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Objective: Our objective was to elucidate long-term clinical and functional effects of intramyocardial stem cell transplant and to identify patients who will show sustained benefit., Methods: Long-term outcomes of 35 patients after intramyocardial CD133(+) bone marrow stem cell transplant during coronary artery bypass grafting were compared with those of a control group of 20 patients after coronary artery bypass grafting alone. Clinical effects were assessed with the New York Heart Association classification system and the Minnesota Living With Heart Failure questionnaire. Electrocardiography, 24-hour Holter monitoring, echocardiography, myocardial perfusion scanning, magnetic resonance imaging, and computed tomography were performed. Logistic regression analyses were used to identify prognostic factors for improvement in long-term left ventricular ejection fraction after stem cell treatment., Results: The stem cell group revealed similar New York Heart Association and life quality scores to the control group. Myocardial perfusion score at the area of risk was significantly increased in the stem cell group after 36-month follow-up (P = .024 vs control). Multivariate logistic regression analysis revealed a 44-fold higher probability of at least 5% improvement in left ventricular ejection fraction for patients with preoperative left ventricular ejection fraction not greater than 40% than for patients with preoperative ejection fraction greater than 40% (P = .018). Furthermore, patients operated on between 7 and 12 weeks after myocardial infarction had a 56-fold higher chance of at least 5% improvement in left ventricular ejection fraction than patients treated later than 12 weeks after infarction (P = .023)., Conclusions: Intramyocardial stem cell therapy was safe but lacked significant lasting benefits beyond 6 months in our study cohort with a limited number of patients. Preoperative left ventricular ejection fraction and time since myocardial infarction may be critical parameters for selection of patients who can benefit most from intramyocardial stem cell treatment during coronary artery bypass grafting., (Copyright © 2011 The American Association for Thoracic Surgery. All rights reserved.)

Objective: The development of biological valve prostheses with lifetime native-like performance and optimal host engraftment is an ultimate goal of heart valve tissue engineering. We describe a new concept for autologous graft coating based on a CD133(+)-stem-cells-plus-fibrin (SC+F) complex processed from bone marrow and peripheral blood of a single patient., Methods: CD133(+)-SC (1 × 10(6) cells/mL) from human bone marrow and autologous fibrin (20 mg/mL) were administered simultaneously via spray administration using the novel Vivostat Co-Delivery System. During static cultivation, SC+F performance was monitored for 20 days after delivery and compared with controls. For dynamic testing SC+F-composite was sprayed on a decellularized porcine pulmonary valve and transferred to a bioreactor under pulsatile flow conditions for 7 days., Results: Static cultivation of SC+F-composite induced significant improvements in stem cell proliferation as compared with controls. For dynamic testing, microscopic analyses on a smooth engineered heart valve surface detected homogenous distribution of stem cells. Ultrasonic analysis revealed native-like valve performance. Applied CD133(+) stem cells differentiated into endothelial-like cells positive for CD31 and vascular endothelial growth factor receptor 2 and engrafted the valve. However, occasional delamination was observed., Conclusion: SC+F serves as an excellent autologous matrix for intraoperative tissue engineering of valve prostheses promising optimal in vivo integration. However, stability remains an issue.

Stem cell treatment for acute or chronic ischemic myocardium has gained major attention in the last decade. Experimental and clinical studies have shown evidence for functional improvement after cell-based treatments in acute or chronically ischemic jeopardized myocardium. Since 2001 we have performed bone marrow-derived CD133+ stem cell transplantations with concomitant coronary artery bypass surgery. Although our focus is mainly on the functional results of the stem cell treatment, possible long-term side effects of the new therapeutic strategy should also be addressed. Here we present for the first time the long-term follow-up safety results of the Rostock trial after direct intramyocardial stem cell treatment in 32 patients.

Despite improvements in emergency treatment, myocardial infarction is often the beginning of a downward spiral leading to congestive heart failure. Other than heart transplantation, current therapeutic means aim at enabling the organism to survive with a heart that is working at a fraction of its original capacity. It is therefore no surprise that cardiac stem cell therapy has raised many hopes. However, neither the ideal source and type of stem cell nor the critical cell number and mode of application have been defined so far. Early reports on myocardial repair by adult bone marrow stem cells from rodent models promoted an unparalleled boost of clinical and experimental cell therapy studies. The phenomenon of stem/progenitor cell-induced angiogenesis in ischemic myocardium has ever since been reproduced by numerous groups in a variety of small and large animal models. Myogenesis, however, is an altogether different matter. Many of the initial clinical studies were fueled by the suggestion that early hematopoietic stem cells have a plasticity high enough to enable cross-lineage differentiation into cells of cardiomyocyte phenotype, but the initial enthusiasm has largely faded. The myogenic potential of stroma cell-derived mesenchymal stem cells is much better documented in animal models, but transfer to the clinical setting faces a variety of obstacles. In clinical pilot trials, we and others have demonstrated the feasibility and safety of administering progenitor cells derived from autologous bone marrow to the myocardium of patients with ischemic heart disease. Clinical efficacy data are still rare, but the few controlled trials that have been completed uniformly show a tendency towards better heart function in cell-treated patients. This review is an attempt to describe the scientific basis for cardiac cell therapy from the point of view of the clinician, focusing on problems that arise with beginning translation into the clinical setting.

Matrigel promotes angiogenesis in the myocardium from ischemic injury and prevents remodelling of the left ventricle. We assessed the therapeutic efficacy of intracardiac matrigel injection and matrigel-mediated stem cell homing in a rat myocardial infarction (MI) model. Following MI, matrigel (250 μl) or phosphate-buffered solution (PBS) was delivered by intracardiac injection. Compared to the MI control group (MI-PBS), matrigel significantly improved left ventricular function ( n= 11, P < 0.05) assessed by pressure-volume loops after 4 weeks. There is no significant difference in infarct size between MI-matrigel (MI-M; 21.48 ± 1.49%, n= 10) and MI-PBS hearts (20.98 ± 1.25%, n= 10). The infarct wall thickness of left ventricle is significantly higher ( P < 0.01) in MI-M (0.72 ± 0.02 mm, n= 10) compared with MI-PBS (0.62 ± 0.02 mm, n= 10). MI-M hearts exhibited higher capillary density (border 130.8 ± 4.7 versus 115.4 ± 6.0, P < 0.05; vessels per high-power field [HPF; 400×], n= 6) than MI-PBS hearts. c-Kit stem cells (38.3 ± 5.3 versus 25.7 ± 1.5 c-Kit cells per HPF [630×], n= 5, P < 0.05) and CD34 cells (13.0 ± 1.51 versus 5.6 ± 0.68 CD34 cells per HPF [630×], n= 5, P < 0.01) were significantly more numerous in MI-M than in MI-PBS in the infarcted hearts ( n= 5, P < 0.05). Intracardiac matrigel injection restores myocardial functions following MI, which may attribute to the improved recruitment of CD34 and c-Kit stem cells. [ABSTRACT FROM AUTHOR]

Stromal cell-derived factor-1α (SDF-1α) mediated mobilization and homing of stem cells showed promising potential in stem cell based tissue engineering and regenerative medicine. However local and sustained release of SDF-1α is indispensable for stem cell mediated regenerative process due to its short half-life under inflammatory conditions. In this study, a gene activated collagen substrate (GAC) was formed via assembly of plasmid encoding SDF-1α into a collagen substrate to create a microenvironment favoring stem cell homing. Local release of SDF-1α from the transfected cells on GAC and its effect on CD117+ stem cell homing were investigated. Non-viral poly-ethyleneimine (25kDa PEI)/DNA complexes were mixed with rat tail collagen solution to form the GAC. Optimization of GAC was carried out based on collagen effects on the PEI/DNA complexes, viability and luciferase expression of COS7 cells on GAC. CD117+ stem cells homing in response to SDF-1α local expression from transfected cells on GAC were investigated in a flow chamber in vitro and in a mouse hind limb model in vivo. The gene expression, migration of CD117+ stem cells and the induced inflammation were investigated with immunostaining, reverse transcription polymerase chain reaction (RT-PCR) and H&E staining. The optimized parameters for GAC were DNA dosage 10 μg/cm2, molar ratio of PEI nitrogen in primary amine to DNA phosphate (N/P ratio) 4 and mass ratio of collagen to DNA (C/D ratio) 1.0. It kept cell viability above 75% and transfection efficiency around 5.8 × 105 RLU/mg protein. GAC allowed the sustained gene release up to 60 days. GAC mediated SDF-1α gene release induced migration and homing of CD117+ stem cells in vitro and in vivo significantly, and the inflammation of GAC reduced significantly two weeks after transplantation. GAC is a promising stem cell based therapeutic strategy for regenerative medicine. [ABSTRACT FROM AUTHOR]

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Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. Especially the treatment of ischemic heart disease challenges physicians despite recent advances in medical and operative strategies. Due to the considerable developments in regenerative medicine cell-based treatment for ischemic heart disease has attracted great interest in the last decade. Numerous experimental and clinical approaches employing stem cell treatment from various sources and using different methods of cell delivery have shown improvement in cardiac function after acute or chronic ischemic jeopardy. In this report we will focus on our long-term experience on the safety of bone marrow derived CD133+ stem cell transplantation with concomitant coronary artery bypass surgery and provide an overview of the current knowledge on utilizing cell-based treatment for ischemic heart disease. [ABSTRACT FROM AUTHOR]

Although studies in vivo revealed promising results in bone regeneration after implantation of scaffolds together with osteogenic progenitor cells, basic questions remain how material surfaces control the biology of mesenchymal stem cells (MSC).We used human MSC derived from bone marrow and studied the osteogenic differentiation on calcium phosphate surfaces. In osteogenic differentiation medium MSC differentiated to osteoblasts on hydroxyapatite and BONITmatrix®, a degradable xerogel composite, within 14 days. Cells revealed a higher alkaline phosphatase (ALP) activity and increased RNA expression of collagen I and osteocalcin using real-time RTPCR compared with cells on tissue culture plastic. To test whether material surface characteristics alone are able to stimulate osteogenic differentiation, MSC were cultured on the materials in expansion medium without soluble additives for osteogenic differentiation. Indeed, cells on calcium phosphate without osteogenic differentiation additives developed to osteoblasts as shown by increased ALP activity and expression of osteogenic genes, which was not the case on tissue culture plastic. Because we reasoned that the stimulating effect on osteogenesis by calcium phosphate surfaces depends on an altered cell-extracellular matrix interaction we studied the dynamic behaviour of focal adhesions using cells transfected with GFP labelled vinculin. On BONITmatrix®, an increased mobility of focal adhesions was observed compared with cells on tissue culture plastic. In conclusion, calcium phosphate surfaces are able to drive MSC to osteoblasts in the absence of osteogenic differentiation supplements in the medium. An altered dynamic behaviour of focal adhesions on calcium phosphate surfaces might be involved in the molecular mechanisms which promote osteogenic differentiation. [ABSTRACT FROM AUTHOR]

Objective: Our objective was to elucidate long-term clinical and functional effects of intramyocardial stem cell transplant and to identify patients who will show sustained benefit. Methods: Long-term outcomes of 35 patients after intramyocardial CD133+ bone marrow stem cell transplant during coronary artery bypass grafting were compared with those of a control group of 20 patients after coronary artery bypass grafting alone. Clinical effects were assessed with the New York Heart Association classification system and the Minnesota Living With Heart Failure questionnaire. Electrocardiography, 24-hour Holter monitoring, echocardiography, myocardial perfusion scanning, magnetic resonance imaging, and computed tomography were performed. Logistic regression analyses were used to identify prognostic factors for improvement in long-term left ventricular ejection fraction after stem cell treatment. Results: The stem cell group revealed similar New York Heart Association and life quality scores to the control group. Myocardial perfusion score at the area of risk was significantly increased in the stem cell group after 36-month follow-up (P = .024 vs control). Multivariate logistic regression analysis revealed a 44-fold higher probability of at least 5% improvement in left ventricular ejection fraction for patients with preoperative left ventricular ejection fraction not greater than 40% than for patients with preoperative ejection fraction greater than 40% (P = .018). Furthermore, patients operated on between 7 and 12 weeks after myocardial infarction had a 56-fold higher chance of at least 5% improvement in left ventricular ejection fraction than patients treated later than 12 weeks after infarction (P = .023). Conclusions: Intramyocardial stem cell therapy was safe but lacked significant lasting benefits beyond 6 months in our study cohort with a limited number of patients. Preoperative left ventricular ejection fraction and time since myocardial infarction may be critical parameters for selection of patients who can benefit most from intramyocardial stem cell treatment during coronary artery bypass grafting. [ABSTRACT FROM AUTHOR]