently generated iPSCs derived from individual human Japanese subjects bearing 50 different haplo types, which are compatible with the immune system in 90% of the Japanese population [63], in a novel cell-based approach to the emerging field of personalized medicine. However, due to the high differentiation potential of ESCs and iPSCs, protocols must be developed so as to guide and refine the isolation and differentiation of ESCs or iPSCs before human transplantation of these cells.

Endothelial cell (EC) differentiation from stem/progenitor cells is a complicated process, governed by various molecular signaling pathways. In vitro, derivation of vascular cells can be triggered by a variety of conditions, including co-culturing with other cells lines as described below, or culturing in other defined conditions including specific mixtures of cytokines, genetic engineering, and manipulation of micro environmental conditions including the extracellular matrix (ECM) and the use of shear stress.

Currently, no standardized protocol exists for differentiating stem/progenitor cell derived endothelial cells. To increase the differentiation efficiency of spontaneous EB-differentiation from ESCs/iPSCs, techniques such as co-culture with mouse embryo fibroblasts [64], OP9 [65], S17 [65,66], MS-5 [65], and mouse ECs [66] prior to sub-culture have been performed. However, in such experiments, the positive ECs only accounted for 10% of the total cell population. Recently, other improvements on EB-based protocols have been reported including addition of VEGF-A [67], hypoxia induction [68] and TGF-β [69] signaling pathway suppression. Kane et al. [70] have successfully developed a direct EC differentiation method, which can generate functional ECs from human ESCs in a serum-free and feeder free manner. Animal models have demonstrated the therapeutic effect of these cells in vivo. Thus, this differentiation protocol can be potentially used for ischemic disease treatment in clinic.

The combination of multiple EC-specific markers and functional analysis selective for ECs is necessary for derivation and identification of stem/progenitor cell-derived ECs. Many bio-markers, such as Dil-labeled acetylated low density lipoprotein (Dil-Ac-LDL) uptake, CD31, VEGF-R1 or Flt-1, VEGF-R2 or Flk-1/KDR, VCAM-1/CD106, VE-cadherin/CD144, endothelial nitric oxide synthase (eNOS), vWF, Tie1, and Tie2, are functionally important for endothelial formation, maintenance and remodeling [63]. However, since VEGF-R2 is expressed in both iPSCs [66-71] and in ECs [72], it cannot be used to specifically identify ECs differentiation. We recently demonstrated that over expression CXCR4 [60] or NPY stimulation can increase differentiation of stem/progenitor cells into ECs [73].

Importantly, it has been demonstrated that EPCs can differentiate into VSMCs [74]. Vascular smooth muscle cells (VSMCs) are important for the maturation of vasculature; they cover the outside of the endothelium of the blood vessels, and maintain appropriate blood pressure and control blood flow. The genes/markers employed for functional VSMC differentiation like alpha- smooth muscle actin

(α-SMA), smooth muscle-myosin heavy chain (SM-MHC), smoothelia 22 have been recognized recently [63].

Mesenchymal stem cells (MSCs), which can be isolated from both adult and fetal tissues, are perhaps the most promising sources for therapy. These cells raise fewer ethical concerns than ESC, and are both relatively abundant and easy to prepare and expand for transplantation. MSCs, including heterogeneous cell subsets, exhibit multi-lineage differentiation potential [75-77] yet, controversy exists regarding their efficacy as a cell-based therapeutic platform. The clinical application of MSCs has raised concerns regarding their safety with respect to tumor formation and immune rejection. Nevertheless, preliminary results from the use of MSCs in clinical trials showed improved left ventricular function [78,79].

Cell delivery

The number and migration of circulating EPCs have been shown to be bio-reporters for endothelial dysfunction in cardiovascular disease [80]. It has been demonstrated that endothelial injury accompanied with insufficient circulating EPCs is associated with progression of cardiovascular sequelae. Several methods, including intravascular injection and direct tissue injection into the infarcted myocardial region, are used currently to deliver cell-based therapies. Stem/progenitor cell homing to infarcted region is limited by multiple factors, including long circulation time, coronary blood flow, intra venous and left ventricular blood flow. Therefore, determining the optimal, most efficient cell delivery method to injured coronary vasculature and myocardium is vital for the potential of regenerative medicine to be realized.

Intracoronary Application of Stem/Progenitor CellsNon-invasive intravenous delivery of stem/progenitor cells is an

attractive technology easily achieved in the clinic, where repeated administration of cell-based therapy can occur [81]. Intracoronary delivery of stem/progenitor cells has revealed a cardiac retention of a relatively small fraction (1.3% to 2.6%) of cells after administration of bone marrow cells (BMCs) [82]. BMCs contain several cell sub-populations including hematopoietic stem cells, mesenchymal stem cells, endothelial progenitor cells and other cell populations. Meta-analyses of several clinical trials has concluded that there is an absolute increase of 3% to 4% in the ejection fraction of the left ventricle after intracoronary infusion of autologous BMCs [83] however, this salutary effect is reduced when patients were re-evaluated at 12 months after cell administration [84].

Intra myocardial application of stem/progenitor cells

End-cardinal injection of stem/progenitor cells is used to deliver stem/progenitor cells to the myocardium [85]. Although this retrograde intra-arterial catheter technique is considered a safe and minimally invasive method for possible cell-based therapy of chronic ischemic heart disease [86], injections in unintended locations, unintended cell loss into the ventricular chamber and undesired ventricular arrhythmias of ventricular origin can occur during and after cell transplantation [87]. Intra myocardial stem/progenitor cell injection in combination with coronary artery bypass graft (CABG) surgery has been performed in a well-exposed ischemic area, which allowed for repeated injection within different sites in the peri-infarction border zone of the regionally infarcted left ventricle with a small gauge needle [88-90]. Recent reports reveal that this method appears to overcome some limitations of endo-cardinal intra myocardial injection and results in a high stem cell persistence, engraftment and re-vascularization [88-91].


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Tissue engineering for cardiovascular disease

A recent development in cell-based therapy is the incorporation of established principles and techniques used in diverse applications of tissue engineering. This merger offers the promise of functional tissue creation for therapeutic application in cardiovascular disease, offering approaches to increased stem/progenitor cell delivery efficiency through both increased numbers and survival of transplanted cells [92].

New vessel formation has been reported in Matrigel cell sheets seeded with a combination of human endothelial and umbilical cord blood-derived mesenchymal progenitor cells [93]. The addition of fibroblasts can effectively promote angiogenesis, improve survival of seeded cells, and subsequently result in heart functional restoration [94,95].

For coronary artery syndromes and disease, assuring that transplanted stem/progenitor cells survive in the ischemic microenvironment is challenging because of the severely compromised oxygen and nutrient supply. Porous collagen matrix seeded with EPCs and MSCs applied onto the epicardium after MI, has been reported to promote angiogenesis and increase cell survival [96]. In heart development, angiogenesis is intimately linked with myocardial growth and remodeling. Impaired angiogenesis, known to contribute to impaired coronary collateral vessel formation [97], is correlated with reduced left ventricular ejection fraction [17,98]. We recently have reported the development of strategies to engineer a vascularized cell sheet comparable to native myocardium [99] using a tri-cell culture, with growth factors, selective gene expression manipulations and novel pro-angiogenic scaffolds. Engineered 3-D neonatal cardio myocyte sheets containing pre-formed EC networks promoting capillary formation were associated with attenuated left ventricular remodeling [54]. In addition, the application of pre-vascularized cardiac tissue patches with modified iPSCs showed more myocardial-like passive mechanical properties and higher cell survival, and led to improvements in left ventricular mechanical performance [100]. To support the integration of transplanted cells into injured myocardium so that contractile performance of the heat would be improved, some new materials like PEG hydro gels [101], polymer nanofibers [102] or combinations of ECM and poly dimethylsiloxane (PDMS) films [103] have also been used.

Another reported method for engineering functional replacement tissue is achieved by seeding stem/progenitor cells on temperature sensitive dishes, which can release cell mono layers by alteration the hydrophobic/hydrophilic switch of the surface. Effective revascularization in the ischemic tissues has been confirmed using human smooth muscle cell (SMC) seeded temperature sensitive sheets [104].

Both peritoneum and omentum have been reported clinically to promote wound healing and to stimulate revascularization of ischemic tissues [105,106]. Six decades ago, O’ Shaughnessy was first to report cardio-omentopexy procedures in which pedicled omental grafts were used to provide a vascular supply for the epicardial surface of ischemic human hearts. Recently, we have successfully developed a tri-cell seeded peritoneal patch, which resulted in the functional development of collateral circulation from the cell patch to the native coronary arteries in association with enhancement in left ventricular function after MI [99]. Native biomaterials used as substrates are an attractive option when used in combination with stem/progenitor cells and have demonstrated such favorable and desired outcomes as improved cardiac contractility (via direct myogenesis or due to

paracrine effects from stem cells), enhanced tissue nutrition (via angiogenesis), and enhanced cell survival (via anti-apoptosis), which combine to reduce or reverse myocardial remodeling, limit infarct size and improve the heart’s mechanical performance. Furthermore, by combining genetic engineering with cell therapy, it may be possible to enhance the regenerative capacity of these stem/progenitor cells, which is particularly relevant in the context of adult autologous cell therapy, and to therefore provide additional benefits that may overcome many of the limitations of cell or gene therapy alone.

ConclusionsThe endothelium plays an essential role in maintaining circulatory

homeostasis by the release of factors that relax and contract vascular smooth muscle and assure appropriate blood flow to tissues, including the myocardium. Any change in the vasomotor regulatory balance may be characterized, at least in part, as endothelial dysfunction that leads to impaired control of vascular tone and may seminally participate in the pathogenesis of myriad cardiovascular diseases. This review summarizes evidence for endothelial dysfunction in cardiovascular diseases and overview relevant to the important role of EPCs in treatment of cardiovascular diseases especially in coronary artery disease. A better understanding of the mechanism(s) of endothelial dysfunction may expose new preventive strategies to reduce cardiovascular morbidity and mortality.

Despite the promise of such therapies, much work remains to be done before alternative treatments for endothelial dysfunction-related cardiovascular disorders will be widely available to patients. The challenge ahead lies in identifying specific unique mechanisms or more likely networks of articulated mechanisms that are responsible for tissue responses to various drugs and cell-based therapy. Although novel approaches directed at neovascularization and focused on ameliorating aspects of endothelial dysfunction are rapidly advancing, many challenging questions remain regarding the precise mechanisms involved in vascularization of the heart, including coronary vasculature origin, vascular cell fate, vessel growth, and maintenance. Future studies aimed at optimal technology for specific stem/progenitor cell applications, the best cell types, and improvements in cell delivery techniques are needed in order to develop clinically relevant approaches.

Acknowledgements

The authors wish to thank Christian Paul for technical assistance.

References

1. Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288: 373-376.

2. Quyyumi AA (1998) Endothelial function in health and disease: new insights into the genesis of cardiovascular disease. Am J Med 105: 32S-39S.

3. Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE (1990) Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 323: 22-27.

4. Klein L, Massie BM, Leimberger JD, O’Connor CM, Pina IL, et al. (2008) Admission or changes in renal function during hospitalization for worsening heart failure predict postdischarge survival: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF). Circ Heart Fail 1: 25-33.

5. WRITING GROUP MEMBERS, Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, et al. (2010) Heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation 121: e46-46e215.

6. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, et al. (2002) Prognostic value of coronary vascular endothelial dysfunction. Circulation 106: 653-658.


Page 6 of 8

Autacoids Cardiac Cell Transplantation & Endothelial Dysfunction ISSN:2161-0479 Autacoids, an open access journal

7. Smart N, Dube KN, Riley PR (2009) Coronary vessel development and insight towards neovascular therapy. Int J Exp Pathol 90: 262-283.

8. Red-Horse K, Ueno H, Weissman IL, Krasnow MA (2010) Coronary arteries form by developmental reprogramming of venous cells. Nature 464: 549-553.

9. Cai CL, Martin JC, Sun Y, Cui L, Wang L, et al. (2008) A myocardial lineage derives from Tbx18 epicardial cells. Nature 454: 104-108.

10. Zhou B, Ma Q, Rajagopal S, Wu SM, Domian I, et al. (2008) Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature 454: 109-113.

11. Davel AP, Wenceslau CF, Akamine EH, Xavier FE, Couto GK, et al. (2011) Endothelial dysfunction in cardiovascular and endocrine-metabolic diseases: an update. Braz J Med Biol Res 44: 920-932.

12. Capobianco S, Chennamaneni V, Mittal M, Zhang N, Zhang C (2010) Endothelial progenitor cells as factors in neovascularization and endothelial repair. World J Cardiol 2: 411-420.

13. Sodha NR, Boodhwani M, Clements RT, Feng J, Xu SH, et al. (2008) Coronary microvascular dysfunction in the setting of chronic ischemia is independent of arginase activity. Microvasc Res 75: 238-246.

14. Fisher SA (2010) Vascular smooth muscle phenotypic diversity and function. Physiol Genomics 42A: 169-187.

15. Li J, Brown LF, Hibberd MG, Grossman JD, Morgan JP, et al. (1996) VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis. Am J Physiol 270: H1803-1811.

16. Levy AP (1998) Hypoxic regulation of VEGF mRNA stability by RNA-binding proteins. Trends Cardiovasc Med 8: 246-250.

17. Olivetti G, Ricci R, Beghi C, Guideri G, Anversa P (1986) Response of the border zone to myocardial infarction in rats. Am J Pathol 125: 476-483.

18. Drexler H, Hornig B (1999) Endothelial dysfunction in human disease. J Mol Cell Cardiol 31: 51-60.

19. Hasdai D, Gibbons RJ, Holmes DR Jr, Higano ST, Lerman A (1997) Coronary endothelial dysfunction in humans is associated with myocardial perfusion defects. Circulation 96: 3390-3395.

20. Lanza GA, Crea F (2010) Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management. Circulation 121: 2317-2325.

21. Szmitko PE, Wang CH, Weisel RD, de Almeida JR, Anderson TJ, et al. (2003) New markers of inflammation and endothelial cell activation: Part I. Circulation 108: 1917-1923.

22. Kirschbaum SW, van Geuns RJ (2009) Cardiac magnetic resonance imaging to detect and evaluate ischemic heart disease. Hellenic J Cardiol 50: 119-126.

23. Nekolla SG, Reder S, Saraste A, Higuchi T, Dzewas G, et al. (2009) Evaluation of the novel myocardial perfusion positron-emission tomography tracer 18F-BMS-747158-02: comparison to 13N-ammonia and validation with microspheres in a pig model. Circulation 119: 2333-2342.

24. Nicol ED, Stirrup J, Reyes E, Roughton M, Padley SP, et al. (2008) Sixty-four-slice computed tomography coronary angiography compared with myocardial perfusion scintigraphy for the diagnosis of functionally significant coronary stenoses in patients with a low to intermediate likelihood of coronary artery disease. J Nucl Cardiol 15: 311-318.

25. Schachinger V, Britten MB, Zeiher AM (2000) Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101: 1899-1906.

26. Kothawade K, Bairey Merz CN (2011) Microvascular coronary dysfunction in women: pathophysiology, diagnosis, and management. Curr Probl Cardiol 36: 291-318.

27. Bonetti PO, Lerman LO, Lerman A (2003) Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 23: 168-175.

28. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, et al. (2007) ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and

the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 116: e148-304.

29. Morishita R, Aoki M, Kaneda Y, Ogihara T (2001) Gene therapy in vascular medicine: recent advances and future perspectives. Pharmacol Ther 91: 105-114.

30. Isner JM (2002) Myocardial gene therapy. Nature 415: 234-239.

31. Henry TD, Annex BH, McKendall GR, Azrin MA, Lopez JJ, et al. (2003) The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation 107: 1359-1365.

32. Simons M, Annex BH, Laham RJ, Kleiman N, Henry T, et al. (2002) Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation 105: 788-793.

33. Frank PG, Woodman SE, Park DS, Lisanti MP (2003) Caveolin, caveolae, and endothelial cell function. Arterioscler Thromb Vasc Biol 23: 1161-1168.

34. Bock-Marquette I, Saxena A, White MD, Dimaio JM, Srivastava D (2004) Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature 432: 466-472.

35. Smart N, Risebro CA, Melville AA, Moses K, Schwartz RJ, et al. (2007) Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization. Nature 445: 177-182.

36. Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, et al. (1999) Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85: 221-228.

37. Shi Q, Rafii S, Wu MH, Wijelath ES, Yu C, et al. (1998) Evidence for circulating bone marrow-derived endothelial cells. Blood 92: 362-367.

38. Fujiyama S, Amano K, Uehira K, Yoshida M, Nishiwaki Y, et al. (2003) Bone marrow monocyte lineage cells adhere on injured endothelium in a monocyte chemoattractant protein-1-dependent manner and accelerate reendothelialization as endothelial progenitor cells. Circ Res 93: 980-989.

39. BrÃ¼hl T, Heeschen C, Aicher A, Jadidi AS, Haendeler J, et al. (2004) p21Cip1 levels differentially regulate turnover of mature endothelial cells, endothelial progenitor cells, and in vivo neovascularization. Circ Res 94: 686-692.

40. Duong Van Huyen JP, Smadja DM, Bruneval P, Gaussem P, Dal-Cortivo L, et al. (2008) Bone marrow-derived mononuclear cell therapy induces distal angiogenesis after local injection in critical leg ischemia. Mod Pathol 21: 837-846.

41. Feygin J, Mansoor A, Eckman P, Swingen C, Zhang J (2007) Functional and bioenergetic modulations in the infarct border zone following autologous mesenchymal stem cell transplantation. Am J Physiol Heart Circ Physiol 293: H1772-1780.

42. Bailey AS, Jiang S, Afentoulis M, Baumann CI, Schroeder DA, et al. (2004) Transplanted adult hematopoietic stems cells differentiate into functional endothelial cells. Blood 103: 13-19.

43. Grant MB, May WS, Caballero S, Brown GA, Guthrie SM, et al. (2002) Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Nat Med 8: 607-612.

44. Timmermans F, Plum J, Yoder MC, Ingram DA, Vandekerckhove B, et al. (2009) Endothelial progenitor cells: identity defined? J Cell Mol Med 13: 87-8102.

45. Rafii S, Lyden D (2003) Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 9: 702-712.

46. Burchfield JS, Dimmeler S (2008) Role of paracrine factors in stem and progenitor cell mediated cardiac repair and tissue fibrosis. Fibrogenesis Tissue Repair 1: 4.

47. Narmoneva DA, Vukmirovic R, Davis ME, Kamm RD, Lee RT (2004) Endothelial cells promote cardiac myocyte survival and spatial reorganization: implications for cardiac regeneration. Circulation 110: 962-968.

48. Rubart M, Field LJ (2006) Cardiac regeneration: repopulating the heart. Annu Rev Physiol 68: 29-49.

49. Uemura R, Xu M, Ahmad N, Ashraf M (2006) Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res 98: 1414-1421.

http://dx.doi.org/10.4172/2161-0479.1000101

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Page 7 of 8

Autacoids Cardiac Cell Transplantation & Endothelial Dysfunction ISSN:2161-0479 Autacoids, an open access journal

50. Asahara T, Kawamoto A (2004) Endothelial progenitor cells for postnatal vasculogenesis. Am J Physiol Cell Physiol 287: C572-579.

51. Campagnolo P, Cesselli D, Al Haj Zen A, Beltrami AP, Krankel N, et al. (2010) Human adult vena saphena contains perivascular progenitor cells endowed with clonogenic and proangiogenic potential. Circulation 121: 1735-1745.

52. Cho HJ, Lee N, Lee JY, Choi YJ, Ii M, et al. (2007) Role of host tissues for sustained humoral effects after endothelial progenitor cell transplantation into the ischemic heart. J Exp Med 204: 3257-3269.

53. Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, et al. (2002) Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 106: 1913-1918.

54. Sekine H, Shimizu T, Hobo K, Sekiya S, Yang J, et al. (2008) Endothelial cell coculture within tissue-engineered cardiomyocyte sheets enhances neovascularization and improves cardiac function of ischemic hearts. Circulation 118: S145-152.

55. Xu Q (2006) The impact of progenitor cells in atherosclerosis. Nat Clin Pract Cardiovasc Med 3: 94-9101.

56. Kumar AH, Caplice NM (2010) Clinical potential of adult vascular progenitor cells. Arterioscler Thromb Vasc Biol 30: 1080-1087.

57. Lapidot T, Kollet O (2002) The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2m(null) mice. Leukemia 16: 1992-2003.

58. Pasha Z, Wang Y, Sheikh R, Zhang D, Zhao T, et al. (2008) Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium. Cardiovasc Res 77: 134-142.

59. Carr AN, Howard BW, Yang HT, Eby-Wilkens E, Loos P, et al. (2006) Efficacy of systemic administration of SDF-1 in a model of vascular insufficiency: support for an endothelium-dependent mechanism. Cardiovasc Res 69: 925-935.

60. Zhang D, Fan GC, Zhou X, Zhao T, Pasha Z, et al. (2008) Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium. J Mol Cell Cardiol 44: 281-292.

61. Losordo DW, Schatz RA, White CJ, Udelson JE, Veereshwarayya V, et al. (2007) Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation 115: 3165-3172.

62. Jujo K, Hamada H, Iwakura A, Thorne T, Sekiguchi H, et al. (2010) CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction. Proc Natl Acad Sci U S A 107: 11008-11013.

63. Kane NM, Xiao Q, Baker AH, Luo Z, Xu Q, et al. (2011) Pluripotent stem cell differentiation into vascular cells: a novel technology with promises for vascular re (generation). Pharmacol Ther 129: 29-49.

64. Zamora M, MAnner J, Ruiz-Lozano P (2007) Epicardium-derived progenitor cells require beta-catenin for coronary artery formation. Proc Natl Acad Sci U S A 104: 18109-18114.

65. Vodyanik MA, Bork JA, Thomson JA, Slukvin II (2005) Human embryonic stem cell-derived CD34+ cells: efficient production in the coculture with OP9 stromal cells and analysis of lymphohematopoietic potential. Blood 105: 617-626.

66. Kaufman DS, Hanson ET, Lewis RL, Auerbach R, Thomson JA (2001) Hematopoietic colony-forming cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A 98: 10716-10721.

67. Nourse MB, Halpin DE, Scatena M, Mortisen DJ, Tulloch NL, et al. (2010) VEGF induces differentiation of functional endothelium from human embryonic stem cells: implications for tissue engineering. Arterioscler Thromb Vasc Biol 30: 80-89.

68. Prado-Lopez S, Conesa A, Arminan A, Martanez-Losa M, Escobedo-Lucea C, et al. (2010) Hypoxia promotes efficient differentiation of human embryonic stem cells to functional endothelium. Stem Cells 28: 407-418.

69. James D, Nam HS, Seandel M, Nolan D, Janovitz T, et al. (2010) Expansion and maintenance of human embryonic stem cell-derived endothelial cells by TGFbeta inhibition is Id1 dependent. Nat Biotechnol 28: 161-166.

70. Kane NM, Meloni M, Spencer HL, Craig MA, Strehl R, et al. (2010) Derivation of endothelial cells from human embryonic stem cells by directed differentiation:

analysis of microRNA and angiogenesis in vitro and in vivo. Arterioscler Thromb Vasc Biol 30: 1389-1397.

71. Levenberg S, Golub JS, Amit M, Itskovitz-Eldor J, Langer R (2002) Endothelial cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A 99: 4391-4396.

72. Fruttiger M (2002) Development of the mouse retinal vasculature: angiogenesis versus vasculogenesis. Invest Ophthalmol Vis Sci 43: 522-527.

73. Wang Y, Zhang D, Ashraf M, Zhao T, Huang W, et al. (2010) Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction. Am J Physiol Heart Circ Physiol 298: H275-286.

74. Simper D, Stalboerger PG, Panetta CJ, Wang S, Caplice NM (2002) Smooth muscle progenitor cells in human blood. Circulation 106: 1199-1204.

75. Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, et al. (2001) Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 98: 2396-2402.

76. Dominici M, Paolucci P, Conte P, Horwitz EM (2009) Heterogeneity of multipotent mesenchymal stromal cells: from stromal cells to stem cells and vice versa. Transplantation 87: S36-S42.

77. Nauta AJ, Fibbe WE (2007) Immunomodulatory properties of mesenchymal stromal cells. Blood 110: 3499-3506.

78. Chen SL, Fang WW, Ye F, Liu YH, Qian J, et al. (2004) Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 94: 92-95.

79. Abdel-Latif A, Bolli R, Tleyjeh IM, Montori VM, Perin EC, et al. (2007) Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med 167: 989-997.

80. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, et al. (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348: 593-600.

81. Cheng Z, Ou L, Zhou X, Li F, Jia X, et al. (2008) Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance. Mol Ther 16: 571-579.

82. Hofmann M, Wollert KC, Meyer GP, Menke A, Arseniev L, et al. (2005) Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation 111: 2198-2202.

83. Martin-Rendon E, Brunskill SJ, Hyde CJ, Stanworth SJ, Mathur A, et al. (2008) Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review. Eur Heart J 29: 1807-1818.

84. Strauer BE, Ott G, Schannwell CM, Brehm M (2009) Bone marrow cells to improve ventricular function. Heart 95: 98-99.

85. Hermann PC, Huber SL, Herrler T, von Hesler C, Andrassy J, et al. (2008) Concentration of bone marrow total nucleated cells by a point-of-care device provides a high yield and preserves their functional activity. Cell Transplant 16: 1059-1069.

86. Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, et al. (2003) Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 107: 2294-2302.

87. Strauer BE, Steinhoff G (2011) 10 years of intracoronary and intramyocardial bone marrow stem cell therapy of the heart: from the methodological origin to clinical practice. J Am Coll Cardiol 58: 1095-1104.

88. Kaminski A, Steinhoff G (2008) Current status of intramyocardial bone marrow stem cell transplantation. Semin Thorac Cardiovasc Surg 20: 119-125.

89. Stamm C, Kleine HD, Choi YH, Dunkelmann S, Lauffs JA, et al. (2007) Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: safety and efficacy studies. J Thorac Cardiovasc Surg 133: 717-725.

90. Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, et al. (2003) Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 361: 45-46.

91. Klein HM, Ghodsizad A, Marktanner R, Poll L, Voelkel T, et al. (2007) Intramyocardial implantation of CD133+ stem cells improved cardiac function without bypass surgery. Heart Surg Forum 10: E66-E69.













































Page 8 of 8


92. Simpson D, Liu H, Fan TH, Nerem R, Dudley SC Jr (2007) A tissue engineering approach to progenitor cell delivery results in significant cell engraftment and improved myocardial remodeling. Stem Cells 25: 2350-2357.

93. Melero-Martin JM, De Obaldia ME, Kang SY, Khan ZA, Yuan L, et al. (2008) Engineering robust and functional vascular networks in vivo with human adult and cord blood-derived progenitor cells. Circ Res 103: 194-202.

94. Radisic M, Park H, Chen F, Salazar-Lazzaro JE, Wang Y, et al. (2006) Biomimetic approach to cardiac tissue engineering: oxygen carriers and channeled scaffolds. Tissue Eng 12: 2077-2091.

95. Radisic M, Park H, Martens TP, Salazar-Lazaro JE, Geng W, et al. (2008) Pre-treatment of synthetic elastomeric scaffolds by cardiac fibroblasts improves engineered heart tissue. J Biomed Mater Res A 86: 713-724.

96. Derval N, Barandon L, Dufourcq P, Leroux L, LamaziÃ¨re JM, et al. (2008) Epicardial deposition of endothelial progenitor and mesenchymal stem cells in a coated muscle patch after myocardial infarction in a murine model. Eur J Cardiothorac Surg 34: 248-254.

97. Martin A, Komada MR, Sane DC (2003) Abnormal angiogenesis in diabetes mellitus. Med Res Rev 23: 117-145.

98. Yoon CH, Koyanagi M, Iekushi K, Seeger F, Urbich C, et al. (2010) Mechanism of improved cardiac function after bone marrow mononuclear cell therapy: role of cardiovascular lineage commitment. Circulation 121: 2001-2011.

99. Dai B, Huang W, Xu M, Millard RW, Gao MH, et al. (2011) Reduced collagen

deposition in infarcted myocardium facilitates induced pluripotent stem cell engraftment and angiomyogenesis for improvement of left ventricular function. J Am Coll Cardiol 58: 2118-2127.

100. Stevens KR, Kreutziger KL, Dupras SK, Korte FS, Regnier M, et al. (2009) Physiological function and transplantation of scaffold-free and vascularized human cardiac muscle tissue. Proc Natl Acad Sci USA 106: 16568-16573.

101. Kim DH, Lipke EA, Kim P, Cheong R, Thompson S, et al. (2010) Nanoscale cues regulate the structure and function of macroscopic cardiac tissue constructs. Proc Natl Acad Sci USA 107: 565-570.

102. Badrossamay MR, McIlwee HA, Goss JA, Parker KK (2010) Nanofiber assembly by rotary jet-spinning. Nano Lett 10: 2257-2261.

103. Alford PW, Feinberg AW, Sheehy SP, Parker KK (2010) Biohybrid thin films for measuring contractility in engineered cardiovascular muscle. Biomaterials 31: 3613-3621.

104. Hobo K, Shimizu T, Sekine H, Shin’oka T, Okano T, et al. (2008) Therapeutic angiogenesis using tissue engineered human smooth muscle cell sheets. Arterioscler Thromb Vasc Biol 28: 637-643.

105. Taheri SA, Ashraf H, Merhige M, Miletich RS, Satchidanand S, et al. (2005) Myoangiogenesis after cell patch cardiomyoplasty and omentopexy in a patient with ischemic cardiomyopathy. Tex Heart Inst J 32: 598-601.

106. O’Leary DP (1999) Use of the greater omentum in colorectal surgery. Dis Colon Rectum 42: 533-539.

This article was originally published in a special issue, Cardiac Cell Transplantation & Endothelial Dysfunction handled by Editor(s). Dr.Wangde Dai, University of Southern California, USA. Dr. Roman Laszlo,UniversityofTubingen,Germany.









3http://www.ncbi.nlm.nih.gov/pubmed/22051336








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