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Impact of Cell Composition and Geometry on Human Induced Pluripotent Stem Cells-Derived Engineered Cardiac Tissue.

Jue, 04/06/2017 - 19:52
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Impact of Cell Composition and Geometry on Human Induced Pluripotent Stem Cells-Derived Engineered Cardiac Tissue.

Sci Rep. 2017 Apr 03;7:45641

Authors: Nakane T, Masumoto H, Tinney JP, Yuan F, Kowalski WJ, Ye F, LeBlanc AJ, Sakata R, Yamashita JK, Keller BB

Abstract
The current study describes a scalable, porous large-format engineered cardiac tissue (LF-ECT) composed of human induced pluripotent stem cells (hiPSCs) derived multiple lineage cardiac cells with varied 3D geometries and cell densities developed towards the goal of scale-up for large animal pre-clinical studies. We explored multiple 15 × 15 mm ECT geometries using molds with rectangular internal staggered posts (mesh, ME), without posts (plain sheet, PS), or long parallel posts (multiple linear bundles, ML) and a gel matrix containing hiPSC-derived cardiomyocytes, endothelial, and vascular mural cells matured in vitro for 14 days. ME-ECTs displayed the lowest dead cell ratio (p < 0.001) and matured into 0.5 mm diameter myofiber bundles with greater 3D cell alignment and higher active stress than PS-ECTs. Increased initial ECT cell number beyond 6 M per construct resulted in reduced cell survival and lower active stress. The 6M-ME-ECTs implanted onto 1 week post-infarct immune tolerant rat hearts engrafted, displayed evidence for host vascular coupling, and recovered myocardial structure and function with reduced scar area. We generated a larger (30 × 30 mm) ME-ECT to confirm scalability. Thus, large-format ECTs generated from hiPSC-derived cardiac cells may be feasible for large animal preclinical cardiac regeneration paradigms.

PMID: 28368043 [PubMed - in process]

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Cardiomyogenic Differentiation of Human Dental Follicle-derived Stem Cells by Suberoylanilide Hydroxamic Acid and Their In Vivo Homing Property.

Lun, 04/03/2017 - 18:10
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Cardiomyogenic Differentiation of Human Dental Follicle-derived Stem Cells by Suberoylanilide Hydroxamic Acid and Their In Vivo Homing Property.

Int J Med Sci. 2016;13(11):841-852

Authors: Sung IY, Son HN, Ullah I, Bharti D, Park JM, Cho YC, Byun JH, Kang YH, Sung SJ, Kim JW, Rho GJ, Park BW

Abstract
The purpose of the present study was to investigate the in vitro cardiomyogenic differentiation potential of human dental follicle-derived stem cells (DFCs) under the influence of suberoylanilide hydroxamic acid (SAHA), a member of the histone deacetylase inhibitor family, and analyze the in vivo homing capacity of induced cardiomyocytes (iCMs) when transplanted systemically. DFCs from extracted wisdom teeth showed mesenchymal stem cell (MSC) characteristics such as plate adherent growing, expression of MSC markers (CD44, CD90, and CD105), and mesenchymal lineage-specific differentiation potential. Adding SAHA to the culture medium induced the successful in vitro differentiation of DFCs into cardiomyocytes. These iCMs expressed cardiomyogenic markers, including alpha-smooth muscle actin (α-SMA), cardiac muscle troponin T (TNNT2), Desmin, and cardiac muscle alpha actin (ACTC1), at both the mRNA and protein level. For the assessment of homing capacity, PKH26 labeled iCMs were intraperitoneally injected (1×10(6) cells in 100 µL of PBS) into the experimental mice, and the ratios of PKH26 positive cells to the total number of injected cells, in multiple organs were determined. The calculated homing ratios, 14 days after systemic cell transplantation, were 5.6 ± 1.0%, 3.6 ± 1.1%, and 11.6 ± 2.7% in heart, liver, and kidney respectively. There was no difference in the serum levels of interleukin-2 and interleukin-10 at 14 days after transplantation, between the experimental (iCM injected) and control (no injection or PBS injection) groups. These results demonstrate that DFCs can be an excellent source for cardiomyocyte differentiation and regeneration. Moreover, the iCMs can be delivered into heart muscle via systemic administration without eliciting inflammatory or immune response. This can serve as the pilot study for further investigations into the in vitro cardiomyogenic differentiation potential of DFCs under the influence of SAHA and the in vivo homing capacity of the iCMs into the heart muscle, when injected systemically.

PMID: 27877076 [PubMed - indexed for MEDLINE]

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Sirtuin1 Regulates the Stem Cell Therapeutic Effects on Regenerative Capability for Treating Severe Heart Failure in a Juvenile Animal Model.

Lun, 04/03/2017 - 18:10
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Sirtuin1 Regulates the Stem Cell Therapeutic Effects on Regenerative Capability for Treating Severe Heart Failure in a Juvenile Animal Model.

Ann Thorac Surg. 2016 Sep;102(3):803-12

Authors: Ozawa H, Miyagawa S, Fukushima S, Itoh E, Harada A, Saito A, Ueno T, Toda K, Kuratani T, Sawa Y

Abstract
BACKGROUND: This study hypothesized that autologous cell transplantation therapy could have greater therapeutic efficacy in juvenile patients than in adult patients, related to differences in sirtuin1 (SIRT1) expression in transplanted cells.
METHODS: A model of heart failure was established in mini-pigs by using coronary artery occlusion. Stem cell cultures were established from juvenile and adult mini-pigs. The cells were prepared as cell sheets and transplanted into corresponding adult or juvenile mini-pigs, and the therapeutic effects were examined in vivo and in vitro. Next, SIRT1 knockdown cells were established using small interfering RNAs for SIRT1, and the therapeutic effects of the cells were examined in vitro and in vivo in Lewis rat models of heart failure.
RESULTS: Cardiac function showed significantly more improvement in juvenile than in adult pigs. Histologic analysis revealed significant reduction of myocardial fibrosis and hypertrophic response in juvenile pigs. In vitro analysis demonstrated that doubling time was significantly shorter, the ratio of Ki67-positive cells was significantly greater, and the expression of SIRT1, hypoxia-induced factor-1α, hepatocyte growth factor, and stromal cell-derived factor-1 was significantly upregulated in juvenile cells. SIRT1 knockdown cells showed decreased proliferation and cytokine release potential compared with wild-type cells. Transplantation of SIRT1 knockdown stem cell sheets showed lesser improvement of cardiac function after severe heart failure in Lewis rats than in controls.
CONCLUSIONS: Sirtuin1 expression in transplanted cells enhances the skeletal stem cell sheet therapeutic effects for treating severe heart failure in a juvenile animal model.

PMID: 27157055 [PubMed - indexed for MEDLINE]

Categorías: Terapia celular

Chitosan hydrogel improves mesenchymal stem cell transplant survival and cardiac function following myocardial infarction in rats.

Jue, 03/30/2017 - 14:48
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Chitosan hydrogel improves mesenchymal stem cell transplant survival and cardiac function following myocardial infarction in rats.

Exp Ther Med. 2017 Feb;13(2):588-594

Authors: Xu B, Li Y, Deng B, Liu X, Wang L, Zhu QL

Abstract
Myocardial infarction (MI) remains the leading cause of cardiovascular-associated mortality and morbidity. Improving the retention rate, survival and cardiomyocyte differentiation of mesenchymal stem cells (MSCs) is important in improving the treatment of patients with MI. In the present study, temperature-responsive chitosan hydrogel, an injectable scaffold, was used to deliver MSCs directly into the infarcted myocardium of rats following MI. Histopathology and immunohistochemical staining were used to evaluate cardiac cell survival and regeneration, and cardiac function was assessed using an echocardiograph. It was demonstrated that chitosan hydrogel increased graft size and cell retention in the ischemic heart, promoted MSCs to differentiate into cardiomyocytes and increased the effects of MSCs on neovasculature formation. Furthermore, chitosan hydrogel enhanced the effect of MSCs on the improvement of cardiac function and hemodynamics in the infarcted area of rats following MI. These findings suggest that chitosan hydrogel is an appropriate material to deliver MSCs into infarcted myocardium.

PMID: 28352335 [PubMed - in process]

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Epac-Rap1-activated mesenchymal stem cells improve cardiac function in rat model of myocardial infarction.

Mié, 03/29/2017 - 14:45
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Epac-Rap1-activated mesenchymal stem cells improve cardiac function in rat model of myocardial infarction.

Cardiovasc Ther. 2017 Apr;35(2):

Authors: Khan I, Ali A, Akhter MA, Naeem N, Chotani MA, Iqbal H, Kabir N, Atiq M, Salim A

Abstract
INTRODUCTION: Rap1, a member of Ras superfamily of small GTP-binding proteins, is involved in cardiovascular biology in numerous ways. It is an evolutionary conserved regulator of adhesion, polarity, differentiation and growth.
AIMS: Our aim was to analyze Rap1-activated rat bone marrow mesenchymal stem cells (MSCs) for their potential role in adhesion and cardiac differentiation.
METHODS: Myocardial infarction (MI) was produced in Sprague Dawley (SD) rats through occlusion of the left anterior descending coronary artery. MSCs were treated with 8-pCPT-2'-O-Me-cAMP (CPT) to activate Rap1. Normal (untreated) and CPT-treated MSCs were transplanted through intramyocardial injection in respective groups. Cardiac function was assessed by echocardiography at 2 and 4 weeks after cell transplantation. Histological analysis was performed to observe changes at tissue level.
RESULTS: Homing of CPT-treated MSCs was significantly (***P<.001) higher as compared to normal MSCs in the infarcted hearts. This may be due to increase in the gene expression of some of the cell adhesion molecules as evident by qRT-PCR analysis. Significant (***P<.001) improvement in the restoration of heart function in terms of left ventricular diastolic and systolic internal diameters (LVIDd, LVIDs), % ejection fraction, % fraction shortening and end-systolic and end-diastolic volumes were observed in CPT-treated MSCs as compared to the MI model. Histological analyses showed significant (***P<.001) reduction in scar formation in the CPT-treated group. Differentiation of treated MSCs into functional cardiomyocytes was evident through immunohistochemical staining. LV wall thickness was also preserved significantly (***P<.001). Blood vessel formation was more pronounced in CPT-treated group although both cell therapy groups showed significant increase as compared to MI model.
CONCLUSION: Our findings showed that pharmacological activation of Epac-Rap1 improves cardiac function through better survival, adhesion and differentiation of transplanted cells. Transplantation of these MSCs in the infarct area restored functional myocardium.

PMID: 28039940 [PubMed - indexed for MEDLINE]

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The Athena trials: Autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction.

Mié, 03/29/2017 - 14:45
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The Athena trials: Autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction.

Catheter Cardiovasc Interv. 2017 Feb 01;89(2):169-177

Authors: Henry TD, Pepine CJ, Lambert CR, Traverse JH, Schatz R, Costa M, Povsic TJ, David Anderson R, Willerson JT, Kesten S, Perin EC

Abstract
OBJECTIVE: To assess safety and feasibility of autologous adipose-derived regenerative cells (ADRCs), for treatment of chronic ischemic cardiomyopathy patients.
BACKGROUND: Preclinical and early clinical trials suggest ADRCs have excellent potential for ischemic conditions.
METHODS: The Athena program consisted of two parallel, prospective, randomized (2:1, active: placebo), double-blind trials assessing intramyocardial (IM) ADRC delivery [40-million, n = 28 (ATHENA) and 80-million (ATHENA II) cells, n = 3]). Patients with an EF ≥20% but ≤45%, multivessel coronary artery disease (CAD) not amenable to revascularization, inducible ischemia, and symptoms of either angina (CCS II-IV) or heart failure (NYHA Class II-III) on maximal medical therapy were enrolled. All patients underwent fat harvest procedure (≤450 mL adipose), on-site cell processing (Celution® System, Cytori Therapeutics), electromechanical mapping, and IM delivery of ADRCs or placebo.
RESULTS: Enrollment was terminated prematurely due to non-ADRC-related adverse events and subsequent prolonged enrollment time. Thirty-one patients (17-ADRCs, 14-placebo) mean age 65 ± 8 years, baseline LVEF(%) 31.1 ± 8.7 (ADRC), 31.8 ± 7.7 (placebo) were enrolled. Change in V02 max favored ADRCs (+45.4 ± 222 vs. -9.5 ± 137 mL/min) but there was no difference in left ventricular function or volumes. At 12-months, heart failure hospitalizations occurred in 2/17 (11.7%) [ADRC] and 3/14 (21.4%) [placebo]. Differences in NYHA and CCS classes favored ADRCs at 12-months with significant improvement in MLHFQ (-21.6 + 13.9 vs. -5.5 + 23.8, P = 0.038).
CONCLUSIONS: A small volume fat harvest, automated local processing, and IM delivery of autologous ADRCs is feasible with suggestion of benefit in "no option" CAD patients. Although the sample size is limited, the findings support feasibility and scalability for treatment of ischemic cardiomyopathy with ADRCs. © 2016 Wiley Periodicals, Inc.

PMID: 27148802 [PubMed - indexed for MEDLINE]

Categorías: Terapia celular

Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia: from a stem cell derived cardiomyocyte-based model to clinical biomarkers of disease outcome.

Lun, 03/27/2017 - 08:50
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Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia: from a stem cell derived cardiomyocyte-based model to clinical biomarkers of disease outcome.

Eur Heart J. 2017 Feb 18;:

Authors: Akdis D, Saguner AM, Shah K, Wei C, Medeiros-Domingo A, von Eckardstein A, Lüscher TF, Brunckhorst C, Chen HS, Duru F

Abstract
Aims: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is characterized by fibrofatty infiltration of the myocardium and ventricular arrhythmias that may lead to sudden cardiac death. It has been observed that male patients develop the disease earlier and present with more severe phenotypes as compared to females. Thus, we hypothesized that serum levels of sex hormones may contribute to major arrhythmic cardiovascular events (MACE) in patients with ARVC/D.
Methods and results: The serum levels of five sex hormones, sex hormone-binding globulin, high sensitivity troponin T, pro-brain natriuretic peptide, cholesterol, triglycerides, insulin, and glucose were measured in 54 ARVC/D patients (72% male). Twenty-six patients (48%) experienced MACE. Total and free testosterone levels were significantly increased in males with MACE as compared to males with a favourable outcome, whereas estradiol was significantly lower in females with MACE as compared to females with a favourable outcome. Increased testosterone levels remained independently associated with MACE in males after adjusting for age, body mass index, Task Force criteria, ventricular function, and desmosomal mutation status. Furthermore, an induced pluripotent stem cell-derived ARVC/D cardiomyocyte model was used to investigate the effects of sex hormones. In this model, testosterone worsened and estradiol improved ARVC/D-related pathologies such as cardiomyocyte apoptosis and lipogenesis, strongly supporting our clinical findings.
Conclusions: Elevated serum testosterone levels in males and decreased estradiol levels in females are independently associated with MACE in ARVC/D, and directly influence disease pathology. Therefore, determining the levels of sex hormones may be useful for risk stratification and may open a new window for preventive interventions.

PMID: 28329361 [PubMed - as supplied by publisher]

Categorías: Terapia celular

Stem Cell Technology in Cardiac Regeneration: A Pluripotent Stem Cell Promise.

Lun, 03/27/2017 - 08:50
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Stem Cell Technology in Cardiac Regeneration: A Pluripotent Stem Cell Promise.

EBioMedicine. 2017 Feb;16:30-40

Authors: Duelen R, Sampaolesi M

Abstract
Despite advances in cardiovascular biology and medical therapy, heart disorders are the leading cause of death worldwide. Cell-based regenerative therapies become a promising treatment for patients affected by heart failure, but also underline the need for reproducible results in preclinical and clinical studies for safety and efficacy. Enthusiasm has been tempered by poor engraftment, survival and differentiation of the injected adult stem cells. The crucial challenge is identification and selection of the most suitable stem cell type for cardiac regenerative medicine. Human pluripotent stem cells (PSCs) have emerged as attractive cell source to obtain cardiomyocytes (CMs), with potential applications, including drug discovery and toxicity screening, disease modelling and innovative cell therapies. Lessons from embryology offered important insights into the development of stem cell-derived CMs. However, the generation of a CM population, uniform in cardiac subtype, adult maturation and functional properties, is highly recommended. Moreover, hurdles regarding tumorigenesis, graft cell death, immune rejection and arrhythmogenesis need to be overcome in clinical practice. Here we highlight the recent progression in PSC technologies for the regeneration of injured heart. We review novel strategies that might overcome current obstacles in heart regenerative medicine, aiming at improving cell survival and functional integration after cell transplantation.

PMID: 28169191 [PubMed - indexed for MEDLINE]

Categorías: Terapia celular

Mesenchymal Stem Cells with eNOS Over-Expression Enhance Cardiac Repair in Rats with Myocardial Infarction.

Lun, 03/27/2017 - 08:50
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Mesenchymal Stem Cells with eNOS Over-Expression Enhance Cardiac Repair in Rats with Myocardial Infarction.

Cardiovasc Drugs Ther. 2017 Feb;31(1):9-18

Authors: Chen L, Zhang Y, Tao L, Yang Z, Wang L

Abstract
PURPOSE: Transplantation of mesenchymal stem cells (MSCs) is a promising therapeutic option for patients with acute myocardial infarction.
METHODS: We show here that the ectopic overexpression of endothelial nitric oxide synthases (eNOS), an endothelial form of NOS, could enhance the ability of MSCs in treating ischemic heart damage after the occlusion of the coronary artery.
RESULTS: Adenoviral delivery of human eNOS gene into mouse bone marrow-derived MSCs (BM-MSCs) conferred resistance to oxygen glucose deprivation (OGD)-induced cell death in vitro, and elevated the bioavailability of nitric oxide when injected into the myocardium in vivo. In a rat model of acute myocardial infarction, the transplantation of eNOS-overexpressing BM-MSCs significantly reduced myocardial infarct size, corrected hemodynamic parameters and increased capillary density. We also found that the synergistic effects were consistently better than either treatment alone.
CONCLUSIONS: These findings reveal a positive role of elevated eNOS expression in cardiac repair, and suggest the combination of eNOS and MSC transplant therapy as a potential approach for treating myocardial infarction.

PMID: 27913896 [PubMed - indexed for MEDLINE]

Categorías: Terapia celular

Miracle cells for natural dentistry - A review.

Jue, 03/23/2017 - 00:54
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Miracle cells for natural dentistry - A review.

J Oral Biol Craniofac Res. 2017 Jan-Apr;7(1):49-53

Authors: Somani R, Jaidka S, Bajaj N, Arora S

Abstract
Stem cells are undifferentiated cells that can differentiate into specialized cells. Recently, enormous growth has been seen in the recognition of stem cell-based therapies, which have the potential to ameliorate the life of patients with conditions that span from Parkinson's disease to cardiac ischemia to bone or tooth loss. This research has produced new but unexplored possibilities in the regeneration of different organs and tissues. Presently, research is focused on the proficiency of stem cells and their utilization in dentistry, which is gaining interest. The tooth is nature's "esteem" for these precious stem cells and there are a number of these cells in permanent and primary teeth, as well as in the wisdom teeth. Dental stem cells are easy, convenient, and affordable to collect. They hold promise for a range of very potential therapeutic applications, such as in the treatment of cancer, spinal cord injury, brain damage, myocardial infarction, hearing loss, diabetes, wound healing, baldness, etc. Since these cells were used to regenerate damaged tissue in medical therapy successfully, it is possible that the dentist in future might use stem cell to regenerate lost or damaged dental and periodontal structures. This paper reviews the current concepts, characteristics of stem cells in regeneration, and its subsequent uses in dentistry.

PMID: 28316922 [PubMed - in process]

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Mar, 03/21/2017 - 00:00

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