Bone Marrow Mononuclear Stem Cells Research Articles

Results of a phase 1, randomized, double-blind, placebo-controlled trial of bone marrow mononuclear stem cell administration in patients following ST-elevation myocardial infarction

Initial clinical trials from Europe have demonstrated that the administration of bone marrow-derived mononuclear cells (BMCs) may improve left ventricular (LV) function in patients following ST-elevation myocardial infarction (STEMI). However, results from trials performed in the United States have not yet been presented. We developed a phase 1, randomized, placebo-controlled, double-blind trial to investigate the effects of BMC administration in patients following STEMI on recovery of LV function using cardiac magnetic resonance imaging (cMRI). Forty patients with moderate to large anterior STEMIs were randomized to 100 million intracoronary BMCs versus placebo 3 to 10 days following successful primary angioplasty and stenting (percutaneous coronary intervention) of the left anterior descending coronary artery. Administration of BMC was safely performed in a high-risk cohort with minimal major adverse clinical event rates, and all patients remain alive to date. Left ventricular ejection fraction increased from 49.0% +/- 9.5% at baseline to 55.2% +/- 9.8% at 6 months by cMRI in the BMC group (P < .05), which was not different from the increase in the placebo group (48.6% +/- 8.5% to 57.0% +/- 13.4%, P < .05). Left ventricular end-diastolic volume decreased by 4 mL/m(2) in the BMC group at 6 months but increased significantly in the placebo group (17 mL/m(2), P < .01). This phase 1 study from the United States confirms the ongoing safety profile of BMC administration in patients following STEMI. The improvement in LV ejection fraction at 6 months by cMRI in the cell therapy group was not different than the placebo group. However, BMC administration had a favorable effect on LV remodeling at 6 months.

Effect of intramyocardial delivery of autologous bone marrow mononuclear stem cells on the regional myocardial perfusion

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%, p<0.001), and global EF increased (from 38 +/- 6.1% to 41.5 +/- 8.4%, p<0.001) three months after BM-MNC delivery. Analysis of ROI resulted in a significant increase in unipolar voltage (index of myocardial viability) (from 7.9 +/- 3.0 mV to 9.9 +/- 2.7 mV at FUP, p<0.001) and local linear shortening (index of local wall motion disturbances) (from 11.0 +/- 3.9% to 12.7 +/- 3.4%, p=0.01). NOGA-guided analysis of the intramyocardially treated area revealed a significantly increased tracer uptake both at rest (from 56.7 +/- 16.1% to 62.9 +/- 14.2%, p=0.003) and at stress (from 59.3 +/- 14.2% to 62.3 +/- 14.9%, p=0.01). Patients exhibiting >or=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.

IS1-01 Liver functions after bone marrow mononuclear stem cells infusion (SCI) in infants with Extra Hepatic Biliary Atresia(Liver and Biliary ductal system,Share Smiles with Sick Children, Dreams and Innovation for Pediatric Surgery)

IS1-01 Liver functions after bone marrow mononuclear stem cells infusion (SCI) in infants with Extra Hepatic Biliary Atresia(Liver and Biliary ductal system,Share Smiles with Sick Children, Dreams and Innovation for Pediatric Surgery)

Bone marrow mononuclear stem cells: potential in the treatment of myocardial infarction

Despite advances in the management of myocardial infarction, congestive heart failure following myocardial infarction continues to be a major worldwide medical problem. Mononuclear cells from bone marrow are currently being studied as potential candidates for cell-based therapy to repair and regenerate damaged myocardium, with mixed results. The success of this strategy requires structural repair through both cardiomyogenesis and angiogenesis but also functional repair. However, pre-clinical and clinical studies with the intracoronary administration of cells indicate limited cardiomyogenesis and cell survival, controversial functional benefit and suggest paracrine effects mediated by the administered cells. Further investigations for optimizing therapeutic benefit focus on the requirement for stable cell engraftment and the involvement of cytokines in this process. This includes a large and varied range of strategies including cell or heart pre-treatment, tissue engineering and protein therapy. Although cell-based therapy holds promise in the future treatment of myocardial infarction, its current use is significantly hampered by biological and technological challenges.

TCT-194: Efficiency of Intramyocardial Injections of Aautologous Bone Marrow Mononuclear Stem Cells in Patients with Ischemic Heart Failure: Long-term Results

TCT-194: Efficiency of Intramyocardial Injections of Aautologous Bone Marrow Mononuclear Stem Cells in Patients with Ischemic Heart Failure: Long-term Results

Efficiency of Intramyocardial Injections of Autologous Bone Marrow Mononuclear Stem Cells in Patients with Ischemic Heart Failure: Long-Term Results

Introduction: Intramyocardial injection of autologous bone marrow mononuclear cells (BMMC) is believed to be a promising method for the treatment of patients with chronic ischemic heart disease. Hypothesis: To evaluate long-term results of intramyocardial bone marrow cell injection in patients with severe ischemic heart failure. Methods: Ninety nine ischemic heart failure patients (age 58 ± 5) with left ventricle ejection fraction (LVEF) ≤35% and III-IV NYHA and CCS functional classes without possibility for conventional revascularization were randomized into two groups: 1 group (n=49) - received intramyocardial BMMC injection and patients of the second group (n=50) were treated with standard medical therapy for HF. The NOGA system was used to administer 4.9 x107 BMMC into the infarction border zone. We analyzed all clinical data at 6 and 12 month of the follow-up period. Results: None of the patients developed periprocedural complications following BMMC injections. In the first group, the injections led to improvement of CCS class (3.5 ± 0.5 vs 2.1 ± 0.6 after 6 months and 1.9 ± 0.6 after 12 months (p<0.05 vs. baseline) and NYHA functional class (3.4 ± 0.1 vs 2.3 ± 0.2 after 6 months and 2.0 ± 0.2 after 12 months; p<0.05). The same characteristics in patients of the 2 group therapy remained unaltered (p = NS). LVEF increased in group 1 (34 ± 2% vs 42 ± 3%; p<0.05) while it tended to decrease in the control group (34 ± 2% vs 31 ± 3%; p = NS). Summed rest score improved in the first group after 6 months (14.7 ± 5.4 vs 10.7 ± 4.9; p<0.05). The improvement of stress score was more noticeable (18.2 ± 5.4 vs 9.4 ± 4.2; p<0.05). Neither stress nor rest score changed in patients of the second group. At the moment after 12 month follow up period 5 patients (10.2%) from group 1 died compared with 14 patients (28%) from group 2 (log rank test, p=0.008). Conclusions: Intramyocardial injection of autologous bone marrow mononuclear cells in ischemic heart failure patients is a safe procedure that improves clinical symptoms and has beneficial effecton LV function.

Cell therapy with autologous bone marrow mononuclear stem cells is associated with superior cardiac recovery compared with use of nonmodified mesenchymal stem cells in a canine model of chronic myocardial infarction

Stem cell therapy can facilitate cardiac repair in infarcted myocardium, but the optimal cell type remains uncertain. We conducted a randomized, blind, and placebo-controlled comparison of autologous bone marrow mononuclear cell and mesenchymal stem cell therapy in a large-animal model of chronic myocardial infarction. Eleven weeks after coronary ligation, 24 dogs received intramyocardial injections of mononuclear cells (227.106 +/- 32.106 cells), mesenchymal stem cells (232.106 +/- 40.106 cells), or placebo (n = 8 per group). Cardiac performance and remodeling were assessed up to 16 weeks' follow-up. At echocardiographic analysis, the wall motion score index showed a sustained improvement after mononuclear cell transfer (from 1.8 +/- 0.1 to 1.5 +/- 0.07) and a moderate late improvement after mesenchymal stem cell transfer (from 1.9 +/- 0.08 to 1.7 +/- 0.1). After mononuclear cell transfer, end-systolic elastance increased (from 2.23 +/- 0.25 to 4.42 +/- 0.55 mm Hg/mL), infarct size decreased (from 13% +/- 0.67% to 10% +/- 1.17%), N-terminal B-type natriuretic propeptide level decreased (from 608 +/- 146 to 353 +/- 118 pmol/L), and relative wall area and arterial density increased. Vascular endothelial growth factor receptor 2 expression was upregulated in the border zone. No change in cardiac contractility or histologic parameters was noted in the mesenchymal stem cell group. In a canine model of chronic myocardial infarction, bone marrow mononuclear cell transfer is superior to mesenchymal stem cell transfer in improvement of cardiac contractility and regional systolic function and reduction in infarct size and plasma N-terminal B-type natriuretic propeptide level. Functional improvement is associated with a favorable angiogenic environment and neovascularization.

Combined delivery approach of bone marrow mononuclear stem cells early and late after myocardial infarction: the MYSTAR prospective, randomized study

Combined intracoronary and intramyocardial administration might improve outcomes for bone-marrow-derived stem cell therapy for acute myocardial infarction (AMI). We compared the safety and feasibility of early and late delivery of stem cells with combined therapy approaches. Patients with left ventricular ejection fraction less than 45% after AMI were randomly assigned stem cell delivery via intramyocardial injection and intracoronary infusion 3-6 weeks or 3-4 months after AMI. Primary end points were changes in infarct size and left ventricular ejection fraction 3 months after therapy. A total of 60 patients were treated. The mean changes in infarct size at 3 months were -3.5 +/- 5.1% (95% CI -5.5% to -1.5%, P = 0.001) in the early group and -3.9 +/- 5.6% (95% CI -6.1% to -1.6%, P = 0.002) in the late group, and changes in ejection fraction were 3.5 +/- 5.6% (95% CI 1.3-5.6%, P = 0.003) and 3.4 +/- 7.0% (95% CI 0.7-6.1%, P = 0.017), respectively. At 9-12 months after AMI, ejection fraction remained significantly higher than at baseline in both groups. In the early and late groups, a mean of 200.3 +/- 68.7 x 10(6) and 194.8 +/- 60.4 x 10(6) stem cells, respectively, were delivered to the myocardium, and 1.30 +/- 0.68 x 10(9) and 1.29 +/- 0.41 x 10(9) cells, respectively, were delivered into the artery. A high number of cells was required for significant improvements in the primary end points. Combined cardiac stem cell delivery induces a moderate but significant improvement in myocardial infarct size and left ventricular function.

Abstract 2874: Bone Marrow-Derived Mononuclear Cell Transfer Is Associated with Superior Cardiac Recovery and Neovascularization as Compared to Nonmodified Mesenchymal Stem Cell Therapy in Chronic Myocardial Infarction

Background: Cell type with optimal efficacy for cardiac repair remains under discussion. We conducted a randomized, blind and placebo-controlled study with head-to-head comparison of autologous bone marrow mononuclear cells (BMNC) and autologous non-modified mesenchymal stem cells (BMSC) therapy in a large animal model of chronic MI. Methods: Eleven weeks after coronary ligation, 24 dogs received intramyocardial injections of placebo (n = 8), BMNC (227.10 6 ± 32.10 6 cells, n = 8) or nonmodified-MSC (232.10 6 ± 40.10 6 cells, n = 8). Cardiac performance and remodelling were assessed up to 16 weeks follow-up (FU). Results: (Table ) BMNC injection induced a decrease in the WMSI at 8 and 16 weeks as compared to baseline (BL). In contrast, injection of the BMSC was associated with a moderate decrease at 16 weeks vs BL. Furthermore, LV end-systolic elastance (Ees) increased only after injection of BMNC and remained unchanged after BMSCs injection. Conclusions: In the canine model of chronic MI, myocardial BMNC transfer is superior to non-modified BMSC to reduce infarct size, improve regional systolic function and cardiac contractility. Functional improvement is associated with favourable angiogenic environment and neovascularization.

Treatment with Autologous Bone Marrow Mononuclear Cells in Patients with Critical Lower Limb Ischaemia. A Pilot Study

Treatment with autologous, bone marrow mononuclear stem cells has shown effects in patients with chronic limb ischaemia in one randomized clinical study. The aim of the study was to test the potential effect of stem cell treatment in a strict defined group of patients with stable critical limb ischaemia (CLI). A prospective, combined-centre pilot study. Eight patients with CLI of the lower extremities, and without any other treatment options. Bone marrow cells were harvested from the patient's iliac crest and, after separation, injected into the calf muscles of the affected leg. Outcome was evaluated by digital subtraction angiography (DSA), visual analogue scale (VAS) and several non-invasive circulatory physiological tests. There were no complications from the procedures. Two patients were amputated two months after cell injection. Five patients reported pain relief after four months. Five patients could be evaluated at eight months. According to VAS and physiological tests, they were all either stable or showed improvement. This method seems to be a safe option for treating patients with CLI. Inclusion of patients took a long time, mainly because many patients with CLI are offered endovascular treatment in our institution. While symptomatic improvement was found in individual patients, larger trials are required to investigate efficacy. This will probably require multi-centre participation.

Autologous transplantation of bone marrow mononuclear stem cells by mini-thoracotomy in dilated cardiomyopathy: technique and early results.

There are few studies concerning bone marrow mononuclear cell (BMMC) transplantation in cases of nonischemic dilated cardiomyopathy. This study describes a novel technique of BMMC transplantation and the results up to one year after the procedure. This was a case series to evaluate the safety and viability of the procedure, at Instituto de Cardiologia do Rio Grande do Sul. Nine patients with symptomatic dilated cardiomyopathy, functional class III/IV and left ventricular ejection fraction (LVEF) < 35% received BMMC (9.6 +/- 2.6 x 107 cells) at 20 sites in the ventricular wall, by means of thoracotomy of length 5 cm in the fifth left intercostal space. Echocardiograms and nuclear magnetic resonance (NMR) were performed. There were no major complications. The functional class results for the first six patients (preoperatively and at two, four, eight and twelve-month follow-ups, respectively) were: [IV-2, III-4] to [I-5, II-1] to [I-3, II-3] to [I-2, II-3] and [I-2, II-3]. Echocardiograms showed LVEF: 25.9 +/- 8.2; 32.9 +/- 10.4; 29.4 +/- 7.2; 25.1 +/- 7.9; 25.4 +/- 6.8% (p = 0.023); and % left ventricular (LV) fiber shortening: 12.6 +/- 4.4; 16.4 +/- 5.4; 14.3 +/- 3.7; 12.1 +/- 4.0; 12.2 +/- 3.4% (p = 0.021). LV performance variation seen on NMR was non-significant. Intramyocardial transplantation of BMMC in dilated cardiomyopathy cases is feasible and safe. There were early improvements in symptoms and LV performance. Medium-term evaluation revealed regression of LV function, although maintaining improved functional class.

Comparison of different needle diameters and flow rates on bone marrow mononuclear stem cell viability: an ex vivo experimental study

Considerable information is available regarding the experimental and clinical applications of bone marrow derived stem cells (BMDSC) for regenerative medicine. Optimized stem cell delivery systems might help to maintain better stem cell viability. We have investigated whether needle diameters and flow rates through the needles cause any difference in terms of BMDSC viability.

Selection using the alpha-1 integrin (CD49a) enhances the multipotentiality of the mesenchymal stem cell population from heterogeneous bone marrow stromal cells

Bone marrow-derived mesenchymal stem cells consist of a developmentally heterogeneous population of cells obtained from colony forming progenitors. As these colonies express the alpha-1 integrin (CD49a), here we single-cell FACS sorted CD49a+ cells from bone marrow in order to create clones and then compared their colony forming efficiency and multilineage differentiation capacity to the unsorted cells. Following selection, 40% of the sorted CD49a+ cells formed colonies, whereas parental cells failed to form colonies following limited dilution plating at 1 cell/well. Following ex vivo expansion, clones shared a similar morphology to the parental cell line, and also demonstrated enhanced proliferation. Further analysis by flow cytometry using a panel of multilineage markers demonstrated that the CD49a+ clones had enhanced expression of CD90 and CD105 compared to unsorted cells. Culturing cells in adipogenic, osteogenic or chondrogenic medium for 7, 10 and 15 days respectively and then analysing them by quantitative PCR demonstrated that CD49a+ clones readily underwent multlineage differentiation into fat, bone and cartilage compared to unsorted cells. These results thus support the use of CD49a selection for the enrichment of mesenchymal stem cells, and describes a strategy for selecting the most multipotential cells from a heterogeneous pool of bone marrow mononuclear stem cells.

Bone Marrow Mononuclear Stem Cells Transplanted in Rat Infarct Myocardium Improved the Electrical Conduction without Evidence of Proarrhythmic Effects

PurposeThe arrhythmogenic effect of stem cells transplantation (SCT) in an infarct myocardium is still unknown. We investigated arrhythmogenicity of SCT in rat cryo-infarct model.Materials and MethodsIn rat cryo-infarct model, bone marrow mononuclear stem cells (MNSC, 1 × 107 cells) were transplanted into the infarct border zone (BZ) of the LV epicardium. We compared the optical mapping and inducibility of ventricular tachycardia/fibrillation (VT/VF) among normal (n = 5), cryo-infarct (n = 6), and SCT rats (n = 6).ResultsThe VT/VF inducibility was higher in the cryoinfarct (47.2%, p = 0.001) and SCT groups (34.6%, p = 0.01) than in the normal group (12.8%). The induced VT/VF episodes persisted for more than 2 minutes in 4.3%, 26.4% and 17.3% in the normal, cryo-infarct and SCT group, respectively. In the SCT group, the action potential duration at 70% was shorter at the SCT site than the BZ during SR (75.2 ± 8.1 vs. 145.6 ± 4.4 ms, p = 0.001) and VT (78.2 ± 13.0 vs. 125.7 ± 21.0 ms, p = 0.001). Conduction block was observed at the SCT site and BZ during VT. However, no reentry or ectopic foci were observed around the SCT sites.ConclusionThe electrical conduction was improved by SCT without evidence of augmentation of arrhythmia in the rat cryo-infarct model.

Cryopreservation of human platelets and bone marrow and peripheral blood totipotential mononuclear stem cells.

Human platelets in sufficient numbers for a therapeutic transfusion can be collected for preservation either by pooling ABO- and Rh-compatible platelets or by apheresis procedures using mechanical cell-separating machines. Human platelets have been frozen successfully with 5 or 6% dimethyl sulfoxide (DMSO) and stored at -150 or -180 degrees C, respectively. Platelets frozen with 5% DMSO have been stored at -150 degrees C for at least 3 years, and platelets frozen with 6% DMSO have been stored at -80 degrees C for at least 2 years. Approximately 95% of the DMSO usually is removed by washing the platelets after thawing, and the residual DMSO produces no untoward effects. Washed platelets resuspended in plasma can be stored at room temperature for 6 to 8 hr before transfusion. Platelets thus frozen have freeze-thaw-wash recovery values of about 80%. In vivo survival values are only about 50% those seen with fresh platelets, and it is necessary to transfuse twice as many to achieve comparable results. Studies have shown that these platelets have satisfactory circulation, reduce clinical bleeding, and shorten the prolonged bleeding times associated with thrombocytopenia. Studies are now being made on human bone marrow and peripheral blood, from which totipotential cells devoid of immunocompetent cells can be isolated and frozen.