Bone Marrow-derived Mononuclear Cells Research Articles

Abstract 4535: Therapeutic Angiogenesis by Mononuclear Cell Implantation for Critical Digit Ischemia of Patients with Connective Tissue Diseases

Systemic sclerosis (SSc or scleroderma) is an autoimmune connective tissue disease characterized by diffuse fibrosis, degenerative changes, and microvascular abnormalities. The vasculopathy mainly affects small arteries and capillaries and causes insufficient blood flow, which leads to clinical manifestations, such as Raynaud’s syndrome, fingertip ulcers, and gangrene. Recently, implantation of bone marrow-derived mononuclear cells (MNCs) has been successfully used for therapeutic neovascularization in Buerger’s disease that is thought to be an “autoimmune” vasculitis. The purpose of this study is to determine the efficacy of autologous MNC implantation into the ischemic digits of patients with connective tissue diseases. This study was performed as a prospective, non-randamized, and multicenter clinical trial. Thirty-four patients (19 SSc, 5 SLE, 2 CREST, 2 MCTD, 4 APS, 2 PN) who had painful ischemic digits with skin ulcers were enrolled in this study. Autologous MNCs obtained from bone marrow or peripheral blood were implanted into the ischemic digits. Ischemic pain and ulcers improved remarkably after MNC implantation. In particular, SSc patients showed dramatic improvement of these parameters (18 of 19 patients, 94.7%). In patients with other types of connective tissue diseases, pain and ulcers improved in 12 of 15 patients (80.0%). No serious adverse event was observed. These results demonstrate that implantation of autologous MNCs from bone marrow or peripheral blood into ischemic digits is feasible, safe and effective for improvement of pain and skin ulcers in patients with connective tissue diseases including SSc. Thus, larger, randomized and controlled trials for this cell therapy in patients with connective tissue diseases will be warranted.

Use of Ferumoxides for Stem Cell Labeling

Although numerous clinical trials have shown promising results with regards to the cardiac regenerative capacity of different types of stem cells, there remains virtually no evidence of the fate of stem cells in these human studies, primarily owing to safety concerns associated with the use of cell-labeling strategies. In this study, we utilized two cell types that are used extensively in cardiac regeneration studies, namely bone marrow-derived human mononuclear cells and C2C12 skeletal myoblasts. The US FDA-approved compounds feridex (ferumoxide) and protamine sulfate (as a transfection agent) were used in combination for cellular labeling. We assessed the effect of this cell labeling strategy on cellular viability, proliferation and differentiation both in vitro and in vivo. The ferumoxide-protamine sulfate combination had no effect on cellular viability, proliferation or differentiation. We show that the labeled human mononuclear cells were easily identified within the rat myocardium 1 month following injection into the myocardium. These human cells expressed human-specific cardiac troponin I, whereas the neighboring rat myocardium did not. Furthermore, we demonstrated that this labeling strategy can be used with high accuracy for magnetic separation of the labeled cells based on the intracellular ferumoxide particles. The ferumoxide-protamine sulfate combination can be used safely and effectively to enhance the detection and isolation of cardiogenic stem cell populations.

Therapeutic potential of stem cells in elderly patients with cardiovascular disease

The success of treatment for acute myocardial infarction and chronic myocardial ischemia has improved general medical care in Europe, resulting in an increasing population of patients with chronic and congestive heart failure. By applying currently available therapeutic options the quality of life and lifespan of these patients have both increased. However, amongst patients––predominantly the elderly––who remain symptomatic despite intensive medical treatment, autologous bone marrow-derived mononuclear cells may trigger attempts to repopulate lost tissues directly as a novel therapeutic option. In this concised paper the current understanding of stem cell therapy and early clinical experiences are discussed and related to the application of stem cells in elderly patients with myocardial ischemia.

Leptin and EPCs in Arterial Injury

See related article, pages 536–544 Endothelial progenitor cells (EPCs) were introduced to a broad scientific readership in 1997 by Asahara et al, who demonstrated that CD34+ cells from the peripheral blood can adopt an endothelial cell-like phenotype in vitro.1 This culture-modified cell type (subsequently also termed endothelial outgrowth cells) improved ischemic neovascularization after intravenous transfusion.2 The prospect of ameliorating tissue ischemia by ex vivo–expanded autologous angioblasts resulted in extensive research activities, including the therapeutic application in patients with myocardial ischemia.3 However, the results are still conflicting, which is at least partially attributable to the fact that EPCs comprise a heterogenous pool of subpopulations originating from distinct sources and displaying diverse phenotypes.4 For instance, the common characterization of EPCs as CD34+CD133+VEGF-R2+ by flow cytometry has been recently questioned in different studies showing that only CD133−CD45− cells differentiate into endothelial cells.5,6 Early outgrowth of endothelial-like cells from mononuclear cells cultured for 5 to 7 days in the presence of endothelial growth factors represent a monocyte-like subtype with low proliferative capacity secreting high …

Cell therapy--success does not come easy

More than 6 years ago the initial report on clinical application of bone marrow-derived mononuclear cells (BMMNCs) in patients with acute myocardial infarction (AMI) opened up a new era of regenerative cardiology and brought with it great enthusiasm and expectations.1 Since then, numerous clinical trials have been carried out with the aim of assessing the efficacy and safety of stem cell therapy. In all cases the safety of the therapy was proved, but its effectiveness still remains a matter of controversy and fierce debate.2 Since stem cell therapy trials in patients with AMI began, the primary outcome measure has been the change in left ventricular (LV) ejection fraction (EF). The LV volumes have also been analysed to assess more accurately the cause of the changes in LVEF after bone marrow cell (BMC) therapy.1,3–6 So far, the data on the effectiveness of BMC infusion in improving the global LV contractility remain equivocal. For example, the ASTAMI trial showed no improvement of LVEF and no reduction of end-diastolic volume in patients treated with intracoronary transfer of BMCs. In this trial, a significant improvement of LVEF was observed not only in patients treated with BMCs, but also in the control group.7 The BOOST trial showed an initial improvement in LVEF 6 months after BMC infusion, but the difference between the BMC arm and the control group was no longer significant at 18 months.8 On the other hand, REPAIR-AMI, so far the largest randomized placebo-controlled study, showed a significant … *Corresponding author. Tel: +48 32 353 9543, Fax: +48 32 353 9543, Email: michal.tendera{at}gmail.com or michal.tendera{at}gcm.pl

Cerebral and Peripheral Amyloid Phagocytes— an Old Liaison with a New Twist

In this month's issue of Nature Medicine, Town et al. suggest that peripheral macrophages invading the brain reduce cerebral amyloidosis and thus may play a key role in the pathogenesis of Alzheimer's disease (AD). This observation intensifies the longstanding controversy of whether mononuclear cells such as macrophages and/or microglial cells are beneficial or detrimental in AD.

Bone marrow-derived mononuclear cell therapy induces distal angiogenesis after local injection in critical leg ischemia

Critical leg ischemia is associated with a high risk of amputation when revascularization is not possible. Cell therapy based on bone marrow-derived mononuclear cells or with peripheral mononuclear cells, collected after stimulation with G-CSF has been used in an attempt to stimulate angiogenesis. Although several studies have raised the hope that such cell therapy may be effective in critical leg ischemia, no direct demonstration of angiogenesis induced by bone marrow-derived mononuclear cell/peripheral mononuclear cell injection has been reported in man. The aim of this study was to identify and to evaluate the extent of the angiogenic process associated with cell therapy in critical leg ischemia in man. To address this question, this pathological study was conducted in patients enrolled in the OPTIPEC clinical trial (Optimization of Progenitor Endothelial Cells in the Treatment of Critical leg ischemia), an interventional cell therapy study in critical leg ischemia. Amputation specimens from these patients were submitted to a standardized dissection protocol. In three patients, an active angiogenesis was observed in the distal part of the ischemic limb but not in the gastrocnemius muscle, the site of bone marrow cell injection. All the newly formed vessels were positive for endothelial cell markers (CD31, CD34, von Willebrand factor) and negative for markers of lymphatic vessels (podoplanin). Immunohistochemical staining for Ki-67 and c-kit showed extensive endothelial cell proliferation within the new vessels. Bone marrow-derived mononuclear cell therapy in patients with critical leg ischemia induces an active, substained angiogenesis in the ischemic and distal parts of the treated limb, although this may not prevent amputation in some patients with very severe ischemia.

Enhancing Efficacy of Stem Cell Transplantation to the Heart with a PEGylated Fibrin Biomatrix

Bone marrow-derived mononuclear cell (BMNC) transplantation provides the possibility of rescue or regeneration of myocardium lost during acute myocardial infarction (AMI). The extensive death of transplanted cells and the lack of sustained engraftment may limit its application. We investigated whether delivery of BMNCs by an injectable PEGylated fibrin biomatrix that covalently binds hepatocyte growth factor (HGF) would enhance the rate of cell engraftment and improve cardiac function. Balb/C female mice with AMI secondary to left anterior descending coronary ligation were randomly assigned to one of six groups: the Saline control group (n = 8) received a myocardial injection of saline (50 microL); the Cell group (n = 10) received a myocardial injection in the peri-infarct and infarct zones consisting of 500,000 murine BMNCs suspended in 50 microL saline; and the Biomatrix + HGF (n = 9) and Biomatrix + HGF + Cell (n = 9) group hearts received the HGF-loaded injectable biomatrix (identical volume) with or without entrapped BMNCs. Control groups consisting of the biomatrix alone (n = 9) and Biomatrix + Cells (n = 9) without HGF were also included for comparison. The left ventricular (LV) function was measured by echocardiography at days 14 and 28 post-MI. All animals were euthanized 4 weeks after AMI and transplantation for evaluation of angiogenesis, apoptosis, and fibrosis by immunohistochemistry. Cell prevalence rate at 4 weeks increased 15-fold in hearts receiving the Biomatrix + HGF + Cell delivery (p < 0.01), which was accompanied by the lowest levels of apoptosis and the highest LV function recovery among the treated groups.

Hypoxia Inducible Factor-1&amp;#945;, Endothelial Progenitor Cells, Monocytes,Cardiovascular Risk, Wound Healing, Cobalt and Hydralazine:A Unifying Hypothesis

Bone marrow-derived mononuclear cells differentiate into endothelial cells in adult animals, including humans. These cells, endothelial progenitor cells (EPCs), play central roles in neovascularization in a variety of physiological and pathological processes. EPCs numbers are clinically relevant; in patients with vascular disease, EPC numbers are predictive of hard clinical endpoints and correlate with vascular health in patients without manifest atherosclerosis. EPCs express CXCR4 which allows homing to sites of neovascularization. The homing signal released by the target tissues is SDF-1 which is the ligand for CXCR4. With release of SDF-1 and reversal of the marrow/periphery gradient, EPCs are mobilized to the periphery where they are recruited to SDF-1 expressing tissues. The SDF-1/CXCR4 axis is the final common pathway for EPC mobilization by hypoxia, angiogenic peptides and G-CSF. Expression of SDF-1 in target tissues and CXCR4 in EPCs as well as angiogenic cytokines such as VEGF are regulated by hypoxia inducible factor-1 alpha (HIF-1 alpha). This paper discusses evidence suggesting that depressed HIF-1 alpha-mediated gene programming is the most fundamental of all cardiovascular risk factors and discusses the manipulation of this system with existing drugs such as cobalt or hydralazine. By stabilizing HIF-1 alpha protein, these compounds will enhance EPC mobilization and function, thereby improving cardiovascular health overall. This paper discusses why previous studies with EPC transplantation or mobilization with G-CSF have had negative results and proposes the use of Cobalt and Hydralazine to enhance EPC function to overcome the dysfunctional EPC phenotype that is seen in patients with vascular disease or cardiovascular risk factors.

Effect of intramyocardial bone marrow cell injection on diastolic function in patients with chronic myocardial ischemia

To evaluate the effect of intramyocardial bone marrow cell injection on diastolic function in patients with chronic myocardial ischemia. In 24 patients (19 male; 65 +/- 9 years) with refractory angina (Canadian Cardiovascular Society [CCS] class III-IV) 84.6 +/- 28.7 x 10(6) bone marrow-derived mononuclear cells were injected intramyocardially (using the NOGA system) in regions with ischemia on Tc-99m tetrofosmin single photon emission computed tomography (SPECT). Diastolic function was evaluated at baseline and at three months using magnetic resonance imaging (MRI) and tissue Doppler imaging (TDI). MRI revealed an increased early (E) peak filling rate (374 +/- 121 mL/second vs. 412 +/- 102 mL/second; P = 0.04), whereas the atrial (A) peak filling rate remained unchanged (340 +/- 81 mL/second vs. 334 +/- 93 mL/second; P = not significant [NS]). The E/A peak flow ratio increased from 1.09 +/- 0.33 to 1.23 +/- 0.47 at three months (P = 0.02). TDI demonstrated a significant improvement in early diastolic velocity (E') from 4.4 +/- 1.7 cm/second to 4.8 +/- 1.6 cm/second at three months (P = 0.03), whereas the late diastolic velocity (A') remained unchanged (6.0 +/- 1.6 cm/second vs. 6.0 +/- 1.7 cm/second; P = NS). Consequently, the E'/A' ratio increased from 0.74 +/- 0.19 to 0.84 +/- 0.28 at three months (P = 0.02). Intramyocardial bone marrow cell injection in patients with chronic myocardial ischemia improved MRI and TDI-derived parameters of diastolic function.

Intracoronary Autologous Bone Marrow−Derived Mononuclear Cell Transplantation Improves Coronary Collateral Vessel Formation and Recruitment Capacity in Patients With Ischemic Cardiomyopathy: A Combined Hemodynamic and Scintigraphic Approach

This study investigated the effects of intracoronary autologous bone marrow-derived mononuclear cell (BMC) transplantation on coronary microcirculation. Fifteen patients with ischemic cardiomyopathy were treated by intracoronary infusion of BMCs via the patent infarct-related artery. The thermodilution-derived coronary flow reserve, index of microvascular resistance, pressure-derived collateral flow index, and coronary wedge pressure were measured at baseline and at 6 months. Successive balloon inflations during BMC transplantation were performed to observe the recruitment in pressure-derived collateral flow index and coronary wedge pressure, and the percentage changes between baseline and 6 months were calculated. The mean (SD) coronary flow reserve increased from 1.3 (0.4) to 2.1 (0.5), and the mean (SD) index of microvascular resistance decreased from 44.9 (24.4) to 21.2 (14.1) (P = .001 for both). The mean (SD) improvement in pressure-derived collateral flow index (from 0.14 [0.05] to 0.22 [0.08]) was also statistically significant (P = .001). Similarly, the percentage improvements in pressure-derived collateral flow index and coronary wedge pressure were statistically significant (P = .01 for both). The percentage improvement in perfusion assessed by single-photon emission computed tomography strongly correlated with the percentage changes in pressure-derived collateral flow index (r = 0.88, P = .001) and coronary wedge pressure (r = 0.69, P = .01). These results demonstrate for the first time (to our knowledge) that intracoronary autologous BMC transplantation improves coronary collateral vessel formation and recruitment capacity in human subjects.

Characteristics and Function of Cryopreserved Bone Marrow–Derived Endothelial Progenitor Cells

This study examined ex vivo expansion of bone marrow-derived endothelial progenitor cell (EPC) from cryopreserved bone marrow-derived mononuclear cells, and evaluated proliferation and migration function of the cryopreserved EPC (Cryo-EPC). Bone marrow samples were taken from swine iliac bone (n = 6). Isolated bone marrow-derived mononuclear cells were cultured or cryopreserved at -80 degrees C for 2 to 3 months. After cell culture for 4 days, attached cells, EPCs with or without cryopreservation, were collected. Direct fluorescent staining by acetylated low-density lipoprotein, isolectin B4, and 4',6-diamidino-2-phenylindole were performed to confirm the attached cells as EPC. Endothelial progenitor cell proliferation by vascular endothelial growth factor was evaluated by the tetrazolium method. Endothelial progenitor cell migration in response to stromal-derived factor-1alpha was also evaluated by using a Boyden chamber assay. The percentage of cells positively stained by direct fluorescent staining by acetylated low-density lipoprotein and isolectin B4 was similar between fresh and Cryo-EPC (EPC = 96.0 +/- 0.42 versus Cryo-EPC = 95.2 +/- 1.2; p = 0.21). Vascular endothelial growth factor increased proliferation activity in fresh and Cryo-EPC (p < 0.01). Stromal-derived factor-1alpha increased migration activity in fresh and Cryo-EPC (p < 0.01). There was no difference in proliferation and migration activity between fresh and Cryo-EPC. Ex vivo expansion by cell culture was a useful method for collection of bone marrow-derived EPC from cryopreserved mononuclear cells. Proliferation and migration function of EPC is preserved after cryopreservation.

Progenitor Cell Therapy in Patients With Critical Limb Ischemia Without Surgical Options

To provide a review on progenitor cell therapy for critical limb ischemia. Critical limb ischemia is estimated to develop in 500 to 1000 individuals per million persons per year and has a major impact on the quality of life. Despite recent advances in surgical and radiologic vascular procedures, a large number of patients ( approximately 40%) are not eligible for these revascularization procedures. New strategies for revascularization need to be explored. Recent evidence indicates that bone marrow-derived mononuclear cells are a potential new therapeutic target. A comprehensive review of all published literature on progenitor cell therapy in patients with critical limb ischemia was performed. Twenty-five clinical studies that reported on the use of mononuclear cells or progenitor cells for the treatment of patients with critical limb ischemia have been published, of which 18 were included in this review. Seven studies were published in Chinese, Japanese, or Polish and, therefore, not included. Pioneering clinical studies report promising results for progenitor cell-based therapies for chronic limb ischemia, but no definite proof is available because the clinical studies thus far have been small and lacked double-blinded controls. Larger, randomized, blinded, placebo-controlled trials to investigate the potential clinical effects of bone marrow progenitor cell administration in patients with critical limb ischemia are needed.

Adult bone marrow-derived mononuclear cells expressing chondroitinase AC transplanted into CNS injury sites promote local brain chondroitin sulphate degradation

Injury to the CNS of vertebrates leads to the formation of a glial scar and production of inhibitory molecules, including chondroitin sulphate proteoglycans. Various studies suggest that the sugar component of the proteoglycan is responsible for the inhibitory role of these compounds in axonal regeneration. By degrading chondroitin sulphate chains with specific enzymes, denominated chondroitinases, the inhibitory capacity of these proteoglycans is decreased. Chondroitinase administration involves frequent injections of the enzyme at the lesion site which constitutes a rather invasive method. We have produced a vector containing the gene for Flavobacterium heparinum chondroitinase AC for expression in adult bone marrow-derived cells which were then transplanted into an injury site in the CNS. The expression and secretion of active chondroitinase AC was observed in vitro using transfected Chinese hamster ovarian and gliosarcoma cells and in vivo by immunohistochemistry analysis which showed degraded chondroitin sulphate coinciding with the location of transfected bone marrow-derived cells. Immunolabelling of the axonal growth-associated protein GAP-43 was observed in vivo and coincided with the location of degraded chondroitin sulphate. We propose that bone marrow-derived mononuclear cells, transfected with our construct and transplanted into CNS, could be a potential tool for studying an alternative chondroitinase AC delivery method.

Angiotensin II accelerates osteoporosis by activating osteoclasts

Recent clinical studies suggest that several antihypertensive drugs, especially angiotensin-converting enzyme inhibitors, reduced bone fractures. To clarify the relationship between hypertension and osteoporosis, we focused on the role of angiotensin II (Ang II) on bone metabolism. In bone marrow-derived mononuclear cells, Ang II (1x10(-6) M) significantly increased tartrate-resistant acid phosphatase (TRAP) -positive multinuclear osteoclasts. Of importance, Ang II significantly induced the expression of receptor activator of NF-kappaB ligand (RANKL) in osteoblasts, leading to the activation of osteoclasts, whereas these effects were completely blocked by an Ang II type 1 receptor blockade (olmesartan) and mitogen-activated protein kinase kinase inhibitors. In a rat ovariectomy model of estrogen deficiency, administration of Ang II (200 ng/kg/min) accelerated the increase in TRAP activity, accompanied by a significant decrease in bone density and an increase in urinary deoxypyridinoline. In hypertensive rats, treatment with olmesartan attenuated the ovariectomy-induced decrease in bone density and increase in TRAP activity and urinary deoxypyridinoline. Furthermore, in wild-type mice ovariectomy with five-sixths nephrectomy decreased bone volume by microcomputed tomography, whereas these change was not detect in Ang II type 1a receptor-deficient mice. Overall, Ang II accelerates osteoporosis by activating osteoclasts via RANKL induction. Blockade of Ang II might become a novel therapeutic approach to prevent osteoporosis in hypertensive patients.

Autologous Bone Marrow-Derived Mononuclear Cell Therapy Prevents the Damage of Viable Myocardium and Improves Rat Heart Function Following Acute Anterior Myocardial Infarction

We examined the effects of bone marrow-derived mononuclear cells (BMDMNCs) on preventing viable myocardium damage from myocardial infarction (MI) in a rat MI model. Saline (group 1) or BMDMNCs (group 2) were implanted into the infarct area (IA) of 1-week-old anterior wall MI Sprague-Dawley (SD) rats. Twenty SD rats without MI served as the controls (group 3). The results demonstrated that in remote viable myocardium, the integrated area (microm2) of connexin43 spots was lower, whereas the number of apoptotic nuclei were higher in group 1 than in groups 2 and 3 on day 90 following BMDMNC implantation (all p<0.001). Additionally, the number of vessels and survival myocardium in the IA was lower in group 1 than in groups 2 and 3 (all p<0.005). Furthermore, the mRNA expressions of nitric oxide synthase, interleukin-8/Gro-alpha, interleukin-10 and matrix metalloproteinase-9 were higher in group 2 than in groups 1 and 3 in peri-IA (all p<0.05). On days 42 and 90, the left ventricular (LV) function was lower in group 1 than in groups 2 and 3 (p<0.001). Autologous BMDMNC therapy improves LV function, and mitigates molecular and cellular perturbation following MI.

Shock Wave Therapy Applied to Rat Bone Marrow-Derived Mononuclear Cells Enhances Formation of Cells Stained Positive for CD31 and Vascular Endothelial Growth Factor

This study tested the hypothesis that shock wave (SW) therapy applied to bone marrow-derived mononuclear cells (BMDMNCs) enhances the formation of vascular endothelial growth factor (VEGF) and positively stained CD31 (CD31+) cells, an endothelial phenotype. The BMDMNCs (approximately 1.2 x 10(6) cells/2 femoral bones) were obtained from adult male Sprague-Dawley rats and SW therapy was applied once to BMDMNCs in group I (140 SW: defined as 140 shots in total, given at 0.09 mJ/mm2), group II (280 SW), and group III (560 SW). Group IV was not treated by SW and served as the control group. Six experiments were done in each group. The BMDMNCs were cultured following SW therapy and the supernatants were collected on days 1, 3, 7 and 14 for assessment of VEGF levels. Immunocytochemical staining and flow cytometric measurement were performed on days 0 and 14. Experimental results demonstrated that VEGF levels were significantly higher in groups I-III than in group IV, and in group II than in group I at all intervals, and in group II than in group III on day 14 (all p values <0.005). Additionally, the number of positively stained VEGF cells on days 1, 3 and 14 and the number of newly formed CD31+ cells on day 14 were significantly higher in group II than in group IV (all p values <0.001). These data suggest that application of SW to BMDMNCs significantly enhanced VEGF production and promoted differentiation of BMDMNCs into endothelial phenotype cells.

Fat is not all bad: how to make good use of adipose tissue

Myocardial infarction (MI) continues to represent a major health problem. Improved healing and/or regeneration of infarcted myocardium by injection of progenitor cells has been proposed as a promising approach to prevent cardiac remodelling or even restore myocardial tissue. Several adult stem cell types have shown efficacy in the preclinical setting, including skeletal myoblasts, umbilical cord cells, bone marrow-derived mononuclear cells, and, more recently, adipose tissue-derived stem cells.1,2 Although the debate as to which cell type (or combinations thereof) is best suited for the treatment of acute MI continues, the mesenchymal stem cell (MSC)3 is particularly interesting. Thus, MSCs have been shown to be multipotent, to be capable of homing to infarcted myocardium, inducing angiogenesis and differentiating into myogenic cells, can be easily expanded ex vivo , and are possibly immune privileged.1–4 MSCs can be isolated from several organs, including bone marrow, umbilical cord blood, and adipose tissue, of which subcutaneous fat appears most easily and repeatedly accessible for high yield MSC isolation.2,5 Bone marrow-derived MSCs have already shown significant benefit in animal models of MI-induced left ventricular dysfunction.1 For example, in swine with MI produced by a 30 min coronary artery occlusion, allogenic bone marrow-derived MSCs injected into the coronary artery 3 days after reperfusion resulted in a reduction in infarct size and improvement of left ventricular function at 4 weeks follow-up.6 More recently, adipose tissue-derived MSCs have also shown potential in rodent studies. Thus, in models of permanent coronary artery ligation,7–9 MSC application (either as a grafted monolayer7 or via intramyocardial injection8,9), administered either immediately8 or 3–4 weeks after induction of MI,7,9 resulted in improved left ventricular geometry and function another 4–8 weeks later. Although these … *Corresponding author. Tel: +31-10-4638066; fax: +31-10-4089494. E-mail address : d.duncker{at}erasmusmc.nl

The Role of Endothelial Progenitor Cells and Statins in Endothelial Function: A Review

Endothelial dysfunction, a well recognized marker of cardiovascular risk, is an early event in arteriosclerosis process. Diabetes mellitus, hypertension and dyslipidemia, known risk factors for coronary disease have been associated with endothelial dysfunction, which improves after the control of these factors. Statins have additional benefits on endothelial function not related to decreasing cholesterol levels, known as pleiotropic effects. Most recently it has been reported the effect of statins promoting bone marrow-derived mononuclear cells. These cells are positive for CD34 and KDR superficial markers of endothelial cellular lineage, which is consistent with the hypothesis that they constitute the endothelial progenitor cells. Circulating endothelial progenitor cells are involved in the repair process of the endothelium after endothelial-cell injury in myocardial ischemia, angina and other stressful situations. Recent studies have demonstrated an inverse relationship between the EPC count in peripheral blood and risk of developing a cardiovascular event. In addition, circulating EPC correlates with the presence of endothelial dysfunction and could play a role as a surrogate biologic marker in vascular function. The effect of statins on endothelial progenitor cells might contribute to improve endothelial function leading to a decrease in vascular risk, independently of their impact on LDL cholesterol. In this paper, we review the role of statins in EPC mobilization, its effect in endothelial function restoration and the relevance of this finding in cardiovascular risk. We also review future therapeutic implications.

Repair of large full‐thickness articular cartilage defects by transplantation of autologous uncultured bone‐marrow‐derived mononuclear cells

The objective of this study was to investigate the feasibility of autologous uncultured bone marrow-derived mononuclear cell transplantation in large full-thickness cartilage regeneration. After fixing with a hinged external fixator, the entire surface of the left tibial plateau was resected and large full-thickness cartilage defects were formed in 48 rabbits. Animals were divided into four groups: autologous uncultured bone marrow-derived mononuclear cells with fibrin gel (BMC), autologous uncultured peripheral blood-derived mononuclear cells with fibrin gel (PBC), fibrin gel alone (GEL), or nothing (CON) transplanted to the articular cavity 7 days after the operation. The rabbits were killed 8 or 12 weeks after the operation. The repair of defects was investigated histologically and scored using a histological and histochemical grading scale that was modified from the International Cartilage Repair Society Visual Histological Assessment Scale. To evaluate the regenerated cartilage, we also morphometrically measured the staining area positive for Safranin-O or type II collagen and calculated the percentages of the positive staining areas with respect to the regenerated soft tissue area. Histological findings showed that the BMC group had superior cartilage repair compared with the other groups, and that the PBC and CON group showed better cartilage repair than did the GEL group. Histological scores and morphometrical measurements also showed the same results quantitively. The transplantation of autologous uncultured bone marrow-derived mononuclear cells contributes to articular cartilage repair. The easy and safe method used in this study is potentially viable for clinical application.