Other articles by Marianne C. Verhaar on PubMed

• Bone-marrow-derived Cells Contribute to Endothelial Repair After Thrombotic Microangiopathy Blood. Feb, 2002  |   Pubmed ID: 11822359
• Endothelial Progenitor Cells: Mainly Derived from the Monocyte/macrophage-containing CD34- Mononuclear Cell Population and Only in Part from the Hematopoietic Stem Cell-containing CD34+ Mononuclear Cell Population Circulation. Nov, 2003  |   Pubmed ID: 14638532
• Bone-marrow-derived Cells Contribute to Glomerular Endothelial Repair in Experimental Glomerulonephritis The American Journal of Pathology. Aug, 2003  |   Pubmed ID: 12875975 Glomerular endothelial injury plays an important role in the pathogenesis of renal diseases and is centrally involved in renal disease progression. Glomerular endothelial repair may help maintain renal function. We examined whether bone-marrow (BM)-derived cells contribute to glomerular repair. A rat allogenic BM transplant model was used to allow tracing of BM-derived cells using a donor major histocompatibility complex class-I specific mAb. In glomeruli of chimeric rats we identified a small number of donor-BM-derived endothelial and mesangial cells, which increased in a time-dependent manner. Induction of anti-Thy-1.1-glomerulonephritis (transient mesangial and secondary glomerular endothelial injury) caused a significant, more than fourfold increase in the number of BM-derived glomerular endothelial cells at day 7 after anti-Thy-1.1 injection compared to chimeric rats without glomerular injury. The level of BM-derived endothelial cells remained high at day 28. We also observed a more than sevenfold increase in the number of BM-derived mesangial cells at day 28. BM-derived endothelial and mesangial cells were fully integrated in the glomerular structure. Our data show that BM-derived cells participate in glomerular endothelial and mesangial cell turnover and contribute to microvascular repair. These findings provide novel insights into the pathogenesis of renal disease and suggest a potential role for stem cell therapy.
• Endothelial Progenitor Cell Dysfunction: a Novel Concept in the Pathogenesis of Vascular Complications of Type 1 Diabetes Diabetes. Jan, 2004  |   Pubmed ID: 14693715 Type 1 diabetes is associated with reduced vascular repair, as indicated by impaired wound healing and reduced collateral formation in ischemia. Recently, endothelial progenitor cells (EPCs) have been identified as important regulators of these processes. We therefore explored the concept that EPCs are dysfunctional in diabetes. The number of EPCs obtained from type 1 diabetic patients in culture was 44% lower compared with age- and sex-matched control subjects (P < 0.001). This reduction was inversely related to levels of HbA(1c) (R = -0.68, P = 0.01). In addition, we demonstrated that patient EPCs were also impaired in function using an in vitro angiogenesis assay. Conditioned media from patient EPCs were significantly reduced in their capacity to support endothelial tube formation in comparison to control EPCs. Therefore, despite culturing the EPCs under normoglycemic conditions, functional differences between patient and control EPCs were maintained. Our findings demonstrate that adverse metabolic stress factors in type 1 diabetes are associated with reduced EPC numbers and angiogenicity. We hypothesize that EPC dysfunction contributes to the pathogenesis of vascular complications in type 1 diabetes.
• A Study of Neovascularization in the Rat Ischemic Hindlimb Using Araldite Casting and Spalteholtz Tissue Clearing Cardiovascular Pathology : the Official Journal of the Society for Cardiovascular Pathology. Nov-Dec, 2005  |   Pubmed ID: 16286037 Understanding neovascularization is an important prerequisite for therapeutic advances aimed at the salvation of ischemic tissues. We explored an alternative strategy to corrosion casting for visualizing neovascularization in a rat hindlimb ischemia model.
• Cardiac Ischemic Score Determines the Presence of Coronary Collateral Circulation Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. Aug, 2005  |   Pubmed ID: 16189621 The presence of coronary collaterals is of vital importance during acute ischemia, however, marked interindividual variability exists. We examined the extent to which the burden of cardiac ischemia, expressed as a cardiac ischemic score, affects coronary collateral presence.
• Prognostic Significance of Coronary Collaterals in Patients with Coronary Heart Disease Having Percutaneous Transluminal Coronary Angioplasty The American Journal of Cardiology. Aug, 2005  |   Pubmed ID: 16054465 We examined the presence and extent of coronary collaterals as a prognostic determinant of cardiovascular outcome in a prospective case-cohort study of 655 patients admitted for elective coronary angioplasty. In patients with ischemic heart disease, the angiographic presence of coronary collaterals may mark an unfavorable prognosis, particularly in relatively high-risk patients.
• CD34+ Cells Home, Proliferate, and Participate in Capillary Formation, and in Combination with CD34- Cells Enhance Tube Formation in a 3-dimensional Matrix Arteriosclerosis, Thrombosis, and Vascular Biology. Sep, 2005  |   Pubmed ID: 16020750 Emerging evidence suggests that human blood contains bone marrow (BM)-derived endothelial progenitor cells that contribute to postnatal neovascularization. Clinical trials demonstrated that administration of BM-cells can enhance neovascularization. Most studies, however, used crude cell populations. Identifying the role of different cell populations is important for developing improved cellular therapies.
• Presence of the Metabolic Syndrome Does Not Impair Coronary Collateral Vessel Formation in Patients with Documented Coronary Artery Disease Diabetes Care. Mar, 2005  |   Pubmed ID: 15735208 The metabolic syndrome confers an increased risk for cardiovascular morbidity and mortality. The presence of coronary collaterals may have beneficial effects during myocardial ischemia and may improve cardiovascular outcome in patients with coronary artery disease. Impaired collateral formation could be one of the reasons for the increased cardiovascular risk in patients with the metabolic syndrome. The aim of the present study was to determine the influence of the metabolic syndrome and insulin resistance on the presence of coronary collaterals.
• Erythropoietin and the Cardiorenal Syndrome: Cellular Mechanisms on the Cardiorenal Connectors American Journal of Physiology. Renal Physiology. Nov, 2006  |   Pubmed ID: 16885153 We have recently proposed severe cardiorenal syndrome (SCRS), in which cardiac and renal failure mutually amplify progressive failure of both organs. This frequent pathophysiological condition has an extremely poor prognosis. Interactions between inflammation, the renin-angiotensin system, the balance between the nitric oxide and reactive oxygen species and the sympathetic nervous system form the cardiorenal connectors and are cornerstones in the pathophysiology of SCRS. An absolute deficit of erythropoietin (Epo) and decreased sensitivity to Epo in this syndrome both contribute to the development of anemia, which is more pronounced than renal anemia in the absence of heart failure. Besides expression on erythroid progenitor cells, Epo receptors are present in the heart, kidney, and vascular system, in which activation results in antiapoptosis, proliferation, and possibly antioxidation and anti-inflammation. Interestingly, Epo can improve cardiac and renal function. We have therefore reviewed the literature with respect to Epo and the cardiorenal connectors. Indeed, there are indications that Epo can diminish inflammation, reduce renin-angiotensin system activity, and shift the nitric oxide and reactive oxygen species balance toward nitric oxide. Information about Epo and the sympathetic nervous system is scarce. This analysis underscores the relevance of a further understanding of clinical and cellular mechanisms underlying protective effects of Epo, because this will support better treatment of SCRS.
• Role of Circulating Karyocytes in the Initiation and Progression of Atherosclerosis Hypertension. May, 2006  |   Pubmed ID: 16520401 Cardiovascular disease is still hard to predict in an individual. The main focus in cardiovascular research has been on endothelial cells and vascular smooth muscle cells of the vessel wall and their interactions with the blood flow. Alterations in the properties of the blood have received a lot of attention in biochemical terms. Interestingly, alterations in the properties of circulating cells have received less attention. We propose that presence of 1 or more risk factors together with normal physiological stimuli induce redox-dependent changes in leukocyte gene transcription with pathophysiological responses. Thus, risk factors render leukocytes hypersensitive to normal stimuli. Risk factors can be subdivided into physical and chemical factors. Superimposed on physiological regulators of leukocyte function, these risk factors promote a cellular pro-oxidative state. Redox-sensitive transcription factors are activated, leading to responses involving inflammation, adhesion, migration, and additional reactive oxygen species generation. As a consequence, monitoring of individual gene expression signatures of these cells could well increase our understanding of the mechanisms by which leukocytes and, in particular, monocytes function. Furthermore, transcriptomes of these cells could be used to investigate the aggressiveness of the atherosclerotic process or to guide treatment in the patient with risk factors for atherosclerosis.
• Tetrahydrobiopterin, but Not L-arginine, Decreases NO Synthase Uncoupling in Cells Expressing High Levels of Endothelial NO Synthase Hypertension. Jan, 2006  |   Pubmed ID: 16344367 Endothelial NO synthase (eNOS) produces superoxide when depleted of (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4) and L-arginine by uncoupling the electron flow from NO production. High expression of eNOS has been reported to have beneficial effects in atherosclerotic arteries after relatively short periods of time. However, sustained high expression of eNOS may have disadvantageous vascular effects because of uncoupling. We investigated NO and reactive oxygen species (ROS) production in a microvascular endothelial cell line (bEnd.3) with sustained high eNOS expression and absent inducible NOS and neuronal NOS expression using 4,5-diaminofluorescein diacetate and diacetyldichlorofluorescein as probes, respectively. Unstimulated cells produced both NO and ROS. After stimulation with vascular endothelial growth factor (VEGF), NO and ROS production increased. VEGF-induced ROS production was even further increased by the addition of extra L-arginine. Nomega-nitro-L-arginine methyl ester decreased ROS production. These findings strongly suggest that eNOS is a source of ROS in these cells. Although BH4 levels were increased as compared with another endothelial cell line, eNOS levels were >2 orders of magnitude higher. The addition of BH4 resulted in increased NO production and decreased generation of ROS, indicating that bEnd.3 cells produce ROS through eNOS uncoupling because of relative BH4 deficiency. Nevertheless, eNOS-dependent ROS production was not completely abolished by the addition of BH4, suggesting intrinsic superoxide production by eNOS. This study indicates that potentially beneficial sustained increases in eNOS expression and activity could lead to eNOS uncoupling and superoxide production as a consequence. Therefore, sustained increases of eNOS or VEGF activity should be accompanied by concomitant supplementation of BH4.
• TGF-beta1 Induces Efficient Differentiation of Human Cardiomyocyte Progenitor Cells into Functional Cardiomyocytes in Vitro Stem Cell Research. Nov, 2007  |   Pubmed ID: 19383394 The adult mammalian heart has limited regenerative capacity and was generally considered to contain no dividing cells. Recently, however, a resident population of progenitor cells has been identified, which could represent a new source of cardiomyocytes. Here, we describe the efficient isolation and propagation of human cardiomyocyte progenitor cells (hCMPCs) from fetal heart and patient biopsies. Establishment of hCMPC cultures was remarkably reproducible, with over 70% of adult atrial biopsies resulting in robustly expanding cell populations. Following the addition of transforming growth factor beta, almost all cells differentiated into spontaneously beating myocytes with characteristic cross striations. hCMPC-derived cardiomyocytes showed gap-junctional communication and action potentials of maturing cardiomyocytes. These are the first cells isolated from human heart that proliferate and form functional cardiomyocytes without requiring coculture with neonatal myocytes. Their scalability and homogeneity are unique and provide an excellent basis for developing physiological, pharmacological, and toxicological assays on human heart cells in vitro.
• Technology Insight: Innovative Options for End-stage Renal Disease--from Kidney Refurbishment to Artificial Kidney Nature Clinical Practice. Nephrology. Oct, 2007  |   Pubmed ID: 17895933 The steadily growing number of patients with chronic kidney disease who will eventually develop end-stage renal disease, together with the qualitative limitations of currently available renal replacement therapies, have triggered the exploration of innovative strategies for renal replacement therapy and for salvage of renal function. Currently, new hemodialysis modalities and membranes are being used with the aim of increasing clearance of uremic toxins to afford better metabolic control. In addition to these conventional approaches, there are four innovative potential solutions to the problem of replacing renal function when kidneys fail. The first is a small, implantable device with the potential to be supplemented with human cells ('artificial kidney'). The second involves restoration of the damaged kidney by harnessing recent advances in stem-cell technology and knowledge of developmental programing ('refurbished kidney'). The third is (partially) growing a kidney in vitro with the use of therapeutic cloning ('cultured kidney'). The fourth innovative solution involves the use of other organs to replace various renal functions ('distributed kidney'). In this article we review the efforts that have been made to improve renal replacement therapies, and explore innovative approaches. We will not cover all potential solutions in detail. Rather, we aim to indicate directions of future endeavor and arouse enthusiasm in clinicians and scientists for exploration of these exciting avenues.
• Understanding ENOS for Pharmacological Modulation of Endothelial Function: a Translational View Current Pharmaceutical Design. 2007  |   Pubmed ID: 17584103 Knowledge about the function of endothelial nitric oxide synthase (eNOS), and its regulation in pathophysiological states has tremendously increased. It is now clear that diminished activity of nitric oxide (NO) contributes to endothelial dysfunction, which is a characteristic of impeding atherosclerosis. This review aims to summarize the available knowledge about the impact of important cardiovascular risk factors on NO production by eNOS. There are 4 principle causes of diminished NO bio-activity: decreased expression and/or activity of the eNOS enzyme, eNOS uncoupling, enhanced breakdown or scavenging of NO and impaired transmission of NO-mediated signaling events (failure of the effector mechanisms). From the analysis, it becomes clear, that several aspects of eNOS functionality have only scarcely been tested under conditions of increased (experimental) cardiovascular risk. These aspects include palmitoylation, myristoylation and phosphorylation of the eNOS enzyme. Clear is that enhanced production of reactive oxygen species (ROS) and eNOS uncoupling are relatively important causes of reduced NO-bioactivity in cardiovascular disease states. Ideally, eNOS is sufficiently expressed, produces NO sufficiently and not abundantly, does not produce superoxide and is not scavenged by ROS; the produced NO then reaches its signaling target, mainly soluble guanylyl cyclase (sGC) and elicits a cellular response. Considering which aspects of eNOS are now assessable in a clinical setting and which therapeutic measures are available, there is a great challenge ahead.
• Met-RANTES Reduces Endothelial Progenitor Cell Homing to Activated (glomerular) Endothelium in Vitro and in Vivo American Journal of Physiology. Renal Physiology. Aug, 2007  |   Pubmed ID: 17567937 The chemokine RANTES (regulated upon activation normal T-cell expressed and secreted) is involved in the formation of an inflammatory infiltrate during glomerulonephritis. However, RANTES receptor inhibition, although reducing glomerular leukocyte infiltration, can also increase damage. We hypothesized that RANTES does not only promote the influx and activation of inflammatory leukocytes but also mediates glomerular microvascular repair by stimulating the homing of bone marrow (BM)-derived endothelial progenitor cells. To investigate the role of RANTES in the participation of BM-derived cells in glomerular vascular repair, we used a rat BM transplantation model in combination with reversible anti-Thy-1.1 glomerulonephritis. Twenty-four hours after the induction of glomerulonephritis, BM-transplanted rats were treated for 7 days with either the RANTES receptor antagonist Met-RANTES or saline. The participation of BM-derived endothelial cells in glomerular repair, glomerular monocyte infiltration, and proteinuria was evaluated at days 7 and 28. Furthermore, we used an in vitro perfusion chamber assay to study the role of RANTES receptors in shear-resistant adhesion of the CD34+ stem cells to activated endothelium under flow. In our reversible glomerulonephritis model, RANTES receptor inhibition specifically reduced the participation of BM-derived cells in glomerular vascular repair by more than 40% at day 7 without impairing monocyte influx. However, no obvious change in recovery from proteinuria or morphological damage was observed. Blockade of RANTES receptors on CD34+ cells in vitro partially inhibited platelet-enhanced, shear-resistant firm adhesion of the CD34+ cells to activated endothelium. In conclusion, our data suggest that RANTES is involved in the homing and participation of BM-derived endothelial cells in glomerular repair.
• Premature Atherosclerotic Cardiovascular Disease in Systemic Lupus Erythematosus Arthritis and Rheumatism. May, 2007  |   Pubmed ID: 17469095
• Haematopoietic and Endothelial Progenitor Cells Are Deficient in Quiescent Systemic Lupus Erythematosus Annals of the Rheumatic Diseases. Jul, 2007  |   Pubmed ID: 17329307 Systemic lupus erythematosus (SLE) is associated with a high prevalence of cardiovascular disease. Circulating endothelial progenitor cells (EPCs) contribute to vascular regeneration and repair, thereby protecting against atherosclerotic disease. EPCs are derived from CD34+ haematopoietic stem cells (HSCs), which have an increased propensity for apoptosis in the bone marrow of patients with SLE.
• End-stage Renal Disease Causes an Imbalance Between Endothelial and Smooth Muscle Progenitor Cells American Journal of Physiology. Renal Physiology. Apr, 2007  |   Pubmed ID: 17200161 Patients with end-stage renal disease (ESRD) on hemodialysis have an increased risk of cardiovascular disease (CVD). Circulating endothelial progenitor cells (EPC) contribute to vascular regeneration and repair, thereby protecting against CVD. However, circulating smooth muscle progenitor cells (SPC) may contribute to adverse vascular remodeling. We hypothesized that an imbalance occurs between EPC and SPC in ESRD patients and sampled progenitor cells from 45 ESRD patients receiving regular treatment. Our study is the first to show reduced numbers of CD34+KDR+ hematopoietic stem cell (HSC)-derived EPC (type I EPC). Furthermore, monocyte-derived EPC cultured from mononuclear cells (type II EPC) were reduced in number and had a reduced capacity to stimulate endothelial cell angiogenesis. In contrast, SPC outgrowth was unaffected. In vitro incubation with uremic serum impaired type II EPC outgrowth from healthy donor mononuclear cells and did not influence SPC outgrowth. The hemodialysis procedure itself induced HSC apoptosis and caused an acute depletion of circulating EPC. Taken together, the decreased number and impaired function of EPC are compatible with impaired endogenous vascular repair in hemodialysis patients, whereas the unaffected SPC numbers suggest that the potential of progenitor cells to contribute to adverse remodeling is retained. This EPC-SPC imbalance may contribute to the acceleration of CVD in ESRD patients and could offer novel therapeutic targets.
• Levels of Homocysteine Are Increased in Metabolic Syndrome Patients but Are Not Associated with an Increased Cardiovascular Risk, in Contrast to Patients Without the Metabolic Syndrome Heart (British Cardiac Society). Feb, 2007  |   Pubmed ID: 16952974 The metabolic syndrome is associated with increased cardiovascular risk. Elevated plasma homocysteine may cause or result from insulin resistance, and may indicate vascular risk or be actively involved in atherogenesis. The aim of the study was to investigate the relationship between homocysteine, the metabolic syndrome and the incidence of cardiovascular events in patients with manifest vascular disease.
• Coronary Collateral Circulation: the Effects of Smoking and Alcohol Atherosclerosis. Mar, 2007  |   Pubmed ID: 16696984 The presence or absence of coronary collaterals is of vital importance during acute ischemia. Smoking and alcohol have been suggested to play a role, but data are scarce. We examined the extent to which smoking and alcohol use affect the presence of coronary collateral circulation.
• Endothelial Progenitor Cell Levels in Obese Men with the Metabolic Syndrome and the Effect of Simvastatin Monotherapy Vs. Simvastatin/ezetimibe Combination Therapy European Heart Journal. Nov, 2008  |   Pubmed ID: 18824462 Endothelial progenitor cells (EPCs) contribute to endothelial regeneration and thereby protect against cardiovascular disease (CVD). Patients with manifest CVD have reduced EPC levels, but it is not clear if this also occurs in subjects at high CVD risk without manifest atherosclerotic disease. Therefore, we aimed to first, measure circulating levels of EPCs in subjects without manifest CVD but at high cardiovascular risk due to obesity and presence of the metabolic syndrome. Second, we evaluated the effect on EPC levels of two lipid-lowering treatments.
• Directing Myogenic Mesenchymal Stem Cell Differentiation Circulation Research. Sep, 2008  |   Pubmed ID: 18796639
• Insights into Mechanisms Behind Arteriogenesis: What Does the Future Hold? Journal of Leukocyte Biology. Dec, 2008  |   Pubmed ID: 18678607 Arteriogenesis, the enlargement of collateral vessels, seems a promising new target to improve blood flow to ischemic regions in patients suffering from cardiovascular conditions. With the growing knowledge of the mechanisms involved in arteriogenesis and the factors that influence the process, an increasing number of clinical trials are being performed to stimulate arteriogenesis, providing more insight in therapeutic opportunities for arteriogenesis. The expression of growth factors and the cooperation of surrounding and infiltrating cells seem to be essential in orchestrating the complex processes during arteriogenesis. In this review, we will discuss the regulating mechanisms of arteriogenesis, including the role of growth factors and different cell types and their implementation in a clinical setting. Furthermore, individual differences in the arteriogenic response will be considered, in light of the effect this will have on the success of therapeutic strategies to improve blood flow to ischemic tissue.
• RANTES is Required for Ischaemia-induced Angiogenesis, Which May Hamper RANTES-targeted Anti-atherosclerotic Therapy Thrombosis and Haemostasis. Apr, 2008  |   Pubmed ID: 18392345
• Progenitor Cell Therapy in Patients with Critical Limb Ischemia Without Surgical Options Annals of Surgery. Mar, 2008  |   Pubmed ID: 18376183 To provide a review on progenitor cell therapy for critical limb ischemia.
• Angiogenic Sprouting from the Aortic Vascular Wall is Impaired in the BB Rat Model of Autoimmune Diabetes Microvascular Research. Apr, 2008  |   Pubmed ID: 18241893 Diabetes is associated with impaired neovascularization leading to reduced revascularization of ischemic tissue and impaired wound healing. Endothelial progenitor cells in diabetes were previously shown to be numerically reduced and functionally impaired. We hypothesize that diabetes also has a long-term effect on angiogenic cells residing in the vessel wall. To test this hypothesis, angiogenic sprout formation from ex vitro cultured aortic rings isolated from diabetic and non-diabetic BioBreeding (BB) rats was assessed.
• Protective Actions of PPAR-gamma Activation in Renal Endothelium PPAR Research. 2008  |   Pubmed ID: 19266048 Renal endothelial damage is pivotal in the initiation and progression of renal disease. Damaged renal endothelium may be regenerated through proliferation of local endothelium and circulation-derived endothelial progenitor cells. Activation of the PPAR-gamma-receptors present on endothelial cells affects their cellular behavior. Proliferation, apoptosis, migration, and angiogenesis by endothelial cells are modulated, but may involve both stimulation and inhibition depending on the specific circumstances. PPAR-gamma-receptor activation stimulates the production of nitric oxide, C-type natriuretic peptide, and superoxide dismutase, while endothelin-1 production is inhibited. Together, they augment endothelial function, resulting in blood pressure lowering and direct renoprotective effects. The presentation of adhesion molecules and release of cytokines recruiting inflammatory cells are inhibited by PPAR-gamma-agonism. Finally, PPAR-gamma-receptors are also found on endothelial progenitor cells and PPAR-gamma-agonists stimulate progenitor-mediated endothelial repair. Together, the stimulatory effects of PPAR-gamma-agonism on endothelium make an important contribution to the beneficial actions of PPAR-gamma-agonists on renal disease.
• Amelioration of Anti-Thy1-glomerulonephritis by PPAR-gamma Agonism Without Increase of Endothelial Progenitor Cell Homing American Journal of Physiology. Renal Physiology. Feb, 2008  |   Pubmed ID: 18077601 Impaired glomerular endothelial integrity is pivotal in various renal diseases and depends on both the degree of glomerular endothelial injury and the effectiveness of glomerular endothelial repair. Glomerular endothelial repair is, in part, mediated by bone marrow-derived endothelial progenitor cells. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonists have therapeutic actions independent of their insulin-sensitizing effects, including enhancement of endothelial progenitor cell function and differentiation. We evaluated the effect of PPAR-gamma agonist rosiglitazone (4 mg.kg(-1).day(-1)) on the course of anti-Thy1-glomerulonephritis in rats. Rosiglitazone limited the development of proteinuria and prevented plasma urea elevation (8.1 +/- 0.4 vs. 12.5 +/- 1.1 mmol/l, P = 0.002). Histologically, inflammatory cell influx was not affected, but rosiglitazone-treated rats did show fewer microaneurysmatic glomeruli on day 7 (26 +/- 3 vs. 41 +/- 5%, P = 0.01) and reduced activation of matrix production with reduced renal cortical transforming growth factor-beta, plasminogen activator inhibitor type 1, and fibronectin-1 mRNA expression. However, bone marrow-derived endothelial cell glomerular incorporation was not enhanced (3.1 +/- 0.4 vs. 3.6 +/- 0.3 cells/glomerular cross section; P = 0.31). Rosiglitazone treatment in nonnephritic rats did not influence proteinuria, urea, or renal histology. In conclusion, treatment with PPAR-gamma agonist rosiglitazone ameliorates the course of experimental glomerulonephritis in a nondiabetic model, but not through enhancing incorporation of bone marrow-derived endothelial cells in the glomerulus.
• Prediction Rule for Cardiovascular Events and Mortality in Peripheral Arterial Disease Patients: Data from the Prospective Second Manifestations of ARTerial Disease (SMART) Cohort Study Journal of Vascular Surgery. Dec, 2009  |   Pubmed ID: 19837547 Patients with peripheral arterial disease (PAD) are at high risk of secondary cardiovascular death and events such as myocardial infarction or stroke. To minimize this elevated risk, cardiovascular risk factors should be treated in all PAD patients. Secondary risk management may benefit from a prediction tool to identify PAD patients at the highest risk who could be referred for an additional extensive workup. Stratifying PAD patients according to their risk of secondary events could aid in achieving optimal therapy compliance. To this end we developed a prediction model for secondary cardiovascular events in PAD patients.
• Folic Acid Supplementation Normalizes the Endothelial Progenitor Cell Transcriptome of Patients with Type 1 Diabetes: a Case-control Pilot Study Cardiovascular Diabetology. 2009  |   Pubmed ID: 19706161 Endothelial progenitor cells play an important role in vascular wall repair. Patients with type 1 diabetes have reduced levels of endothelial progenitor cells of which their functional capacity is impaired. Reduced nitric oxide bioavailability and increased oxidative stress play a role in endothelial progenitor cell dysfunction in these patients. Folic acid, a B-vitamin with anti-oxidant properties, may be able to improve endothelial progenitor cell function. In this study, we investigated the gene expression profiles of endothelial progenitor cells from patients with type 1 diabetes compared to endothelial progenitor cells from healthy subjects. Furthermore, we studied the effect of folic acid on gene expression profiles of endothelial progenitor cells from patients with type 1 diabetes.
• Review Article: Endothelial Progenitor Cells in Renal Disease Nephrology (Carlton, Vic.). Apr, 2009  |   Pubmed ID: 19444962 This brief overview is intended to provide basic information about endothelial progenitors, their definition and consensus markers used for their detection, describe the pathways of their mobilization and homing and highlight the mechanisms and manifestations of their incompetence that occurs in some chronic kidney diseases. Discussion is geared towards the potential role of endothelial progenitor cells in organ regeneration, in particular, in kidney regeneration. The concept we attempted to promote attributes to the incompetence of endothelial progenitor cells in failed regeneration and ensuing progression of chronic kidney disease. This field of inquiry remains insufficiently explored, especially in renal diseases. Promising areas for future exploration are emphasized.
• Smooth Muscle Progenitor Cells: Friend or Foe in Vascular Disease? Current Stem Cell Research & Therapy. May, 2009  |   Pubmed ID: 19442197 The origin of vascular smooth muscle cells that accumulate in the neointima in vascular diseases such as transplant arteriosclerosis, atherosclerosis and restenosis remains subject to much debate. Smooth muscle cells are a highly heterogeneous cell population with different characteristics and markers, and distinct phenotypes in physiological and pathological conditions. Several studies have reported a role for bone marrow-derived progenitor cells in vascular maintenance and repair. Moreover, bone marrow-derived smooth muscle progenitor cells have been detected in human atherosclerotic tissue as well as in in vivo mouse models of vascular disease. However, it is not clear whether smooth muscle progenitor cells can be regarded as a 'friend' or 'foe' in neointima formation. In this review we will discuss the heterogeneity of smooth muscle cells, the role of smooth muscle progenitor cells in vascular disease, potential mechanisms that could regulate smooth muscle progenitor cell contribution and the implications this may have on designing novel therapeutic tools to prevent development and progression of vascular disease.
• Endothelial Progenitor Cell Dysfunction in Rheumatic Disease Nature Reviews. Rheumatology. Jun, 2009  |   Pubmed ID: 19434075 Rheumatic disease is characterized by inflammation and endothelial dysfunction, which contribute to accelerated atherosclerosis. Circulating endothelial progenitor cells (EPCs) can restore dysfunctional endothelium and thereby protect against atherosclerotic vascular disease. The number and function of EPCs are, however, affected in rheumatic diseases such as psoriatic arthritis, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and antineutrophil cytoplasmic autoantibody-associated vasculitis. rheumatic disease is often characterized by decreased numbers, and impaired function, of EPCs, although numbers of these cells might increase during the initial years of systemic sclerosis. Pioneering studies show that EPC dysfunction might be improved with pharmacological treatment. How best to restore EPC function, and whether achieving this aim can prevent long-term cardiovascular complications in rheumatic disease, remain to be established.
• The Use of Endothelial Progenitor Cells for Prevascularized Bone Tissue Engineering Tissue Engineering. Part A. Aug, 2009  |   Pubmed ID: 19196146 In vitro vascularization is an upcoming strategy to solve the problem of insufficient blood supply after implantation. Although recent publications show promising results, these studies were generally performed with clinically irrelevant endothelial cell model systems. We tested the use of endothelial progenitor cells (EPC) obtained from umbilical cord blood and human mesenchymal stem cells (hMSC) from the bone marrow for their use in a prevascularized bone tissue engineering setting. MSC were differentiated toward endothelial cells. They formed capillary-like structures containing lumen, stained positive for CD31, attained the ability to take up acetylated low-density lipoproteins, and formed perfused vessels in vivo. However, in a three-dimensional coculture setting with undifferentiated hMSC, the cells stopped expressing CD31 and did not form prevascular structures. EPC from the cord blood were able to form prevascular structures in the same coculture setting, but only when the state of endothelial differentiation was mature. The amount of prevascular structures formed when using EPC was less than when human umbilical vein endothelial cells or human dermal microvascular endothelial cells were used. The degree of organization, however, was higher. We conclude that EPC can be used for complex tissue engineering applications, but the differentiation stage of these cells is important.
• Comment On: Systemic Lupus Erythematosus Patients Exhibit Functional Deficiencies of Endothelial Progenitor Cells Rheumatology (Oxford, England). Apr, 2009  |   Pubmed ID: 19164424
• Circulating Endothelial Progenitor Cell Levels Are Higher During Childhood Than in Adult Life Atherosclerosis. Feb, 2009  |   Pubmed ID: 18571177 Age-related vascular dysfunction contributes to the increased cardiovascular risk in elderly. Endothelial progenitor cells (EPC), a hematopoietic stem cell (HSC) subtype, can improve vascular repair. Therefore, it is hypothesized that a decrease in these circulating progenitor cells during aging plays a role in the enhanced cardiovascular risk. Until now, research has focused on EPC and HSC in the aging adult, but no studies have been conducted in children whereas animal studies specifically suggest a benefit of juvenile bone marrow. We investigated CD34(+)/KDR(+) EPC and CD34(+) HSC numbers by flow cytometry in healthy humans aged 1- to 81-years old. An inverse relation with age was observed for EPC counts [r=-0.37, p=0.007] as well as for HSC counts [r=-0.37, p=0.008]. During childhood significantly higher levels of EPC [p
• Modulation of TGF-β/BMP-6 Expression and Increased Levels of Circulating Smooth Muscle Progenitor Cells in a Type I Diabetes Mouse Model Cardiovascular Diabetology. 2010  |   Pubmed ID: 20858224 Diabetic patients experience exaggerated intimal hyperplasia after endovascular procedures. Recently it has been shown that circulating smooth muscle progenitor cells (SPC) contribute to intimal hyperplasia. We hypothesized that SPC differentiation would be increased in diabetes and focused on modulation of TGF-β/BMP-6 signaling as potential underlying mechanism.
• The Nitric Oxide Donor Molsidomine Rescues Cardiac Function in Rats with Chronic Kidney Disease and Cardiac Dysfunction American Journal of Physiology. Heart and Circulatory Physiology. Dec, 2010  |   Pubmed ID: 20852057 We recently developed a rat model of cardiorenal failure that is characterized by severe left ventricular systolic dysfunction (LVSD) and low nitric oxide (NO) production that persisted after temporary low-dose NO synthase inhibition. We hypothesized that LVSD was due to continued low NO availability and might be reversed by supplementing NO. Rats underwent a subtotal nephrectomy and were treated with low-dose NO synthase inhibition with N(ω)-nitro-l-arginine up to week 8. After 3 wk of washout, rats were treated orally with either the long-acting, tolerance-free NO donor molsidomine (Mols) or vehicle (Veh). Cardiac and renal function were measured on weeks 11, 13, and 15. On week 16, LV hemodynamics and pressure-volume relationships were measured invasively, and rats were killed to quantify histological damage. On week 15, blood pressure was mildly reduced and creatinine clearance was increased by Mols (both P < 0.05). Mols treatment improved ejection fraction (53 ± 3% vs. 37 ± 2% in Veh-treated rats, P < 0.001) and stroke volume (324 ± 33 vs. 255 ± 15 μl in Veh-treated rats, P < 0.05). Rats with Mols treatment had lower end-diastolic pressures (8.5 ± 1.1 mmHg) than Veh-treated rats (16.3 ± 3.5 mmHg, P < 0.05) and reduced time constants of relaxation (21.9 ± 1.8 vs. 30.9 ± 3.3 ms, respectively, P < 0.05). The LV end-systolic pressure-volume relationship was shifted to the left in Mols compared with Veh treatment. In summary, in a model of cardiorenal failure with low NO availability, supplementing NO significantly improves cardiac systolic and diastolic function without a major effect on afterload.
• Reduced Endothelial Progenitor Cells in Children with Hemodialysis but Not Predialysis Chronic Kidney Disease Pediatrics. Oct, 2010  |   Pubmed ID: 20819900 In adults with chronic kidney disease (CKD), reduced levels of vasculoprotective endothelial progenitor cells (EPCs) may contribute to their increased risk of cardiovascular disease. Children with CKD also show signs of cardiovascular disease. However, to our knowledge, there have been no studies on circulating EPC levels in pediatric patients with CKD. We investigated CD34+KDR+ EPC numbers by using flow cytometry in 15 children with predialysis CKD, 13 children on hemodialysis, and 18 age-matched healthy controls. Children on hemodialysis showed 47% reduced EPC levels compared with controls, whereas no significant difference was found for patients with predialysis CKD. Lower EPC levels were found in patients with higher levels of inflammatory marker high-sensitivity C-reactive protein. Our data show, for the first time, that children on hemodialysis have reduced CD34+KDR+ EPC levels, which potentially contributes to their increased cardiovascular risk. In children with predialysis CKD, a decline in renal function was not associated with reduced EPC levels, which may reflect a capacity for preservation of the endogenous repair system during relatively moderate disturbances of the systemic environment.
• Quality of Life in Patients with No-option Critical Limb Ischemia Underlines the Need for New Effective Treatment Journal of Vascular Surgery. Oct, 2010  |   Pubmed ID: 20598482 To provide a solid baseline reference for quality of life (QoL) in patients with no-option critical limb ischemia (CLI). CLI is associated with surgery, endovascular interventions, hospitalization, and a poor prognosis. An increasing number of clinical trials are, therefore, investigating new treatment strategies (eg, therapeutic neovascularization) in patients with CLI. QoL serves as an important secondary endpoint in many of these trials, but solid reference QoL data for patients with no-option CLI are lacking.
• Rationale and Design of the JUVENTAS Trial for Repeated Intra-arterial Infusion of Autologous Bone Marrow-derived Mononuclear Cells in Patients with Critical Limb Ischemia Journal of Vascular Surgery. Jun, 2010  |   Pubmed ID: 20488328 Critical limb ischemia (CLI) continues to form a substantial burden on Western healthcare. Many patients still face amputation as a last treatment option. Autologous bone marrow (BM)-derived cell administration has emerged as a potential new treatment, but proof for sustainable clinical effects of BM-derived cell therapy in CLI is still lacking. The JUVENTAS (reJUVenating ENdothelial progenitor cells via Transcutaneous intra-Arterial Supplementation) trial is the first randomized, placebo-controlled, double-blinded clinical trial on repeated intra-arterial BM mononuclear cell (MNC) infusion in 110 to 160 CLI patients, designed to provide definite proof for the efficacy of stem cell therapy. Primary outcome is the incidence of major amputation at 6 months. Inclusion of patients is well underway. If BM-MNC cells therapy is beneficial, it could become a novel treatment to prevent amputation in patients with CLI.
• LOX-1: Luring Ox-LDL into the Arterial Wall Journal of Hypertension. Jun, 2010  |   Pubmed ID: 20467265
• Erythropoietin Treatment in Patients with Combined Heart and Renal Failure: Objectives and Design of the EPOCARES Study Journal of Nephrology. Jul-Aug, 2010  |   Pubmed ID: 20383871 Anemia is common in patients with the combination of chronic heart failure and chronic kidney disease and is associated with increased mortality. Recent clinical studies suggest that recombinant human erythropoietin (EPO) treatment has desirable as well as undesirable effects, related to its hematopoietic or nonhematopoietic effects. Therefore a translational study is needed to elucidate mechanistic aspects of EPO treatment.
• Differential Impact of Dialysis Modality on Circulating Endothelial Progenitor Cells Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. May, 2010  |   Pubmed ID: 20190239
• Progenitor Cells and Vascular Function Are Impaired in Patients with Chronic Kidney Disease Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. Jun, 2010  |   Pubmed ID: 20083473 Endothelial dysfunction contributes to accelerated atherosclerosis in chronic kidney disease (CKD). Bone marrow-derived endothelial progenitor cells (EPC) constitute an endogenous vascular repair system protecting against atherosclerosis. Smooth muscle progenitor cells (SPC) may stimulate atherosclerosis development. We hypothesized that an imbalance in EPC and SPC occurs in CKD, which may contribute to the increased cardiovascular disease (CVD) risk.
• Exosomes and the Kidney: Prospects for Diagnosis and Therapy of Renal Diseases Kidney International. Dec, 2011  |   Pubmed ID: 21881557 Exosomes are 40-100 nm membrane vesicles secreted into the extracellular space by numerous cell types. These structures can be isolated from body fluids including urine and plasma. Exosomes contain proteins, mRNAs, miRNAs, and signaling molecules that reflect the physiological state of their cells of origin and consequently provide a rich source of potential biomarker molecules. Aside from diagnostic uses, exosome-mediated transfer of proteins, mRNAs, miRNAs, and signaling molecules offer the promise that they may be used for therapeutic purposes. In this review, we integrate new knowledge about exosomes from outside the field of nephrology with recent progress by renal researchers in order to provide a basis for speculation about how the study of exosomes may affect the fields of nephrology and renal physiology in the next few years.
• Loss of Endogenous Bone Morphogenetic Protein-6 Aggravates Renal Fibrosis The American Journal of Pathology. Mar, 2011  |   Pubmed ID: 21356359 Bone morphogenetic protein-6 (BMP-6) suppresses inflammatory genes in renal proximal tubular cells and regulates iron metabolism by inducing hepcidin. In diabetic patients, an increase of myofibroblast progenitor cells (MFPCs), also known as fibrocytes, was found to be associated with decreased BMP-6 expression. We hypothesized that loss of endogenous BMP-6 would aggravate renal injury and fibrosis. Wild type (WT) and BMP-6 null mice underwent unilateral ureteral obstruction. In WT mice, ureteral obstruction down-regulated BMP-6. Obstructed kidneys of BMP-6 null mice showed more casts (1.5-fold), epithelial necrosis (1.4-fold), and brush border loss (1.3-fold). This was associated with more inflammation (1.8-fold more CD45(+) cells) and more pronounced overexpression of profibrotic genes for αSMA (2.0-fold), collagen I (6.8-fold), fibronectin (4.3-fold), CTGF (1.8-fold), and PAI-1 (3.8-fold), despite similar BMP-7 expression. Also, 1.3-fold more MFPCs were obtained from BMP-6 null than from WT mononuclear cell cultures, but in vivo only very few MFPCs were observed in obstructed kidneys, irrespective of BMP-6 genotype. The obstructed kidneys of BMP-6 null mice showed 2.2-fold more iron deposition, in association with 3.3-fold higher expression of the oxidative stress marker HO-1. Thus, ureteral obstruction leads to down-regulation of BMP-6 expression, and BMP-6 deficiency aggravates tubulointerstitial damage and fibrosis independent of BMP-7. This process appears to involve loss of both direct anti-inflammatory and antifibrotic action and indirect suppressive effects on renal iron deposition, oxidative stress, and MFPCs.
• Decreased Kidney Function: an Unrecognized and Often Untreated Risk Factor for Secondary Cardiovascular Events After Carotid Surgery Stroke; a Journal of Cerebral Circulation. Feb, 2011  |   Pubmed ID: 21183753 Chronic kidney disease is an important risk factor for development and progression of atherosclerosis. The objective of the current study was to investigate the contribution of moderate kidney failure to cardiovascular (CV) mortality and morbidity after carotid endarterectomy (CEA). In addition, we investigated which proportion received optimal medical treatment or underwent diagnostic workup of the kidneys prior to CEA.
• Short- and Long-term Effects of Erythropoietin Treatment on Endothelial Progenitor Cell Levels in Patients with Cardiorenal Syndrome Heart (British Cardiac Society). Jan, 2011  |   Pubmed ID: 21071558 Patients with cardiorenal syndrome (CRS) have high cardiovascular morbidity. Endothelial progenitor cells (EPC) constitute an endogenous vascular repairsystem, protecting against atherosclerosis development. Erythropoietin (EPO) treatment may have beneficial effects by mobilizing EPC from the bonemarrow. Our objective is to determine EPC levels and effects of EPO therapy on EPC levels in CRS patients.
• Transcriptome Analysis in Endothelial Progenitor Cell Biology Antioxidants & Redox Signaling. Aug, 2011  |   Pubmed ID: 20812873 The use of endothelial progenitor cells (EPCs) is a promising new treatment option for cardiovascular diseases. Many of the underlying mechanisms that result in an improvement of endothelial function in vivo remain poorly elucidated to this date, however. We summarize the current positions and potential applications of gene-expression profiling in the field of EPC biology. Based on our own and published gene-expression data, we demonstrate that gene-expression profiling can efficiently be used to characterize different EPC types. Furthermore, we highlight the potential of gene-expression profiling for the analysis of changes that EPCs undergo during culture and examine changes in gene transcription in diseased patients. Transcriptome profiling is a powerful tool for the characterization and functional analysis of EPCs in health and disease.
• Healthy Bone Marrow Cells Reduce Progression of Kidney Failure Better Than CKD Bone Marrow Cells in Rats with Established Chronic Kidney Disease Cell Transplantation. 2012  |   Pubmed ID: 23231961 Chronic kidney disease (CKD) is a major health care problem. New interventions to slow or prevent disease progression are urgently needed. We studied functional and structural effects of infusion of healthy and CKD bone marrow cells (BMCs) in a rat model of established CKD. CKD was induced by 5/6 nephrectomy (SNX) in Lewis rats, and disease progression was accelerated with L-NNA and 6% NaCl diet. Six weeks after SNX, CKD rats received healthy eGFP(+) BMCs, CKD eGFP(+) BMCs, or vehicle by single renal artery injection. Healthy BMCs were functionally effective 6 weeks after administration: glomerular filtration rate (GFR; inulin clearance) (0.48±0.16 vs. 0.26±0.14 ml/min/100 g) and effective renal plasma flow (RPF; PAH clearance) (1.6±0.40 vs. 1.0±0.62 ml/min/100 g) were higher in healthy BMC- versus vehicle-treated rats (both p < 0.05). Systolic blood pressure (SBP) and proteinuria were lower 5 weeks after treatment with healthy BMCs versus vehicle (SBP, 151±13 vs. 186±25 mmHg; proteinuria, 33±20 vs. 59±39 mg/day, both p < 0.05). Glomerular capillary density was increased, and less sclerosis was detected after healthy BMCs (both p < 0.05). Tubulointerstitial inflammation was also decreased after healthy BMCs. eGFP(+) cells were present in the glomeruli and peritubular capillaries of the remnant kidney in all BMC-treated rats. CKD BMCs also reduced SBP, proteinuria, glomerulosclerosis, and tubular atrophy versus vehicle in CKD rats. However, CKD BMC therapy was not functionally effective versus vehicle [GFR: 0.28±0.09 vs. 0.26±0.16 ml/min/100 g (NS), RPF: 1.15±0.36 vs. 0.78±0.44 ml/min/100 g (NS)], and failed to decrease tubulointerstitial inflammation and fibrosis. Single intrarenal injection of healthy BMCs in rats with established CKD slowed progression of the disease, associated with increased glomerular capillary density and less sclerosis, whereas injection of CKD BMCs was less effective.
• Lgr5(+ve) Stem/progenitor Cells Contribute to Nephron Formation During Kidney Development Cell Reports. Sep, 2012  |   Pubmed ID: 22999937 Multipotent stem cells and their lineage-restricted progeny drive nephron formation within the developing kidney. Here, we document expression of the adult stem cell marker Lgr5 in the developing kidney and assess the stem/progenitor identity of Lgr5(+ve) cells via in vivo lineage tracing. The appearance and localization of Lgr5(+ve) cells coincided with that of the S-shaped body around embryonic day 14. Lgr5 expression remained restricted to cell clusters within developing nephrons in the cortex until postnatal day 7, when expression was permanently silenced. In vivo lineage tracing identified Lgr5 as a marker of a stem/progenitor population within nascent nephrons dedicated to generating the thick ascending limb of Henle's loop and distal convoluted tubule. The Lgr5 surface marker and experimental models described here will be invaluable for deciphering the contribution of early nephron stem cells to developmental defects and for isolating human nephron progenitors as a prerequisite to evaluating their therapeutic potential.
• Short-term Erythropoietin Treatment Does Not Substantially Modulate Monocyte Transcriptomes of Patients with Combined Heart and Renal Failure PloS One. 2012  |   Pubmed ID: 22957013 Combined heart and renal failure is associated with high cardiovascular morbidity and mortality. Anti-oxidant and anti-inflammatory, non-hematopoietic effects of erythropoietin (EPO) treatment have been proposed. Monocytes may act as biosensors of the systemic environment. We hypothesized that monocyte transcriptomes of patients with cardiorenal syndrome (CRS) reflect the pathophysiology of the CRS and respond to short-term EPO treatment at a recommended dose for treatment of renal anemia.
• Target Organ Cross Talk in Cardiorenal Syndrome: Animal Models American Journal of Physiology. Renal Physiology. Nov, 2012  |   Pubmed ID: 22914779 The combination of chronic kidney disease (CKD) and heart failure (HF) is associated with an adverse prognosis. Although clinical studies hint at a specific bidirectional interaction between HF and CKD, insight into the pathogenesis of cardiorenal syndrome (CRS) remains limited. We review available evidence on cardiorenal interactions from animal models of CKD and HF and discuss several studies that employed a "double-hit" model to research organ cross talk between the heart and kidneys. Regarding cardiac changes in CKD models, parameters of cardiac remodeling are equivocal and cardiac systolic function generally remains preserved. Structural changes include hypertrophy, fibrosis, and microvasculopathy. In models of HF, data on renal pathology are mostly limited to functional hemodynamic changes. Most double-hit models were unable to show that combined renal and cardiac injury induces additive damage to both organs, perhaps because of the short study duration or absence of organ failure. Because of this lack of "dual-failure" models, we have developed two rat models of combined CKD and HF in which renal dysfunction induced by a subtotal nephrectomy preceded cardiac dysfunction. Cardiac dysfunction was induced either functionally by nitric oxide depletion or structurally by myocardial infarction. In both models, we found that cardiac remodeling and failure were worse in CKD rats compared with controls undergoing the same cardiac insult. Variables of renal damage, like glomerulosclerosis and proteinuria, were also further worsened by combined cardiorenal injury. These studies show that target organ cross talk does occur in CRS. These models may be useful for interventional studies in rats.
• Human Embryonic Mesenchymal Stem Cell-derived Conditioned Medium Rescues Kidney Function in Rats with Established Chronic Kidney Disease PloS One. 2012  |   Pubmed ID: 22723882 Chronic kidney disease (CKD) is a major health care problem, affecting more than 35% of the elderly population worldwide. New interventions to slow or prevent disease progression are urgently needed. Beneficial effects of mesenchymal stem cells (MSC) have been described, however it is unclear whether the MSCs themselves or their secretome is required. We hypothesized that MSC-derived conditioned medium (CM) reduces progression of CKD and studied functional and structural effects in a rat model of established CKD. CKD was induced by 5/6 nephrectomy (SNX) combined with L-NNA and 6% NaCl diet in Lewis rats. Six weeks after SNX, CKD rats received either 50 µg CM or 50 µg non-CM (NCM) twice daily intravenously for four consecutive days. Six weeks after treatment CM administration was functionally effective: glomerular filtration rate (inulin clearance) and effective renal plasma flow (PAH clearance) were significantly higher in CM vs. NCM-treatment. Systolic blood pressure was lower in CM compared to NCM. Proteinuria tended to be lower after CM. Tubular and glomerular damage were reduced and more glomerular endothelial cells were found after CM. DNA damage repair was increased after CM. MSC-CM derived exosomes, tested in the same experimental setting, showed no protective effect on the kidney. In a rat model of established CKD, we demonstrated that administration of MSC-CM has a long-lasting therapeutic rescue function shown by decreased progression of CKD and reduced hypertension and glomerular injury.
• 원래의 장소에 혈관 조직 공학에 대 한 비 계 폴리머 기반 디자인: 세포를 형성 하는 내 피 식민지의 모집 및 차별화 동작을 제어 합니다 Macromolecular Bioscience. May, 2012  |   Pubmed ID: 22566363 현장에서 혈관 조직 공학 작은 직경 혈관 대체에 대 한 필요성을 충족 하는 유망한 접근으로 제안 되었습니다. 방법 안내 및 제어 주입 된 로커 스에 셀 채용, 차별화, 그리고 조직 형성을 교육적 셀 프리 비 계를 사용 하 여 구성 됩니다. 여기 우리 혈관 벽을 구성 하는 다른 혈통으로 모집된 Ecfcs의 차별화에 대 한 특별 한 강조와 같은 건설 기계 임대에 대 한 디자인 매개 변수를 검토 합니다. 그릇의 대상 속성 정의 옆 우리 집중 대상 셀 소스, ECFCs, 그리고 여 비 계 내에서 이러한 셀의 운명의 환경 제어. 접근의 잠재 고객은 현재 기술 및 생물 학적 장애물에 비추어 설명 합니다.
• ACE Inhibition in Anti-Thy1 Glomerulonephritis Limits Proteinuria but Does Not Improve Renal Function and Structural Remodeling Nephron Extra. Jan, 2012  |   Pubmed ID: 22479264 ACE inhibitor (ACE-I) treatment effectively inhibits proteinuria and ameliorates the course of various renal diseases. In experimental glomerulonephritis, however, angiotensin II (AngII) infusion has also been shown to be renoprotective. We evaluated the long-term (28 days) course of anti-Thy1 glomerulonephritis in animals with suppressed AngII formation by ACE-I treatment.
• HEALTHY BONE MARROW CELLS REDUCE PROGRESSION OF KIDNEY FAILURE BETTER THAN CKD BONE MARROW CELLS IN RATS WITH ESTABLISHED CHRONIC KIDNEY DISEASE Cell Transplantation. Mar, 2012  |   Pubmed ID: 22469231 Chronic kidney disease (CKD) is a major health care problem. New interventions to slow or prevent disease progression are urgently needed. We studied functional and structural effects of infusion of healthy and CKD bone marrow cells (BMCs) in a rat model of established CKD. CKD was induced by 5/6 nephrectomy (SNX) in Lewis rats, and disease progression was accelerated with L-NNA and 6% NaCl diet. Six weeks after SNX, CKD rats received healthy eGFP⁺BMCs, CKD eGFP⁺BMCs, or vehicle by single renal artery injection. Healthy BMCs were functionally effective six weeks after administration: glomerular filtration rate (GFR; inulin clearance) (0.48±0.16 vs. 0.26±0.14 ml/min/100gr) and effective renal plasma flow (RPF; PAH clearance) (1.6±0.40 vs. 1.0±0.62 ml/min/100gr) were higher in healthy BMC- vs. vehicle-treated rats (both p
• Re: Angiographic Demonstration of Neoangiogenesis After Intra-arterial Infusion of Autologous Bone Marrow Mononuclear Cells in Diabetic Patients with Critical Limb Ischemia Cell Transplantation. 2012  |   Pubmed ID: 22325054
• Subtotal Nephrectomy Plus Coronary Ligation Leads to More Pronounced Damage in Both Organs Than Either Nephrectomy or Coronary Ligation American Journal of Physiology. Heart and Circulatory Physiology. Feb, 2012  |   Pubmed ID: 22140040 Coexistence of chronic kidney disease (CKD) and heart failure (HF) in humans is associated with poor outcome. We hypothesized that preexistent CKD worsens cardiac outcome after myocardial infarction, and conversely that ensuing HF worsens progression of CKD. Subtotally nephrectomized (SNX) or sham-operated (CON) rats were subjected to coronary ligation (CL) or sham surgery in week 9 to realize four groups: CON, SNX, CON + CL, and SNX + CL. Blood pressure and renal function were measured in weeks 8, 11, 13, and 15. In week 16, cardiac hemodynamics and end-organ damage were assessed. Blood pressure was significantly lower in SNX + CL vs. SNX. Despite this, glomerulosclerosis was more severe in SNX + CL vs. SNX. Two weeks after CL, SNX + CL had more cardiac dilatation compared with CON + CL (end-diastolic volume index: 0.28 ± 0.04 vs. 0.19 ± 0.03 ml/100 g body wt; mean ± SD, P < 0.001), although infarct size was similar. During follow-up in SNX + CL, ejection fraction declined. Mortality was only observed in SNX + CL (2 out of 9). In SNX + CL, end-diastolic pressure (18 ± 4 mmHg) and tau (29 ± 9 ms), the time constant of active relaxation, were significantly higher compared with SNX (13 ± 3 mmHg, 20 ± 4 ms; P < 0.01) and CON + CL (11 ± 5 mmHg, 17 ± 2 ms; P < 0.01). The diameter of small arterioles in the myocardium was significantly decreased in SNX + CL vs. CON + CL (P < 0.01). Urinary excretion of NO metabolites was significantly lower in SNX + CL compared with both CL and SNX. This study demonstrates the existence of more heart and more kidney damage in a new model of combined CKD and HF than in the individual models. Such enhanced damage appears to be separate from systemic hemodynamic changes. Reduced nitric oxide availability may have played a role in both worsened glomerulosclerosis and cardiac diastolic function and appears to be a connector in the cardiorenal syndrome.
• Hypoxia Impedes Vasculogenesis of in Vitro Engineered Bone Tissue Engineering. Part A. Jan, 2012  |   Pubmed ID: 21859278 To ensure the survival of engineered bone after implantation, we combined human endothelial colony forming cells (ECFCs) and multipotent stromal cells (MSCs) as a proof of concept in a co-culture model to create in vitro prevascularized bone constructs. We hypothesized that a hypoxic stimulus will contribute to prevascularization of engineered bone. Bone marrow-derived MSCs and ECFCs from human adult peripheral blood were allowed to form co-culture pellets containing ECFCs and MSCs (1:4) or MSCs only in controls. After culture under normoxia or hypoxia (5%), pellets were harvested and processed for immunohistochemistry of CD31, α-smooth muscle actin, and osteocalcin. Expression of vascular endothelial growth factor and SDF-1α was analyzed by PCR to elucidate their involvement in hypoxic stimulation of prevascularization. The normoxic condition in co-cultures of MSCs and ECFCs supported the formation and maintenance of prevascular structures, including organized CD31-positive cells embraced by differentiated mural cells. These structures failed to form in hypoxic conditions, thereby rejecting the hypothesis that hypoxia stimulates prevasculogenesis in three-dimensional engineered bone constructs. Further, the formation of prevascular structures was paralleled by increased SDF-1α expression. It is suggested that actual oxygen levels were below 5% in the hypoxic co-cultures, which prevented prevascular structure formation. In conclusion, our normoxic co-culture model containing cells from clinically relevant sources sustained simultaneous endothelial, smooth muscle, and osteogenic differentiation.
• Regulation of E2F1 by the Von Hippel-Lindau Tumour Suppressor Protein Predicts Survival in Renal Cell Cancer Patients The Journal of Pathology. Jun, 2013  |   Pubmed ID: 23744542 Biallelic mutations of the von Hippel-Lindau (VHL) gene are the most common cause of sporadic and inherited renal cell carcinoma (RCC). Loss of VHL has been reported to affect cell proliferation by deregulating cell cycle associated proteins. We report that the VHL gene product (pVHL) inhibits E2F1 expression at both mRNA and protein level in zebrafish and human RCC cells, while loss of VHL increases E2F1 expression in patient kidney tumour tissue and RCC cells resulting in a delay of cell cycle progression. RCCs from von Hippel-Lindau patients with known germline VHL mutations express significantly more E2F1 compared to sporadic RCCs with either clear-cell (cc) or non-cc histology. Analysis of 138 primary RCCs reveals that E2F1 expression is significantly higher in tumours with a diameter ≤7 cm and with a favourable American Joint Committee on Cancer (AJCC) stage. The expression of E2F1 in RCC significantly correlates with p27 expression, suggesting that increased expression of E2F1 in RCC induces tumour cell senescence via p27. Cox regression analysis shows significant prediction of E2F1 expression for disease-free survival and overall survival, implying that E2F1 expression in kidney tumour is a novel prognostic factor for patients with RCC.
• Impaired Endothelial Progenitor Cell Mobilization and Dysfunctional Bone Marrow Stroma in Diabetes Mellitus PloS One. 2013  |   Pubmed ID: 23555959 Circulating Endothelial Progenitor Cell (EPC) levels are reduced in diabetes mellitus. This may be a consequence of impaired mobilization of EPC from the bone marrow. We hypothesized that under diabetic conditions, mobilization of EPC from the bone marrow to the circulation is impaired -at least partly- due to dysfunction of the bone marrow stromal compartment.
• Bone Marrow Cell Therapy in Hypertensive Kidney Disease: Contribution to Cardiac Fibrosis? Journal of Hypertension. May, 2013  |   Pubmed ID: 23552031
• Inaccuracy in Determining Mean Arterial Pressure with Oscillometric Blood Pressure Techniques American Journal of Hypertension. May, 2013  |   Pubmed ID: 23547036 Accurate determination of MAP is important in the calibration of pressure waveforms for calculating central blood pressure (BP). Currently, a precise, individualized measurement of mean arterial pressure (MAP) can be obtained only with intra-arterial measurements of BP or with applanation tonometry. We conducted a study of whether easy-to-use oscillometric devices, validated for systolic and diastolic BP measurements (BHS protocol), give accurate determinations of MAP.
• Endothelial Cells Require MiR-214 to Secrete Exosomes That Suppress Senescence and Induce Angiogenesis in Human and Mouse Endothelial Cells Blood. May, 2013  |   Pubmed ID: 23532734 Signaling between endothelial cells, endothelial progenitor cells, and stromal cells is crucial for the establishment and maintenance of vascular integrity and involves exosomes, among other signaling pathways. Exosomes are important mediators of intercellular communication in immune signaling, tumor survival, stress responses, and angiogenesis. The ability of exosomes to incorporate and transfer messenger RNAs (mRNAs) encoding for "acquired" proteins or micro RNAs (miRNAs) repressing "resident" mRNA translation suggests that they can influence the physiological behavior of recipient cells. We demonstrate that miR-214, an miRNA that controls endothelial cell function and angiogenesis, plays a dominant role in exosome-mediated signaling between endothelial cells. Endothelial cell-derived exosomes stimulated migration and angiogenesis in recipient cells, whereas exosomes from miR-214-depleted endothelial cells failed to stimulate these processes. Exosomes containing miR-214 repressed the expression of ataxia telangiectasia mutated in recipient cells, thereby preventing senescence and allowing blood vessel formation. Concordantly, specific reduction of miR-214 content in exosome-producing endothelial cells abolishes the angiogenesis stimulatory function of the resulting exosomes. Collectively, our data indicate that endothelial cells release miR-214-containing exosomes to stimulate angiogenesis through the silencing of ataxia telangiectasia mutated in neighboring target cells.
• 중요 한 사지 허 혈 환자에서 헌 혈 골 수 유래 세포 치료: 무작위 통제 임상 실험의 메타 분석 Annals of Surgery. Feb, 2013  |   Pubmed ID: 23426345 배경:: 중요 한 사지 허 혈 (CLI) 말 초 동맥 질환의 가장 진보 된 단계 이며, 일반적으로 바이패스 수술이 나 혈관 내 수술 revascularization로 치료 합니다. 그러나 CLI 환자 들의 상당한 비율이 이러한 치료 전략을 받을 수 있습니다 및 절단 종종 왼쪽 유일한 옵션입니다. 지난 10 년간에서 연구는 골 수 (BM)에 초점을-사지 관류를 개선 하기 위해 neovascularization를 목표로 셀 기반 전략을 파생. 개별 연구에서는 설득의 BM 파생 셀 치료 CLI 환자에 효능을 지금까지 증명 하지 않았다. 목표:: 모든 무작위로 제어 실험 (RCTs) 공부 BM 파생 세포 치료 또는 CLI 환자에서 위약 없이 표준 치료에 비해 고이 방법에 대 한 요약 효능 데이터의 메타 분석을 수행 합니다. 방법:: Medline, Embase, 코크 레인 제어 시험 등록의 전자 데이터베이스에 체계적 검색을 수행 했다. 모든 연구 했다 비판적으로 평가 하 고 데이터 추출 및 랜덤 효과 모델을 사용 하 여 메타 분석 했다. 주요 절단 하 고 절단 무료 생존 기본 끝점으로 간주 됐다. 결과:: 12 RCTs 공동으로 510 CLI 환자를 포함 한 총 식별 하 고 분석 했다. 점수, 고통 없는 도보 거리, 발목-상 완 지 수, 그리고 transcutaneous 산소 측정 통증 즉, 메타 분석 주관적이 고 서로게이트 객관적인 끝점에 BM 파생 세포 치료의 유익한 효과 보였다 (모든 P < 0.00001). 전반적으로, RCTs 0.58 [95% 신뢰 구간 (CI), 0.40-0.84;의 주요 절단에 상대 위험 (RR) 함께 포함 된 시험의 치료 팔 감소 절단 율을 보였다 P = 0.004]. 그러나, 위약 제어 Rcts만 고려 했다 주요 절단 요금에 유익한 효과 상당히 감소 하 고 의미 (RR = 0.78, 95 %ci, 0.40-1.51; P = 0.46). 절단 무료 생존 BM 치료 및 제어 그룹 간에 크게 차이가 없었다 (RR = 1.16; 95 %ci, 0.92-1.48; P = 0.22). 결론::이 메타 분석 CLI 환자에서 BM 파생 세포 치료의 유망한 잠재력을 밑줄. 중요 한 것은, 위약 제어 및 위약 대조 Rcts의 결과 갈리는, 위약을 사용 하 여 이러한 실험의 제어 암 즈에 필요성을 강조 하는 같다. 미래 설계 큰 위약 대조 RCTs 필요 하며 치료 효과의 내 구성을 평가 하기 위해 장기 속 행 데이터를 포함 해야.
• 골 수 변경 및 중요 한 사지 허 혈 환자에서 더 낮은 내 피 뿌리 셀 번호 PloS One. 2013  |   Pubmed ID: 23383236 중요 한 사지 허 혈 (CLI) 낮은 말단 동맥 장애를 특징으로하 고 크게 설명할 수 없는 장애인 허 혈 성 neovascularization 응답. 골 수 (BM) 파생 셀 (EPC) neovascularization에 기여 하는 내 피 뿌리. 우리 가설 수준 및 순환 조상 세포의 기능 감소 및 CLI에 장애 neovascularization에 기여 하는 BM으로 변경.