Stem cells and cardiac repair


Br Med Bull. 2010;94:65-80. Epub 2010 Mar 2.
Cell therapy for cardiac repair.
Lee J, Terracciano CM.
Imperial College London, National Heart and Lung Institute, Harefield Heart Science Centre, Harefield, Middlesex, UB9 6JH, UK.
Heart failure is a leading cause of morbidity and mortality worldwide. The current strategies for treatment are limited and new therapeutic approaches are needed. This review describes research performed in animal models of cardiac disease and clinical trials and discusses the mechanisms involved in possible beneficial effects of cell therapy. Cell therapy is a promising strategy to treat heart failure, as it aims to replenish the failing myocardium with contractile elements. However, cell therapy with adult progenitor cells induces a small improvement in heart function without significant cardiomyogenesis. Paracrine mechanisms are likely to be important. The most effective cell type for therapy remains unclear. Induced pluripotent stem cells have the greatest potential but more information on the properties of this cell type is needed. The integration of cells in the host myocardium and the routes of delivery remain controversial. The differentiation of cardiac cells from pluri- and multipotent cells and the understanding of their properties are growing points in cell therapy. More research is needed to correctly assess the physiological properties of differentiating cells, to dissect the role of the host environment in the integration and differentiation and to define the stage of differentiation required for cell transplantation.
[PubMed – indexed for MEDLINE] • Stem cell therapies to treat muscular dystrophy: progress to date.
• BioDrugs. 2010 Aug 1;24(4):237-47
• Authors: Meregalli M, Farini A, Parolini D, Maciotta S, Torrente Y
• Muscular dystrophies are heritable, heterogeneous neuromuscular disorders and include Duchenne and Becker muscular dystrophies (DMD and BMD, respectively). DMD patients exhibit progressive muscle weakness and atrophy followed by exhaustion of muscular regenerative capacity, fibrosis, and eventually disruption of the muscle tissue architecture. In-frame mutations in the dystrophin gene lead to expression of a partially functional protein, resulting in the milder BMD. No effective therapies are available at present. Cell-based therapies have been attempted in an effort to promote muscle regeneration, with the hope that the host cells would repopulate the muscle and improve muscle function and pathology. Injection of adult myoblasts has led to the development of new muscle fibers, but several limitations have been identified, such as poor cell survival and limited migratory ability. As an alternative to myoblasts, stem cells were considered preferable for therapeutic applications because of their capacity for self-renewal and differentiation potential. In recent years, encouraging results have been obtained with adult stem cells to treat human diseases such as leukemia, Parkinson’s disease, stroke, and muscular dystrophies. Embryonic stem cells (ESCs) can be derived from mammalian embryos in the blastocyst stage, and because they can differentiate into a wide range of specialized cells, they hold potential for use in treating almost all human diseases. Several ongoing studies focus on this possibility, evaluating differentiation of specific cell lines from human ESCs (hESCs) as well as the potential tumorigenicity of hESCs. The most important limitation with using hESCs is that it requires destruction of human blastocysts or embryos. Conversely, adult stem cells have been identified in various tissues, where they serve to maintain, generate, and replace terminally differentiated cells within their specific tissue as the need arises for cell turnover or from tissue injury. Moreover, these cells can participate in regeneration of more than just their specific tissue type. Here we describe multiple types of muscle- and fetal-derived myogenic stem cells, their characterization, and their possible use in treating muscular dystrophies such as DMD and BMD. We also emphasize that the most promising possibility for the management and therapy of DMD and BMD is a combination of different approaches, such as gene and stem cell therapy.
• PMID: 20623990 [PubMed – in process] • Immunodeficiency reduces neural stem/progenitor cell apoptosis and enhances neurogenesis in the cerebral cortex after stroke.

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• Am Heart J. 2010 Jul;160(1):58-64
• Authors: Sürder D, Schwitter J, Moccetti T, Astori G, Rufibach K, Plein S, Lo Cicero V, Soncin S, Windecker S, Moschovitis A, Wahl A, Erne P, Jamshidi P, Auf der Maur C, Manka R, Soldati G, Bühler I, Wyss C, Landmesser U, Lüscher TF, Corti R
• BACKGROUND: Recent studies report that intracoronary administration of autologous bone marrow mononucleated cells (BM-MNCs) may improve remodeling of the left ventricle after acute myocardial infarction (AMI). Subgroup analysis suggest that early treatment between days 4 and 7 after AMI is probably most effective; however, the optimal time point of intracoronary cell administration has never been addressed in clinical trials. Furthermore, reliable clinical predictors are lacking for identifying patients who are thought to have most benefit from cellular therapy. STUDY DESIGN: In a multicenter trial, 192 patients with AMI successfully treated by percutaneous coronary intervention (PCI) of the infarct-related artery will be randomized in a 1:1:1 pattern to 1 control and 2 BM-MNC treatment groups. The control group will be treated with state-of-the-art medical management. The treatment groups will receive intracoronary administration of autologous BM-MNC at 5 to 7 days or 3 to 4 weeks after the initial event, respectively. Left ventricular function as well as scar size, transmural extension, and regional wall motion score will be assessed by cardiac magnetic resonance (CMR) studies at baseline and after 4 and 12 months. METHODS: Fifty milliliters of bone marrow will be harvested by aspiration from the iliac crest and then carried by courier to a centralized cell processing facility. The mononucleated cell fraction will be isolated by density gradient centrifugation, washed, and resuspended in 10 mL of injection medium. The cells will be characterized by fluorescence-activated cell sorting analysis and tested for sterility and potency both “in vitro” and “in vivo.” Bone marrow MNC will then be reinfused directly in the infarct-related coronary artery. END POINTS: The primary end point is the change in global left ventricular (LV) ejection fraction by CMR at 4 months as compared to baseline. Comparisons will then be made between each of the prespecified therapy subgroups (early and late after AMI) and the control group. Secondary end points include change in infarct size, change in regional myocardial thickness, and wall motion at 4 and 12 months compared to baseline. Infarct extension (size and transmural extension), time delay to PCI, and coronary flow characteristics after PCI will be assessed as potential predictors of LV remodeling and change after cell therapy. Major adverse cardiac events (MACE) (death, myocardial infarction, coronary revascularization, rehospitalization for heart failure) will be assessed at 4, 12, and 24 months and time to MACE will be estimated. DISCUSSION: With the present study, we aim to determine the optimal time point of intracoronary administration of autologous BM-MNC after AMI on LV remodeling.
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• J Transl Med. 2010;8:63
• Authors: Leu S, Lin YC, Yuen CM, Yen CH, Kao YH, Sun CK, Yip HK
• BACKGROUND: The therapeutic effect of adipose-derived mesenchymal stem cells (ADMSCs) on brain infarction area (BIA) and neurological status in a rat model of acute ischemic stroke (IS) was investigated. METHODS: Adult male Sprague-Dawley (SD) rats (n = 30) were divided into IS plus intra-venous 1 mL saline (at 0, 12 and 24 h after IS induction) (control group) and IS plus intra-venous ADMSCs (2.0 x 106) (treated interval as controls) (treatment group) after occlusion of distal left internal carotid artery. The rats were sacrificed and brain tissues were harvested on day 21 after the procedure. RESULTS: The results showed that BIA was larger in control group than in treatment group (p < 0.001). The sensorimotor functional test (Corner test) identified a higher frequency of turning movement to left in control group than in treatment group (p < 0.05). mRNA expressions of Bax, caspase 3, interleukin (IL)-18, toll-like receptor-4 and plasminogen activator inhibitor-1 were higher, whereas Bcl-2 and IL-8/Gro were lower in control group than in treatment group (all p < 0.05). Western blot demonstrated a lower CXCR4 and stromal-cell derived factor-1 (SDF-1) in control group than in treatment group (all p < 0.01). Immunohistofluorescent staining showed lower expressions of CXCR4, SDF-1, von Willebran factor and doublecortin, whereas the number of apoptotic nuclei on TUNEL assay was higher in control group than in treatment group (all p < 0.001). Immunohistochemical staining showed that cellular proliferation and number of small vessels were lower but glial fibrillary acid protein was higher in control group than in treatment group (all p < 0.01). CONCLUSIONS: ADMSC therapy significantly limited BIA and improved sensorimotor dysfunction after acute IS.
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• Authors: Mansour S, Roy DC, Bouchard V, Nguyen BK, Stevens LM, Gobeil F, Rivard A, Leclerc G, Reeves F, Noiseux N
• Stem cell therapy has emerged as a promising approach to improve healing of the infarcted myocardium, to treat or prevent cardiac failure, and to restore lost cardiac function. Despite initial excitement, recent clinical trials using nonhomogenous human stem cells preparations showed variable results, raising concerns about the best cell type to transplant. Selected CD133(+) hematopoietic stem cells are promising candidate cells with great potential. COMPARE-acute myocardial infarction (AMI) study is a phase II, randomized, double-blind, placebo-controlled trial evaluating the safety and effectiveness of intracoronary CD133(+)-enriched hematopoietic bone marrow stem cells in patients with acute myocardial infarction and persistent left ventricular dysfunction. Patients who underwent successful percutaneous coronary intervention and present a persistent left ventricular ejection fraction • PMID: 20560029 [PubMed – indexed for MEDLINE] • Chronic treatment with clenbuterol modulates endothelial progenitor cells and circulating factors in a murine model of cardiomyopathy.
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• Authors: Nguyen BK, Maltais S, Perrault LP, Tanguay JF, Tardif JC, Stevens LM, Borie M, Harel F, Mansour S, Noiseux N
• Transplantation of mesenchymal stem cells (MSC) improves repair and function recovery following myocardial infarction (MI), but underlying mechanisms remain to be elucidated. We hypothesize that MSC could achieve protection by paracrine effects through released mediators rather than direct cardiac regeneration. We sought to characterize the effects of MSC-secreted growth factors on extent of early recovery from MI. Swine subjected to acute MI by temporary balloon occlusion of the left anterior descending coronary artery using percutaneous techniques received intracoronary injection of either concentrated MSC-derived growth factors or control medium. Animals were killed at 7 days to evaluate early effects. Treatment with MSC-derived factors significantly reduced cardiac troponin-T elevation and improved echocardiographic parameters, including fractional area shortening, stroke volume, cardiac output, and wall motion score index. Quantitative evaluation of fibrosis by Verhoff staining revealed a reduction of the fibrotic area in the infarcted zone. Similarly, Masson’s trichrome staining revealed reduced myocardial damage as demonstrated by areas of relatively preserved myocardium in the infarcted area. TUNEL assay demonstrated less cardiomyocyte apoptosis. Protein array detected the presence of angiogenic (vascular endothelial growth factor, endothelin, and epiregulin), anti-apoptotic (Galectin-3, Smad-5, sRFP-1, and sRFP-4) and anti-remodeling factors. Reverse transcription polymerase chain reaction confirmed the expression of these factors. In summary, a single intracoronary injection of concentrated biologically active factors secreted by MSC could achieve early protection of ischemic myocardium and improve cardiac repair and contractility. MSC-derived growth factors injection (rather than MSC themselves) should be evaluated as a novel therapy to treat ischemic heart disease, avoiding many practical and technical issues of cell therapy.
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• Authors: Sun L, Zhang T, Lan X, Du G
• OBJECTIVES: The objective was to perform a meta-analysis of clinical trials that investigated the effects of stem cell therapy on left ventricular remodeling in patients after acute myocardial infarction (AMI). BACKGROUND: Intracoronary injection of stem cells in the acute phase of myocardial infarction has been proposed to replace the cardiomyocytes lost and to prevent deleterious pathological remodeling after myocardial infarction. Previously published trials have investigated the effects of cell therapy on left ventricular (LV) remodeling in AMI patients. However, the sample size of these studies is small and the conclusions are inconsistent. METHODS: Trials were identified in the Cochrane Library, EMBASE, and PubMed databases, reviews, and reference lists of relevant articles. The weighted mean difference (WMD) was calculated for net changes in LV end-diastolic and end-systolic volumes (LVEDV and LVESV) by using fixed-effect models. RESULTS: A total of 11 trials (13 comparisons) with 832 participants evaluated the association between stem cell therapy and changes in LVEDV. Compared with the control group, stem cell therapy did not influence the LVEDV changes from baseline to follow-up (WMD: – 1.76 mL, 95% confidence interval [CI]: – 4.61 to 1.08 mL, P = 0.233). A total of 9 trials (11 comparisons) with 797 participants evaluated the association between stem cell therapy and changes in LVESV. Compared with the control group, patients in the cell therapy group had a significantly greater reduction in LVESV from baseline to follow-up (WMD: – 5.08 mL, 95% CI: – 7.80 to – 2.37 mL, P < 0.001). CONCLUSION: This meta-analysis suggests that cell therapy improves left ventricular contractility, but has no effect on LV remodeling.
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• Peripheric stem cell transplantation in children with dilated cardiomyopathy: preliminary report of first two cases.
• Pediatr Transplant. 2010 Mar;14(2):257-60
• Authors: Olguntürk R, Kula S, Sucak GT, OzdoÄŸan ME, Erer D, Saygili A
• We report two pediatric patients with IDC who underwent autologous PSCT. Both cases were referred to our clinic for cardiac transplantation because of end-stage heart failure resistant to conventional therapy with digoxin, diuretics, ACE inhibitors, and sympathomimetics. They had ejection fractions below 35%. In each case, autologous stem cell transplantation was performed via the coronary arteries, and five wk after the procedure transthoracic echocardiography showed a striking gain in their ejection fractions and an improvement in the left ventricular dimensions compared with the initial measurements. Although heart transplantation is the only option for children with IDC, stem cell transplantation can lessen the waiting list mortality and prolong the time for a patient to wait for a suitable donor.
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• Am J Physiol Heart Circ Physiol. 2010 Jul;299(1):H125-33
• Authors: Graham JJ, Foltz WD, Vaags AK, Ward MR, Yang Y, Connelly KA, Vijayaraghavan R, Detsky JS, Hough MR, Stewart DJ, Wright GA, Dick AJ
• Magnetic resonance imaging (MRI) can track progenitor cells following direct intramyocardial injection. However, in the vast majority of post-myocardial infarction (MI) clinical trials, cells are delivered by the intracoronary (IC) route, which results in far greater dispersion within the myocardium. Therefore, we assessed whether the more diffuse distribution of cells following IC delivery could be imaged longitudinally with MRI. In 11 pigs (7 active, 4 controls), MI was induced by 90-min balloon occlusion of the left anterior descending coronary artery. Seven (0) days [median (interquartile range)] following MI, bone marrow progenitor cells (BMCs) were colabeled with an iron-fluorophore and a cell viability marker and delivered to the left anterior descending coronary artery distal to an inflated over-the-wire percutaneous transluminal coronary angioplasty balloon. T2*-weighted images were used to assess the location of the magnetically labeled cells over a 6-wk period post-MI. Immediately following cell delivery, hypointensity characteristic of the magnetic label was observed in the infarct border rather than within the infarct itself. At 6 wk, the cell signal hypointensity persisted, albeit with significantly decreased intensity. BMC delivery resulted in significant improvement in infarct volume and ejection fraction (EF): infarct volume in cell-treated animals decreased from 7.1 +/- 1.5 to 4.9 +/- 1.0 ml (P < 0.01); infarct volume in controls was virtually unchanged at 4.64 +/- 2.1 to 4.39 +/- 2.1 ml (P = 0.7). EF in cell-treated animals went from 30.4 +/- 5.2% preinjection to 34.5 +/- 2.5% 6 wk postinjection (P = 0.013); EF in control animals went from 34.3 +/- 4.7 to 31.9 +/- 6.8% (P = 0.5). Immunohistochemical analysis revealed intracellular colocalization of the iron fluorophore and cell viability dye with the labeled cells continuing to express the same surface markers as at baseline. MRI can track the persistence and distribution of magnetically labeled BMCs over a 6-wk period following IC delivery. Signal hypointensity declines with time, particularly in the first week following delivery. These cells maintain their original phenotype during this time course. Delivery of these cells appears safe and results in improvement in infarct size and left ventricular ejection fraction.
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• Expert Opin Biol Ther. 2010 May;10(5):667-80
• Authors: Jiang M, He B, Zhang Q, Ge H, Zang MH, Han ZH, Liu JP, Li JH, Zhang Q, Li HB, Jin Y, He Q, Gong XR, Yin XY
• OBJECTIVE: We performed a systematic meta-analysis to assess the therapeutic effects of progenitor cell therapy after myocardial infarction (MI). RESEARCH DESIGN/METHODS: Randomized controlled trials of progenitor cell therapy for MI were extracted from MEDLINE. We performed a prospective comparison of progenitor cell therapy versus placebo after acute or chronic MI, with changes in left ventricular ejection fraction (LVEF) as the primary endpoint. We conducted random-effects meta-analyses to pool these outcomes across the studies. RESULTS: A total of 980 patients from 18 studies were analysed. Seventeen trials used bone marrow-derived cells (BMCs). Overall, BMCs significantly increased LVEF, left ventricular end systolic volume and left ventricular end diastolic volume within six months of treatment, and the effect was sustained one year later. Following BMC transplantation regional myocardial anatomy displayed statistically and clinically significant improvements compared with controls, albeit without functional changes. Similar results were observed in the subgroup of patients with impaired LVEF at the baseline. The subgroup analysis suggested a benefit of BMCs on LVEF in acute but not chronic MI. LVEF enhancement seemed to correlate positively with dose and inversely with the storage duration of the BMCs. CONCLUSIONS: BMC transplantation for MI was able to deliver benefits over regular therapy even at an 18-month follow-up, particularly when used to treat acute MI. CD34(+) cell therapy holds promise for MI treatment in the future.
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• Coron Artery Dis. 2010 Jun;21(4):233-43
• Authors: Luan Y, Liu XC, Zhang GW, Shi RF, Zhao XB, Zhao CH, Liu TJ, Lü F, Yang Q, He GW
• BACKGROUND: We aimed to confirm the mid-term results of the new method combined with bone marrow-derived mesenchymal stem cells (MSCs) transplantation and transmyocardial drilling revascularization (TMDR) with degradable stent incorporated with basic fibroblast growth factor and heparin. METHODS: The miniswine underwent acute myocardial infarction by ligation of the left anterior descending coronary artery. Transmyocardial channels with 3.5 mm diameter (TMDR) were made by mechanical drilling in the infarction territory and basic fibroblast growth factor stents were implanted into the channels. Animals were randomly divided into the following four groups (n=6 in each): control; II: MSCs implantation; III: TMDR+stent implantation; IV: TMDR+stent implantation+MSCs implantation. Three months postoperatively, ECG-gated single photon emission computed tomography, histopathological examination, and reverse transcription-polymerase chain reaction were carried out. RESULTS: Left ventricular ejection fraction and myocardial perfusion were significantly improved in group IV than that in other groups (P • PMID: 20375694 [PubMed – indexed for MEDLINE]

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• Cardiovasc Revasc Med. 2010 Apr-Jun;11(2):72-8
• Authors: Flores-Ramìrez R, Uribe-Longoria A, Rangel-Fuentes MM, Gutiérrez-Fajardo P, Salazar-Riojas R, Cervantes-Garcìa D, Treviño-Ortiz JH, Benavides-Chereti GJ, Espinosa-Oliveros LP, Limón-Rodrìguez RH, Monreal-Puente R, González-Treviño JL, Rojas-Martìnez A
• AIM: To assess the safety and efficacy of the intracoronary infusion of CD133+ hematopoietic stem cells to improve ventricular function and quality of life in candidates for heart transplantation due to post-infarct chronic heart failure. METHODS: We selected seven candidates for heart transplantation (six males/one female, age range 44-65 years) in whom all treatment alternatives were exhausted (angioplasty/stent and bypass surgery). These subjects had a symptomatic New York Heart Association (NYHA) scale of at least II and ejection fractions (EFs) below 35%. After obtaining informed consent, CD133+ cells were obtained by stimulation with granulocyte-colony stimulating factor, apheresis, and separation with magnetic beads. Stem cells were implanted in the infarcted zone via intracoronary percutaneous angiography. Evaluations (NYHA scale classification, plasma concentration of pro-B-natriuretic-peptide and the risk of sudden death, echocardiography, cardiac magnetic resonance, and gated-SPECT with MIBI) were performed at baseline and at 3, 6, 12, and 24 months after cell infusion. RESULTS: Stem cell isolation was efficient and safe (around 10(7) cells/patient and >92% CD133+ viable cells). Two patients died during observation due to noncardiac conditions. In the five remaining subjects, the NYHA scale improved and no accounts of hospital admissions for heart failure were documented. Plasma concentrations of pro-B-natriuretic peptide and the risk of sudden death clearly decreased, while the EF increased significantly to 35% and 40% by echocardiography and cardiac MRI, respectively (P=.013 and .009, respectively) 24 months after treatment. No other major adverse events were noticed. CONCLUSIONS: The intracoronary inoculation of CD133+ stem cells was safe and effective to improve ventricular contraction and symptomatic class function in patients with refractory post-infarct heart failure.
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• Asian Cardiovasc Thorac Ann. 2010 Feb;18(2):153-60
• Authors: Bourahla B, Shafy A, Meilhac O, Elmadbouh I, Michel JB, Chachques JC
• Cell transplantation for the regeneration of ischemic myocardium is limited by poor graft viability and low cell retention. Omental flaps in association with growth factors and cell sheets have recently been used to increase the vascularization of ischemic hearts. This experimental study was undertaken to evaluate the hemodynamic evolution and histological modifications of infarcted myocardium treated with mesothelial cells, and to compare the results with those of hearts treated with skeletal myoblasts. Myocardial infarction was created by surgical ligature of 2 coronary branches in 34 sheep; 6 died immediately due to ventricular fibrillation. Mesothelial cells were isolated from greater omentum, and myoblasts from skeletal muscle. After expanding the cells for 3 weeks, infarcted areas were treated with culture medium (control group), mesothelial cells, or myoblasts. After 3 months, echocardiographic studies showed significant limitation of ventricular dilatation and improved ejection fractions in both cell-treated groups compared to the controls. In the mesothelial cell group, histological studies showed significantly more angiogenesis and arteriogenesis than in the control and skeletal myoblast groups. Mesothelial cells might be useful for biological revascularization in patients with ischemic heart disease.
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• Changes in left ventricular filling patterns after repeated injection of autologous bone marrow cells in heart failure patients.
• Scand Cardiovasc J. 2010 Jun;44(3):139-45
• Authors: Diederichsen AC, Møller JE, Thayssen P, Videbaek L, Saekmose SG, Barington T, Kassem M
• OBJECTIVES: We have previously shown that repeated intracoronary infusion of bone marrow cells (BMSC) did not improve left ventricular (LV) ejection fraction in patients with chronic ischemic heart failure. However, the impact of BMSC therapy on LV diastolic filling has remained uncertain. DESIGN: Thirty two patients with LV ejection fraction less than 40% were studied. Each patient underwent three baseline echocardiograms to ensure stable LV filling. Infusion of BMSC was given at baseline and again after four months. Echocardiograms were repeated four, eight and 12 months after the first intervention. Main outcome measures were the ratio of transmitral flow (E) velocity to early mitral annulus (e’) velocity (E/e’), left atrial (LA) volume and plasma levels of N-terminal pro-brain natriuretic peptide (NT-pro-BNP). RESULTS: During the initial observational period there were no changes in main outcome. After treatment with intracoronary BMSC a significant decrease was observed in E/e’ ratio (14.7+/-6.7 vs. 13.2+/-7.7, p=0.04), LA volume (90+/-25 ml vs. 80+/-26 ml, p=0.006) and plasma NT-pro-BNP (p=0.03). The effect was greatest in patients who received the largest amount of CD34(+) cells. CONCLUSION: In this non-randomised study repeated intracoronary BMSC infusions had a beneficial effect on LV filling in patients with chronic ischemic heart failure. Randomised studies are warranted.
• PMID: 20233136 [PubMed – indexed for MEDLINE] • Temporal alterations in cardiac fibroblast function following induction of pressure overload.
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• Cell Tissue Res. 2010 Apr;340(1):117-26
• Authors: Stewart JA, Massey EP, Fix C, Zhu J, Goldsmith EC, Carver W
• Increases in cardiovascular load (pressure overload) are known to elicit ventricular remodeling including cardiomyocyte hypertrophy and interstitial fibrosis. While numerous studies have focused on the mechanisms of myocyte hypertrophy, comparatively little is known regarding the response of the interstitial fibroblasts to increased cardiovascular load. Fibroblasts are the most numerous cell type in the mammalian myocardium and have long been recognized as producing the majority of the myocardial extracellular matrix. It is only now becoming appreciated that other aspects of fibroblast behavior are important to overall cardiac function. The present studies were performed to examine the temporal alterations in fibroblast activity in response to increased cardiovascular load. Rat myocardial fibroblasts were isolated at specific time-points (3, 7, 14, and 28 days) after induction of pressure overload by abdominal aortic constriction. Bioassays were performed to measure specific parameters of fibroblast function including remodeling and contraction of 3-dimensional collagen gels, migration, and proliferation. In addition, the expression of extracellular matrix receptors of the integrin family was examined. Myocardial hypertrophy and fibrosis were evident within 7 days after constriction of the abdominal aorta. Collagen gel contraction, migration, and proliferation were enhanced in fibroblasts from pressure-overloaded animals compared to fibroblasts from sham animals. Differences in fibroblast function and protein expression were evident within 7 days of aortic constriction, concurrent with the onset of hypertrophy and fibrosis of the intact myocardium. These data provide further support for the idea that rapid and dynamic changes in fibroblast phenotype accompany and contribute to the progression of cardiovascular disease.
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• J Cereb Blood Flow Metab. 2010 Aug;30(8):1487-93
• Authors: Kawai H, Yamashita T, Ohta Y, Deguchi K, Nagotani S, Zhang X, Ikeda Y, Matsuura T, Abe K
• Stroke is a major neurologic disorder. Induced pluripotent stem (iPS) cells can be produced from basically any part of patients, with high reproduction ability and pluripotency to differentiate into various types of cells, suggesting that iPS cells can provide a hopeful therapy for cell transplantation. However, transplantation of iPS cells into ischemic brain has not been reported. In this study, we showed that the iPS cells fate in a mouse model of transient middle cerebral artery occlusion (MCAO). Undifferentiated iPS cells (5 x 10(5)) were transplanted into ipsilateral striatum and cortex at 24 h after 30 mins of transient MCAO. Behavioral and histologic analyses were performed at 28 day after the cell transplantation. To our surprise, the transplanted iPS cells expanded and formed much larger tumors in mice postischemic brain than in sham-operated brain. The clinical recovery of the MCAO+iPS group was delayed as compared with the MCAO+PBS (phosphate-buffered saline) group. iPS cells formed tridermal teratoma, but could supply a great number of Dcx-positive neuroblasts and a few mature neurons in the ischemic lesion. iPS cells have a promising potential to provide neural cells after ischemic brain injury, if tumorigenesis is properly controlled.
• PMID: 20216552 [PubMed – indexed for MEDLINE] • Fatal neurotoxicity in a patient with down syndrome treated with chemotherapy, irradiation, stem cell transplant, and clofarabine.
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• Results of intracoronary stem cell therapy after acute myocardial infarction.
• Am J Cardiol. 2010 Mar 15;105(6):804-12
• Authors: Wöhrle J, Merkle N, Mailänder V, Nusser T, Schauwecker P, von Scheidt F, Schwarz K, Bommer M, Wiesneth M, Schrezenmeier H, Hombach V
• To assess the effect of autologous bone-marrow cell (BMC) therapy in patients with acute myocardial infarction in a rigorous double-blind, randomized, placebo-controlled trial. Patients with reperfusion >6 hours after symptom onset were randomly assigned in a 2:1 ratio to receive intracoronary BMC or placebo therapy 5 to 7 days after symptom onset. The patients were stratified according to age, acute myocardial infarction localization, and left ventricular (LV) function. Rigorous double-blinding was ensured using autologous erythrocytes for the placebo preparation that was visually indistinguishable from the active treatment. Serial cardiac magnetic resonance imaging studies were performed before study therapy and after 1, 3, and 6 months. The primary end point was the difference in the LV ejection fraction from baseline to 6 months. The secondary end points included changes in the LV end-diastolic and end-systolic volume indexes and infarct size. A total of 42 patients were enrolled (29 in the BMC group and 13 in the placebo group) in the integrated pilot phase. A mean of 381 x 10(6) mononuclear BMCs were administered. The baseline clinical and cardiac magnetic resonance imaging parameters did not differ. Compared to baseline, the difference in LV ejection fraction for the placebo group versus BMC group was 1.7 +/- 6.4% versus -0.9 +/- 5.5% at 1 month, 3.1 +/- 6.0% versus 1.9 +/- 4.3% at 3 months, and 5.7 +/- 8.4% versus 1.8 +/- 5.3% at 6 months (primary end point; not significant). No difference was found in the secondary end points between the 2 groups, including changes in infarct size or LV end-diastolic and end-systolic volume indexes. In conclusion, in this rigorous double-blind, randomized, placebo-controlled trial, we did not observe an evidence for a positive effect for intracoronary BMC versus placebo therapy with respect to LV ejection fraction, LV volume indexes, or infarct size.
• PMID: 20211323 [PubMed – indexed for MEDLINE] • Combinated transplantation of neural stem cells and collagen type I promote functional recovery after cerebral ischemia in rats.
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• Long-term functional improvement and gene expression changes after bone marrow-derived multipotent progenitor cell transplantation in myocardial infarction.
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• Long-term functional improvement and gene expression changes after bone marrow-derived multipotent progenitor cell transplantation in myocardial infarction.
• Am J Physiol Heart Circ Physiol. 2010 May;298(5):H1348-56
• Authors: Jameel MN, Li Q, Mansoor A, Qiang X, Sarver A, Wang X, Swingen C, Zhang J
• The study examined the long-term outcome of cardiac stem cell transplantation in hearts with postinfarction left ventricular (LV) remodeling. Myocardial infarction (MI) was created by ligating the first and second diagonal branches of the left anterior descending coronary artery in miniature swine. Intramyocardial injections of 50 million LacZ-labeled bone marrow-derived multipotent progenitor cells (MPC) were performed in the periscar region (Cell, n = 7) immediately after MI, whereas, in control animals (Cont, n = 7), saline was injected. Functional outcome was assessed monthly for 4 mo with MRI and (31)P-magnetic resonance spectroscopy. Engraftment was studied on histology, and gene chip (Affymetrix) array analysis was used to study differential expression of genes in the two groups. MPC treatment resulted in improvement of ejection fraction as early as 10 days after MI (Cell, 43.4 +/- 5.1% vs. Cont, 32.2 +/- 5.5%; P < 0.05). This improvement was seen each month and persisted to 4 mo (Cell, 51.2 +/- 4.8% vs. Cont, 35.7 +/- 5.0%; P < 0.05). PCr-to-ATP ratio (PCr/ATP) improved with MPC transplantation, which was most pronounced at high cardiac work states (subendocardial PCr/ATP was 1.70 +/- 0.10 vs. 1.34 +/- 0.14, P < 0.05). There was no significant difference in scar size (scar/LV area * 100) at 10 days postinfarction. However, at 4 mo, there was a significant decrease in scar size in the Cell group (Cell, 4.6 +/- 1.0% vs. Cont, 8.6 +/- 2.4%; P < 0.05). No significant engraftment of MPC was observed. MPC transplantation was associated with a downregulation of mitochondrial oxidative enzymes and increased levels of myocyte enhancer factor 2a and zinc finger protein 91. In conclusion, MPC transplantation leads to long-term functional and bioenergetic improvement in a porcine model of postinfarction LV remodeling, despite no significant engraftment of stem cells in the heart. MPC transplantation reduces regional wall stresses and infarct size and mitigates the adverse effects of LV remodeling, as seen by a reduction in LV hypertrophy and LV dilatation, and is associated with differential expression of genes relating to metabolism and apoptosis.
• PMID: 20173039 [PubMed – indexed for MEDLINE] • Brain self-protection: the role of endogenous neural progenitor cells in adult brain after cerebral cortical ischemia.
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• The year in heart failure.
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• The year in heart failure.
• J Am Coll Cardiol. 2010 Feb 16;55(7):688-96
• Authors: Tang WH, Francis GS
• PMID: 20170796 [PubMed – indexed for MEDLINE] • Direct myocardial implantation of human fetal stem cells in heart failure patients: long-term results.
• Heart Surg Forum. 2010 Feb 1;13(1):E31-5
• Authors: Benetti F, Peñherrera E, Maldonado T, Vera YD, Subramanian V, Geffner L
• BACKGROUND: End-stage heart failure (HF) is refractory to current standard medical therapy, and the number of donor hearts is insufficient to meet the demand for transplantation. Recent studies suggest autologous stem cell therapy may regenerate cardiomyocytes, stimulate neovascularization, and improve cardiac function and clinical status. Although human fetal-derived stem cells (HFDSCs) have been studied for the treatment of a variety of conditions, no clinical studies have been reported to date on their use in treating HF. We sought to determine the efficacy and safety of HFDSC treatment in HF patients. METHODS AND RESULTS: Direct myocardial transplantation of HFDSCs by open-chest surgical procedure was performed in 10 patients with HF due to nonischemic, nonchagasic dilated cardiomyopathy. Before and after the procedure, and with no changes in their preoperative doses of medications (digoxin, furosemide, spironolactone, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, betablockers), patients were assessed for New York Heart Association (NYHA) class, performance in the exercise tolerance test (ETT), ejection fraction (EF), left ventricular end-diastolic dimension (LVEDD) via transthoracic echocardiography, performance in the 6-minute walk test, and performance in the Minnesota congestive HF test. All 10 patients survived the operation. One patient had a stroke 3 days after the procedure, and although she later recovered, she was unable to perform the follow-up tests. Another male patient experienced pericardial effusion 3 weeks after the procedure. Although it resolved spontaneously, the patient abandoned his control tests and died 5 months after the procedure. An autopsy of the myocardium suggested that new young cells were present in the cardiomyocyte mix. At 40 months, the mean (+/-SD) NYHA class decreased from 3.4 +/- 0.5 to 1.33 +/- 0.5 (P = .001); the mean EF increased 31%, from 26.6% +/- 4% to 34.8% +/- 7.2% (P = .005); and the mean ETT increased 291.3%, from 4.25 minutes to 16.63 minutes (128.9% increase in metabolic equivalents, from 2.46 to 5.63) (P < .0001); the mean LVEDD decreased 15%, from 6.85 +/- 0.6 cm to 5.80 +/- 0.58 cm (P < .001); mean performance in the 6-minute walk test increased by 43.2%, from 251 +/- 113.1 seconds to 360 +/- 0 seconds (P = .01); the mean distance increased 64.4%, from 284.4 +/- 144.9 m to 468.2 +/- 89.8 m (P = .004); and the mean result in the Minnesota test decreased from 71 +/- 27.3 to 6 +/- 5.9 (P < .001). CONCLUSION: Although these initial findings suggest direct myocardial implantation of HFDSCs is feasible and improves cardiac function in HF patients at 40 months, more clinical research is required to confirm these observations.
• PMID: 20150037 [PubMed – indexed for MEDLINE] •

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• Transplantation of cardiac progenitor cell sheet onto infarcted heart promotes cardiogenesis and improves function.
• Cardiovasc Res. 2010 Jul 1;87(1):40-9
• Authors: Zakharova L, Mastroeni D, Mutlu N, Molina M, Goldman S, Diethrich E, Gaballa MA
• AIMS: Cell-based therapy for myocardial infarction (MI) holds great promise; however, the ideal cell type and delivery system have not been established. Obstacles in the field are the massive cell death after direct injection and the small percentage of surviving cells differentiating into cardiomyocytes. To overcome these challenges we designed a novel study to deliver cardiac progenitor cells as a cell sheet. METHODS AND RESULTS: Cell sheets composed of rat or human cardiac progenitor cells (cardiospheres), and cardiac stromal cells were transplanted onto the infarcted myocardium after coronary artery ligation in rats. Three weeks later, transplanted cells survived, proliferated, and differentiated into cardiomyocytes (14.6 +/- 4.7%). Cell sheet transplantation suppressed cardiac wall thinning and increased capillary density (194 +/- 20 vs. 97 +/- 24 per mm(2), P < 0.05) compared with the untreated MI. Cell migration from the sheet was observed along the necrotic trails within the infarcted area. The migrated cells were located in the vicinity of stromal-derived factor (SDF-1) released from the injured myocardium, and about 20% of these cells expressed CXCR4, suggesting that the SDF-1/CXCR4 axis plays, at least, a role in cell migration. Transplantation of cell sheets resulted in a preservation of cardiac contractile function after MI, as was shown by a greater ejection fraction and lower left ventricular end diastolic pressure compared with untreated MI. CONCLUSION: The scaffold-free cardiosphere-derived cell sheet approach seeks to efficiently deliver cells and increase cell survival. These transplanted cells effectively rescue myocardium function after infarction by promoting not only neovascularization but also inducing a significant level of cardiomyogenesis.
• PMID: 20118202 [PubMed – indexed for MEDLINE] • New concepts in cardiac stem cell therapy.
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• New concepts in cardiac stem cell therapy.
• Hellenic J Cardiol. 2010 Jan-Feb;51(1):10-4
• Authors: Wojakowski W, Tendera M
• PMID: 20118038 [PubMed – indexed for MEDLINE] • Human cord blood stem cells enhance neonatal right ventricular function in an ovine model of right ventricular training.
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• Human cord blood stem cells enhance neonatal right ventricular function in an ovine model of right ventricular training.
• Ann Thorac Surg. 2010 Feb;89(2):585-93, 593.e1-4
• Authors: Davies B, Elwood NJ, Li S, Cullinane F, Edwards GA, Newgreen DF, Brizard CP
• BACKGROUND: Nonischemic right ventricular dysfunction and cardiac failure is a source of considerable morbidity in children with congenital heart disease. Cell transplantation has not previously been studied in the pediatric setting in which enhancing ventricular function in response to supraphysiologic workloads might be beneficial. METHODS: Engraftment and differentiation of human cord blood stem cells were studied in an immunosuppressed neonatal ovine model of right ventricular training. Week-old sheep underwent pulmonary artery banding and epicardial injection of cord blood stem cells (n=8) or pulmonary artery banding and placebo injection (n=8). Control groups received cord blood stem cells (n=6) or placebo (n=6) injection without pulmonary artery banding. Right ventricular function was measured at baseline and 1 month later using conductance catheter. RESULTS: Cord blood stem cells were detected in the myocardium, spleen, kidney, and bone marrow up to 6 weeks after transplantation and expressed the hematopoietic markers CD45 and CD23. We identified neither differentiation nor fusion of transplanted human cells. In the groups undergoing pulmonary artery banding, cord blood stem cell transplantation was accompanied by functional benefits compared with placebo injection: end-systolic elastance increased by a mean of 1.4 +/- 0.2 mm Hg/mL compared with 0.9 +/- 0.1 mm Hg/mL, and the slope of preload recruitable stroke work increased by 21.1 +/- 2.9 mm Hg compared with 15.8 +/- 2.5 mm Hg. Cord blood stem cell transplantation had no significant effect on right ventricular function in the absence of pulmonary artery banding. CONCLUSIONS: Our data demonstrate that in the presence of increased workload, cord blood stem cells engraft and augment right ventricular function. Transplanted cells adopt hematopoietic fates in the myocardium, bone marrow, and spleen.
• PMID: 20103347 [PubMed – indexed for MEDLINE] •
• Effect of intramyocardial delivery of autologous bone marrow mononuclear stem cells on the regional myocardial perfusion. NOGA-guided subanalysis of the MYSTAR prospective randomised study.
• Thromb Haemost. 2010 Mar 1;103(3):564-71
• Authors: Charwat S, Lang I, Dettke M, Graf S, Nyolczas N, Hemetsberger R, Zamini S, Khorsand A, Sochor H, Maurer G, Glogar D, Gyöngyösi M
• The aim of the sub-study of the MYSTAR randomised trial was to analyse the changes in myocardial perfusion in NOGA-defined regions of interest (ROI) with intramyocardial injections of autologous bone marrow mononuclear cells (BM-MNC) using an elaborated transformation algorithm. Patients with recent first acute myocardial infarction (AMI) and left ventricular (LV) ejection fraction (EF) between 30-45% received BM-MNC by intramyocardial followed by intracoronary injection 68 +/- 34 days post-AMI (pooled data of MYSTAR). NOGA-guided endocardial mapping and 99m-Sestamibi-SPECT (single photon emission computer tomography) were performed at baseline and at three months follow-up (FUP). ROI was delineated as a best polygon by connecting of injection points of NOGA polar maps. ROIs were projected onto baseline and FUP polar maps of SPECT calculating the perfusion severity of ROI. Infarct size was decreased (from 27.2 +/- 10.7% to 24.1 +/- 11.5%, por=5% improvement in perfusion defect severity received a significantly higher number of intramyocardial BM-MNC. In conclusion, combined cardiac BM-MNC delivery induces significant improvement in myocardial viability and perfusion in the intramyocardially injected area.
• PMID: 20076851 [PubMed – indexed for MEDLINE] • Preclinical assessment of stem cell therapies for neurological diseases.
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• Neural stem cell niches and homing: recruitment and integration into functional tissues.
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• Stroke rehabilitation 2009: old chestnuts and new insights.
• Stroke. 2010 Feb;41(2):e88-90
• Authors: Kalra L
• The past year has continued to see growth in stroke rehabilitation literature, ranging from important insights into the basic science of stroke recovery to broader multidisciplinary aspects aimed at improving global quality of life in stroke survivors. The areas that particularly stand out include 1) new evidence on old treatment strategies in clinical rehabilitation; 2) developments in the treatment of “neglected” impairments, such as hemianopia and sensory loss; 3) evaluation of the use of technology in stroke rehabilitation; and 4) advances in neurorestorative treatments after stroke.
• PMID: 20075345 [PubMed – indexed for MEDLINE] •
• Stem cells in human neurodegenerative disorders–time for clinical translation?
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• Stem cell experiments and initial clinical trial of cellular cardiomyoplasty.
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• Stem cell experiments and initial clinical trial of cellular cardiomyoplasty.
• Asian Cardiovasc Thorac Ann. 2009 Dec;17(6):581-6
• Authors: Guhathakurta S, Subramanyan UR, Balasundari R, Das CK, Madhusankar N, Cherian KM
• Growing myocardial cells from human stem cells and stem cell transplantation to repair injured myocardium are new frontiers in cardiovascular research. The 1st stage of this study was conducted to determine whether transplantation of autologous bone marrow stem cells into infarcted myocardium of sheep could differentiate into beating cardiomyocytes. The 2nd stage was to demonstrate transdifferentiation of human bone marrow mesenchymal stem cells to precursor cardiomyocytes in vitro, using a novel conditioning medium. In the 3rd stage, a clinical trial of stem cell implantation in patients with severe myocardial dysfunction involved injection of peripheral blood-derived endothelial precursor cells in 11 patients and autologous bone marrow mononuclear cells in 29. A marginal improvement in myocardial function was noted at 3 months (mean increase in ejection fraction, 6% +/- 1%), although it plateaued at 6 months. The trial proved to be safe because there was no procedure-related mortality. There is growing optimism that stem cell therapy may delay heart transplantation.
• PMID: 20026532 [PubMed – indexed for MEDLINE]

• Intramyocardial transplantation of fibroblasts expressing vascular endothelial growth factor attenuates cardiac dysfunction.
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• Intramyocardial transplantation of fibroblasts expressing vascular endothelial growth factor attenuates cardiac dysfunction.
• Gene Ther. 2010 Mar;17(3):305-14
• Authors: Gonçalves GA, Vassallo PF, dos Santos L, Schettert IT, Nakamuta JS, Becker C, Tucci PJ, Krieger JE
• In this study, we analyzed whether transplantation of cardiac fibroblasts (CFs) expressing vascular endothelial growth factor (VEGF) mitigates cardiac dysfunction after myocardial infarction (MI) in rats. First, we observed that the transgene expression lasts longer (45 vs 7 days) when fibroblasts are used as vectors compared with myoblasts. In a preventive protocol, induction of cardiac neovascularization accompanied by reduction in myocardial scar area was observed when cell transplantation was performed 1 week before ischemia/reperfusion and the animals analyzed 3 weeks later. Finally, the therapeutic efficacy of this approach was tested injecting cells in a fibrin biopolymer, to increase cardiac retention, 24 h post-MI. After 4 weeks, an increase in neovascularization and a decrease in myocardial collagen were observed only in rats that received cells expressing VEGF. Basal indirect or direct hemodynamic measurements showed no differences among the groups whereas under pharmacological stress, only the group that received cells expressing VEGF showed a significant reduction in end-diastolic pressure and improvement in stroke volume and cardiac work. These results indicate that transplantation of CFs expressing VEGF using fibrin biopolymer induces neovascularization and attenuates left ventricle fibrosis and cardiac dysfunction in ischemic heart.
• PMID: 20010629 [PubMed – indexed for MEDLINE] • [Autologous stem cell therapy with surgical myocardial revascularization] • Anadolu Kardiyol Derg. 2009 Dec;9(6):465-6
• Authors: Durdu S, CubukçuoÄŸlu Deniz G, Akar AR
• PMID: 19965316 [PubMed – indexed for MEDLINE] • Relationship of circulating endothelial progenitor cells to the recurrence of atrial fibrillation after successful conversion and maintenance of sinus rhythm.
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• Relationship of circulating endothelial progenitor cells to the recurrence of atrial fibrillation after successful conversion and maintenance of sinus rhythm.
• Europace. 2010 Apr;12(4):517-21
• Authors: Siu CW, Watson T, Lai WH, Lee YK, Chan YH, Ng KM, Lau CP, Lip GY, Tse HF
• AIMS: To determine whether the number of circulating endothelial progenitor cells (EPCs) in patients with persistent atrial fibrillation (AF) predicts arrhythmia recurrence after direct current cardioversion (DCCV). METHODS AND RESULTS: The numbers of circulating CD34+/KDR+ EPCs were determined with flow cytometry in 51 consecutive patients with persistent AF [the mean age: 67 +/- 1.3 years, male (65%)] prior to DCCV and were compared with that of age- and sex-matched controls, and cohorts of patients with coronary artery disease and ischaemic stroke. The AF recurrence rate at 1 year was also determined. The EPCs in patients with persistent AF, patients with coronary artery disease, and patients with ischaemic stroke were significantly lower than that of the age- and sex-matched controls (P < 0.01). One year after successful DCCV, patients with high EPC count (50th to 100th percentile) had a higher recurrence rate of AF when compared with those with low EPC count (less than 50th percentile) (73 vs. 40%, P = 0.02). Cox regression analysis revealed the high EPC count was the only independent predictors for the AF recurrence (HR: 2.29, P = 0.047). CONCLUSION: The number of EPCs is reduced in patients with persistent AF and predicts the recurrence of AF after successful DCCV.
• PMID: 19951966 [PubMed – indexed for MEDLINE]

• The cardiomyocyte lineage is critical for optimization of stem cell therapy in a mouse model of myocardial infarction.
• FASEB J. 2010 Apr;24(4):1073-81
• Authors: Adler ED, Chen VC, Bystrup A, Kaplan AD, Giovannone S, Briley-Saebo K, Young W, Kattman S, Mani V, Laflamme M, Zhu WZ, Fayad Z, Keller G
• We recently described a murine embryonic stem cell (ESC) line engineered to express the activated Notch 4 receptor in a tetracycline (doxcycline; Dox) regulated fashion (tet-notch4 ESCs). Notch 4 induction in Flk1(+) hematopoietic and vascular progenitors from this line respecified them to a cardiovascular fate. We reasoned that these cells would be ideal for evaluating the contribution of the cardiomyocyte and vascular lineages to the functional improvement noted following stem cell transplantation in infarcted hearts. Flk-1(+) Tet-notch4 cells from d 3 embryoid bodies exposed to doxycycline (Dox(+)) were compared to uninduced (Dox(-)) Flk-1(+) cells. Mice underwent transplantation of 5 x 10(5) Dox(+) cells, Dox(-)cells, or an equal volume of serum-free medium after surgically induced myocardial infarction. The mean ejection fraction was 59 + or – 15, 46 + or – 17, and 39 + or – 13% in the Dox(+), Dox(-), and serum-free medium groups, respectively (P • PMID: 19940262 [PubMed – indexed for MEDLINE]

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