31 results on '"Cardiac stem cell therapy"'
Search Results
2. Imaging Cardiac Stem Cell Therapy
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Qin, Xulei, Chen, Ian Y., Wu, Joseph C., Hecker, Markus, Editor-in-Chief, Backs, Johannes, Series Editor, Freichel, Marc, Series Editor, Korff, Thomas, Series Editor, Thomas, Dierk, Series Editor, Ieda, Masaki, editor, and Zimmermann, Wolfram-Hubertus, editor
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- 2017
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3. Cardiac stem cell therapy for infarcted rat hearts
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Tan, Suat Cheng, Clarke, Kieran, Davies, Kay E., and Carr, Carolyn A.
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616.1 ,Medical Sciences ,Stem cells (clinical sciences) ,Cardiovascular disease ,cardiac stem cell therapy ,myocardial infarction ,hypoxic stem cell culture ,prolyl-4-hydroxylase inhibitors - Abstract
Infarction irreversibly damages the heart, with formation of an akinetic scar that may lead to heart failure. Endogenous cardiac stem cells (CSCs) are a promising candidate cell source for restoring lost tissue and thereby preventing heart failure. CSCs would be most beneficial if administered soon after infarction, thus the aim of this project was to optimize CSC culture conditions to enhance their therapeutic potential for myocardial infarction. CSCs were isolated and expanded in vitro via the formation of cardiospheres to give cardiosphere-derived cells (CDCs). Neonatal rat CDCs were found to be heterogenous, containing cells expressing the cardiac stem cell marker, c-Kit, pluripotent cell markers, Oct-4, Sox 2, Klf-4 and Nanog, and early cardiac specific differentiation markers, Nkx 2.5 and GATA 4. Administration of CDCs to the infarcted rat heart increased the cardiac ejection fraction by 9%, capillary density by 9% and reduced scar volume by 33%, compared to the non-treated group. The proliferation rates and the expression of c-Kit were significantly decreased in CSCs isolated from aged rats and after extended culture in vitro, so, CSC culture was optimized using hypoxic preconditioning. Under hypoxia, CDC proliferation rates were 1.7-fold greater, and larger cardiosphere clusters were formed. Hypoxic CDCs had an increased cardiac stem cell population, in that c-Kit was increased by 220% and CD90 and CD105 were decreased by 55% and 35%, respectively, compared to normoxic CDCs. Further, hypoxia induced the expression of CXCR-4 (~3.2-fold), EPO (~3.0-fold) and VEGF (~1.5-fold), indicating that hypoxic preconditioning may stimulate stem cell homing and neovascularization in the infarcted myocardium. Notably, hypoxic CDCs were able to switch to anaerobic glycolytic metabolism and had approximately 80% lower oxygen consumption, suggesting that they may be better adapted to survive within the hypoxic infarct scar, compared with normoxic CDCs. Culture of CDCs with hypoxia-mimicking prolyl-4-hydroxylase inhibitors (PHDIs) using DMOG, BIC and a novel compound, EDBA, induced similar effects to hypoxic culture by increasing c-Kit, EPO, VEGF, CXCR-4, decreasing CD90 and CD105 and increasing glycolytic metabolism. However, PHDI treatment for 24 hours did not alter CDC proliferation rates and cells died after 24 hours. In conclusion, CDCs are a potential cell source for therapy after myocardial infarction and their therapeutic potential can be enhanced using hypoxia or PHDI-preconditioning techniques.
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- 2011
4. Cardiomyocyte Proliferation and Maturation: Two Sides of the Same Coin for Heart Regeneration
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Ming-Tao Zhao, Shiqiao Ye, Juan Su, and Vidu Garg
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cardiomyocyte proliferation ,cardiomyocyte maturation ,cardiomyocyte hypertrophy ,induced pluriopotent stem cells ,cardiac stem cell therapy ,cardiac regeneration ,Biology (General) ,QH301-705.5 - Abstract
In the past few decades, cardiac regeneration has been the central target for restoring the injured heart. In mammals, cardiomyocytes are terminally differentiated and rarely divide during adulthood. Embryonic and fetal cardiomyocytes undergo robust proliferation to form mature heart chambers in order to accommodate the increased workload of a systemic circulation. In contrast, postnatal cardiomyocytes stop dividing and initiate hypertrophic growth by increasing the size of the cardiomyocyte when exposed to increased workload. Extracellular and intracellular signaling pathways control embryonic cardiomyocyte proliferation and postnatal cardiac hypertrophy. Harnessing these pathways could be the future focus for stimulating endogenous cardiac regeneration in response to various pathological stressors. Meanwhile, patient-specific cardiomyocytes derived from autologous induced pluripotent stem cells (iPSCs) could become the major exogenous sources for replenishing the damaged myocardium. Human iPSC-derived cardiomyocytes (iPSC-CMs) are relatively immature and have the potential to increase the population of cells that advance to physiological hypertrophy in the presence of extracellular stimuli. In this review, we discuss how cardiac proliferation and maturation are regulated during embryonic development and postnatal growth, and explore how patient iPSC-CMs could serve as the future seed cells for cardiac cell replacement therapy.
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- 2020
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5. Hematopoietic stem-cell senescence and myocardial repair - Coronary artery disease genotype/phenotype analysis of post-MI myocardial regeneration response induced by CABG/CD133+ bone marrow hematopoietic stem cell treatment in RCT PERFECT Phase 3
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Markus Wolfien, Denise Klatt, Amankeldi A. Salybekov, Masaaki Ii, Miki Komatsu-Horii, Ralf Gaebel, Julia Philippou-Massier, Eric Schrinner, Hiroshi Akimaru, Erika Akimaru, Robert David, Jens Garbade, Jan Gummert, Axel Haverich, Holger Hennig, Hiroto Iwasaki, Alexander Kaminski, Atsuhiko Kawamoto, Christian Klopsch, Johannes T. Kowallick, Stefan Krebs, Julia Nesteruk, Hermann Reichenspurner, Christian Ritter, Christof Stamm, Ayumi Tani-Yokoyama, Helmut Blum, Olaf Wolkenhauer, Axel Schambach, Takayuki Asahara, and Gustav Steinhoff
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Clonal hematopoiesis of indeterminate pathology ,CHIP ,SH2B3 ,Myocardial regeneration ,Cardiac stem cell therapy ,Angiogenesis induction ,Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG). Methods: Transcriptome and variant expression analysis was studied in the phase 3 PERFECT trial post myocardial infarction CABG and CD133+ bone marrow derived hematopoetic stem cells showing difference in left ventricular ejection fraction (∆LVEF) myocardial regeneration Responders (n=14; ∆LVEF +16% day 180/0) and Non-responders (n=9; ∆LVEF -1.1% day 180/0). Subsequently, the findings have been validated in an independent patient cohort (n=14) as well as in two preclinical mouse models investigating SH2B3/LNK antisense or knockout deficient conditions. Findings: 1. Clinical: R differed from NR in a total of 161 genes in differential expression (n=23, q
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- 2020
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6. Application of injectable hydrogels for cardiac stem cell therapy and tissue engineering.
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Alagarsamy, Keshav Narayan, Weiang Yan, Srivastava, Abhay, Desiderio, Vincenzo, Dhingra, Sanjiv, and Yan, Weiang
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Cardiovascular diseases are responsible for approximately one-third of deaths around the world. Among cardiovascular diseases, the largest single cause of death is ischemic heart disease. Ischemic heart disease typically manifests as progressive constriction of the coronary arteries, which obstructs blood flow to the heart and can ultimately lead to myocardial infarction. This adversely affects the structure and function of the heart. Conventional treatments lack the ability to treat the myocardium lost during an acute myocardial infarction. Stem cell therapy offers an excellent solution for myocardial regeneration. Stem cell sources such as adult stem cells, embryonic and induced pluripotent stem cells have been the focal point of research in cardiac tissue engineering. However, cell survival and engraftment post-transplantation are major limitations that must be addressed prior to widespread use of this technology. Recently, biomaterials have been introduced as 3D vehicles to facilitate stem cell transplantation into infarct sites. This has shown significant promise with improved cell survival after transplantation. In this review, we discuss the various injectable hydrogels that have been tried in cardiac tissue engineering. Exploring and optimizing these cell-material interactions will guide cardiac tissue engineering towards developing stem cell based functional 3D constructs for cardiac regeneration. [ABSTRACT FROM AUTHOR]
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- 2019
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7. Targeted Myocardial Restoration with Injectable Hydrogels—In Search of The Holy Grail in Regenerating Damaged Heart Tissue
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Faizus Sazzad, Michał Kuzemczak, Engracia Loh, Wellington Wu, and Theo Kofidis
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hydrogel ,extracellular matrix hydrogels ,myocardial infarctions ,myocardial infarction therapy ,cardiac stem cell therapy ,tissue engineering ,Biology (General) ,QH301-705.5 - Abstract
A 3-dimensional, robust, and sustained myocardial restoration by means of tissue engineering remains an experimental approach. Prolific protocols have been developed and tested in small and large animals, but, as clinical cardiac surgeons, we have not arrived at the privilege of utilizing any of them in our clinical practice. The question arises as to why this is. The heart is a unique organ, anatomically and functionally. It is not an easy target to replicate with current techniques, or even to support in its viability and function. Currently, available therapies fail to reverse the loss of functional cardiac tissue, the fundamental pathology remains unaddressed, and heart transplantation is an ultima ratio treatment option. Owing to the equivocal results of cell-based therapies, several strategies have been pursued to overcome the limitations of the current treatment options. Preclinical data, as well as first-in-human studies, conducted to-date have provided important insights into the understanding of injection-based approaches for myocardial restoration. In light of the available data, injectable biomaterials suitable for transcatheter delivery appear to have the highest translational potential. This article presents a current state-of-the-literature review in the field of hydrogel-based myocardial restoration therapy.
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- 2021
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8. Cardiac Function Improvement and Bone Marrow Response –
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Gustav Steinhoff, Julia Nesteruk, Markus Wolfien, Günther Kundt, Jochen Börgermann, Robert David, Jens Garbade, Jana Große, Axel Haverich, Holger Hennig, Alexander Kaminski, Joachim Lotz, Friedrich-Wilhelm Mohr, Paula Müller, Robert Oostendorp, Ulrike Ruch, Samir Sarikouch, Anna Skorska, Christof Stamm, Gudrun Tiedemann, Florian Mathias Wagner, and Olaf Wolkenhauer
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Randomised double-blinded phase III multicentre trial ,CD133+ ,CD34+ ,Endothelial progenitor cell (EPC) ,SH2B3 ,Lnk adaptor ,Cardiac repair ,Cardiac stem cell therapy ,Angiogenesis ,Medicine ,Medicine (General) ,R5-920 - Abstract
Objective: The phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133+ bone marrow stem cell treatment combined with CABG for induction of cardiac repair. Design: Multicentre, double-blinded, randomised placebo controlled trial. Setting: The study was conducted across six centres in Germany October 2009 through March 2016 and stopped due slow recruitment after positive interim analysis in March 2015. Participants: Post-infarction patients with chronic ischemia and reduced LVEF (25–50%). Interventions: Eighty-two patients were randomised to two groups receiving intramyocardial application of 5 ml placebo or a suspension of 0.5–5 × 106 CD133+. Outcome: Primary endpoint was delta (∆) LVEF at 180 days (d) compared to baseline measured in MRI. Findings (prespecified): Safety (n = 77): 180 d survival was 100%, MACE n = 2, SAE n = 49, without difference between placebo and CD133+. Efficacy (n = 58): The LVEF improved from baseline LVEF 33.5% by +9.6% at 180 d, p = 0.001 (n = 58). Treatment groups were not different in ∆LVEF (ANCOVA: Placebo +8.8% vs. CD133+ +10.4%, ∆CD133+vs placebo +2.6%, p = 0.4). Findings (post hoc): Responders (R) classified by ∆LVEF ≥ 5% after 180 d were 60% of the patients (35/58) in both treatment groups. ∆LVEF in ANCOVA was +17.1% in (R) vs. non-responders (NR) (∆LVEF 0%, n = 23). NR were characterized by a preoperative response signature in peripheral blood with reduced CD133+ EPC (RvsNR: p = 0.005) and thrombocytes (p = 0.004) in contrast to increased Erythropoeitin (p = 0.02), and SH2B3 mRNA expression (p = 0.073). Actuarial computed mean survival time was 76.9 ± 3.32 months (R) vs. +72.3 ± 5.0 months (NR), HR 0.3 [Cl 0.07–1.2]; p = 0.067.Using a machine learning 20 biomarker response parameters were identified allowing preoperative discrimination with an accuracy of 80% (R) and 84% (NR) after 10-fold cross-validation. Interpretation: The PERFECT trial analysis demonstrates that the regulation of induced cardiac repair is linked to the circulating pool of CD133+ EPC and thrombocytes, associated with SH2B3 gene expression. Based on these findings, responders to cardiac functional improvement may be identified by a peripheral blood biomarker signature. TRIAL REGISTRATION: ClinicalTrials.gov NCT00950274.
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- 2017
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9. Cardiac stem cell therapy: Current status
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Sridharan Umapathy
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Bone marrow stem cells ,cardiac stem cell therapy ,cardiopoiesis ,mesenchymal stem cells ,stem cell therapy ,Medicine ,Surgery ,RD1-811 ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Cardiac injury due to any cause leads to cardiac cell damage and thereby to ventricular dysfunction. Unlike current medical therapy, cardiac regeneration by stem cell therapy is a promising approach which has a potential to reverse left ventricular dysfunction. It is conceived to complement and potentially transform available therapeutic armamentarium. Early experience in clinical studies support the safety and feasibility of cell therapy and as adjuvants to established practice. This review discusses type of stem cells used, its therapeutic indications, and its current status.
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- 2017
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10. Exploiting AT2R to Improve CD117 Stem Cell Function In Vitro and In Vivo - Perspectives for Cardiac Stem Cell Therapy
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Marion Ludwig, Anita Tölk, Anna Skorska, Christian Maschmeier, Ralf Gaebel, Cornelia Aquilina Lux, Gustav Steinhoff, and Robert David
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CD117+ stem cells ,Transient AT2R stimulation ,Cardiac stem cell therapy ,HL-1 cell line ,Vasculogenesis ,Cardioprotection ,Physiology ,QP1-981 ,Biochemistry ,QD415-436 - Abstract
Background/Aims: CD117+ stem cell (SC) based therapy is considered an alternative therapeutic option for terminal heart disease. However, controversies exist on the effects of CD117+ SC implantation. In particular, the link between CD117+ SC function and angiotensin-II-type-2 receptor (AT2R) after MI is continuously discussed. We therefore asked whether 1) AT2R stimulation influences CD117+ SC properties in vitro and, 2) which effects can be ascribed to AT2R stimulation in vivo. Methods: We approached AT2R stimulation with Angiotensin II while simultaneously blocking its opponent receptor AT1 with Losartan. CD117 effects were dissected using a 2D-Matrigel assay and HL-1 co-culture in vitro. A model of myocardial infarction, in which we implanted EGFP+ CD117 SC, was further applied. Results: While we found indications for AT2R driven vasculogenesis in vitro, co-culture experiments revealed that CD117+ SC improve vitality of cardiomyocytes independently of AT2R function. Likewise, untreated CD117+ SC had a positive effect on cardiac function and acted cardioprotective in vivo. Conclusions: Therefore, our data show that transient AT2R stimulation does not significantly add to the beneficial actions of CD117+ SC in vivo. Yet, exploiting AT2R driven vasculogenis via an optimized AT2R stimulation protocol may become a promising tool for cardiac SC therapy.
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- 2015
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11. Cardiac Regenerative Medicine: The Potential of a New Generation of Stem Cells.
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Cambria, Elena, Steiger, Julia, Günter, Julia, Bopp, annina, Wolint, Petra, Hoerstrup, Simon P., and Emmert, Maximilian Y.
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Cardiac stem cell therapy holds great potential to prompt myocardial regeneration in patients with ischemic heart disease. The selection of the most suitable cell type is pivotal for its successful application. Various cell types, including crude bone marrow mononuclear cells, skeletal myoblast, and hematopoietic and endothelial progenitors, have already advanced into the clinical arena based on promising results from different experimental and preclinical studies. However, most of these so-called first-generation cell types have failed to fully emulate the promising preclinical data in clinical trials, resulting in heterogeneous outcomes and a critical lack of translation. Therefore, different next-generation cell types are currently under investigation for the treatment of the diseased myocardium. This review article provides an overview of current stem cell therapy concepts, including the application of cardiac stem (CSCs) and progenitor cells (CPCs) and lineage commitment via guided cardiopoiesis from multipotent cells such as mesenchymal stem cells (MSCs) or pluripotent cells such as embryonic and induced pluripotent stem cells. Furthermore, it introduces new strategies combining complementary cell types, such as MSCs and CSCs/CPCs, which can yield synergistic effects to boost cardiac regeneration. [ABSTRACT FROM AUTHOR]
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- 2016
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12. Exploiting AT2R to Improve CD117 Stem Cell Function In Vitro and In Vivo - Perspectives for Cardiac Stem Cell Therapy.
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Ludwig, Marion, Tölk, Anita, Skorska, Anna, Maschmeier, Christian, Gaebel, Ralf, Lux, Cornelia Aquilina, Steinhoff, Gustav, and David, Robert
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C-kit protein , *STEM cell treatment , *IN vitro studies , *HEART diseases , *THERAPEUTICS , *ANGIOTENSIN receptors , *MYOCARDIAL infarction treatment - Abstract
Background/Aims: CD117+ stem cell (SC) based therapy is considered an alternative therapeutic option for terminal heart disease. However, controversies exist on the effects of CD117+ SC implantation. In particular, the link between CD117+ SC function and angiotensin-II-type-2 receptor (AT2R) after MI is continuously discussed. We therefore asked whether 1) AT2R stimulation influences CD117+ SC properties in vitro and, 2) which effects can be ascribed to AT2R stimulation in vivo. Methods: We approached AT2R stimulation with Angiotensin II while simultaneously blocking its opponent receptor AT1 with Losartan. CD117 effects were dissected using a 2D-Matrigel assay and HL-1 co-culture in vitro. A model of myocardial infarction, in which we implanted EGFP+ CD117 SC, was further applied. Results: While we found indications for AT2R driven vasculogenesis in vitro, co-culture experiments revealed that CD117+ SC improve vitality of cardiomyocytes independently of AT2R function. Likewise, untreated CD117+ SC had a positive effect on cardiac function and acted cardioprotective in vivo. Conclusions: Therefore, our data show that transient AT2R stimulation does not significantly add to the beneficial actions of CD117+ SC in vivo. Yet, exploiting AT2R driven vasculogenis via an optimized AT2R stimulation protocol may become a promising tool for cardiac SC therapy. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
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- 2015
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13. In vitro assessment of cytotoxicity and labeling efficiency of 99mTc-HMPAO with stromal vascular fraction of adipose tissue.
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Verma, V.K., Beevi, S.S., Tabassum, A., Kumaresan, K., Kamaraju, R.S., Arbab, A.S., and Chelluri, L.K.
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TECHNETIUM isotopes , *STROMAL cells , *ADIPOSE tissues , *NONINVASIVE diagnostic tests , *RADIONUCLIDE imaging , *REACTIVE oxygen species - Abstract
Introduction Noninvasive radionuclide imaging of cells using technetium99m-hexamethylpropyleneamine oxime ( 99m Tc-HMPAO) is a potential diagnostic tool for several applications. Herein we aimed to evaluate the labeling efficiency and cellular toxicity of 99m Tc-HMPAO with Stromal Vascular Fraction (SVF) of adipose tissue to develop a process tool for theranostic purposes, in particular imaging cardiac stem cell therapy. Methods Ten million cells of SVF were labeled with 99m Tc-HMPAO complex and excess radiolabel was cleared off through washing in PBS. The labeling efficiency of 99m Tc-HMPAO was detected in labeled cells and their subsequent supernatant wash using isotope dose calibrator and gamma camera. The cytotoxicity was assessed for the comparative reactive oxygen species (ROS) by H 2 DCFDDA, apoptotic events by annexin-V and TUNEL assay and mitochondrial potential by JC-1. Results An encouraging labeling efficiency of 33% was observed with 99m Tc-HMPAO complex. The radionuclide labeling of SVF demonstrated significant safety profile as evaluated by apoptotic assays. Conclusion 99m Tc-HMPAO labeling efficiency of 33% of total SV fraction would produce sufficient radioactive signals that would enable for in vivo tracking of cells by SPECT-CT. The radionuclide did not demonstrate any significant impact on the structural or functional organization of the labeled cells. Our study indicates that SVF can be safely labeled with 99m Tc-HMPAO without adverse cytotoxic events and for its potential role in imaging cardiac stem cell therapy. [ABSTRACT FROM AUTHOR]
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- 2014
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14. Blood speaks: Personalised medicine profiling for heart failure patients
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Mark A. Sussman and Fareheh Firouzi
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WT, wild type ,Research paper ,CSC, cardiac stem cell ,EPOR, Erythropoietin receptor ,LAD, Left anterior descending coronary artery, RIVA ,Ang-1, Angiopoeitin 1 ,Clonal hematopoiesis of indeterminate pathology ,Angiogenesis induction ,MNC, Mononuclear cells ,SH2B3, LNK [Src homology 2-B3 (SH2B3)] belongs to a family of SH2-containing proteins with important adaptor functions ,Coronary bypass surgery ,Profiling (information science) ,CABG ,CHIP, Clonal hematopoiesis of indeterminate potential ,PI3K, Phosphoinositide-3-Kinase ,m, mouse ,BM, Bone marrow ,PPMC, Pearson Product Moment Correlation ,CHIP ,BrdU, Brome deoxyuridine ,NR, non-responder ,IGF-1, Insuline-like Growth Factor 1 ,AUC, Area under curve ,BMMNC, Bone marrow mononuclear cell ,General Medicine ,KSL, mouse bone marrow stem cell subpopulation c-KIT+ Sca-I+ lin ,EGF, Epidermal growth factor ,GFP, Green fluorescent protein ,Public Health and Health Services ,MI, myocardial infarction ,lcsh:Medicine (General) ,NGS, Next Generation Sequencing ,medicine.medical_specialty ,2019-20 coronavirus outbreak ,Clinical Sciences ,6MWT, 6-Minute Walk Test ,InDel, mutation insertion or deletion variant ,General Biochemistry, Genetics and Molecular Biology ,CLARA, Clustering for Large Applications ,PDFR, Platelet derived growth factor receptor ,c-KIT/CD117, Stem Cell Factor Receptor c-KIT, CD117 ,HR, Hazard ratio ,IGFBP, Insuline-like growth factor binding proteine ,IHG, Analysis performed in accordance with ISHAGE guidelines ,RFI, Reactome functional interaction ,Machine learning ,Humans ,LAS, Longitudinal axis strain ,Intensive care medicine ,DE, Differential gene expression ,Heart Failure ,GWAS, Genome wide association study ,CI, Confidence interval ,hu, human ,R, responder ,lcsh:R ,Myocardial regeneration ,FACS, Fluorescence activated cell sorter ,DNAseq, desoxyribonucleid acid sequencing ,SNP, Single nucleotide polymorphism, variant ,RT-PCR, Reverse transcriptase polymerase chain reaction ,medicine.disease ,Cardiac stem cell therapy ,GMP, Good Manufacturing Practice ,Post myocardial infarction heart failure ,SDF-1, Stromal Cell-derived Factor 1 ,FDR, False discovery rate ,PDGF, Platelet derived growth factor ,EPO, Erythropoietin ,MRI, Magnetic resonance imaging ,VEGFR, Vascular Endothelial Growth Factor Receptor ,AUR, Arch user repository ,LCRC, Loss of cardiac regeneration capacity ,GADPH, Glyceraldehyde 3 phosphate dehydrogenase ,lcsh:Medicine ,LVESD, Left Ventricular End Systolic Dimension ,VCA, Virus-Capsid-Antigen ,CEC, Circulating endothelial cells, CEC panel, CDs measured in PB ,RNASeq, Ribonucleid acid sequencing ,SUSAR, Suspected Unexpected Serious Adverse Reaction ,GATA4, Transcriptional activator that binds to the consensus sequence 5′-AGATAG-3’ ,IL, Interleukin ,Precision Medicine ,CAP-EPC, Concentrated Ambient Particles – Endothelial Progenitor Cells ,lcsh:R5-920 ,VEGF, Vascular Endothelial Growth Factor ,SH2B3 ,STEMI, ST- segment Elevation Infarction ,CD, Cluster of Differentiation ,SCF, Stem Cell Factor ,PBMNC, Peripheral blood mononuclear cell ,CABG, Coronary Artery Bypass Graft ,HSC, Hemopoeitic stem cell ,ML, Machine learning ,CFU, Colony-forming unit ,PBMNC, mononuclear cells isolated from peripheral blood ,LNK, SH2B adapter protein 3 (lymphocyte adapter protein) ,Coronavirus disease 2019 (COVID-19) ,BMSC, Bone marrow stem cells ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,LVEDV, Left Ventricular End Diastolic Volume ,RWMS, Regional wall motion score ,qPCR, Quantitative polymerase chain reaction ,ROC, Receiver operating characteristics ,CPC, cardiac progenitor cell ,medicine ,EGFR, Epidermal growth factor receptor ,ICH GCP, Tripartite Guidelines Guideline for Good Clinical Practice ,TiCoNE, Time course network enrichment ,ELISA, Enzyme-Linked Immunosorbent Assay ,PEI, Paul-Ehrlich Institute ,LVEF, Left Ventricular Ejection Fraction ,business.industry ,HIF, Hypoxia-Inducible Factor, transcription factor ,PB, Peripheral blood ,EPC, Endothelial Progenitor Cells, EPC panel, CDs measured in PB ,t-SNE, t-distributed stochastic neighbour embedding ,ANCOVA, Analysis of covariance ,WGCNA, Weighted gene coexpression network analysis ,Heart failure ,TNF, Tumor Necrosis Factor ,PCR, Polymerase chain reaction ,business - Abstract
Background Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG). Methods Transcriptome and variant expression analysis was studied in the phase 3 PERFECT trial post myocardial infarction CABG and CD133+ bone marrow derived hematopoetic stem cells showing difference in left ventricular ejection fraction (∆LVEF) myocardial regeneration Responders (n=14; ∆LVEF +16% day 180/0) and Non-responders (n=9; ∆LVEF -1.1% day 180/0). Subsequently, the findings have been validated in an independent patient cohort (n=14) as well as in two preclinical mouse models investigating SH2B3/LNK antisense or knockout deficient conditions. Findings 1. Clinical: R differed from NR in a total of 161 genes in differential expression (n=23, q, Graphical abstract Image, graphical abstract
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- 2020
15. Clinical Application of Adult Stem Cells for Therapy for Cardiac Disease.
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Ghodsizad, Ali, Ruhparwar, Arjang, Bordel, Viktor, Mirsaidighazi, Ebrahim, Klein, Hans Michael, Koerner, Michael M., Karck, Matthias, and El‐Banayosy, Aly
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STEM cell research , *HEART diseases , *THERAPEUTICS , *CELLULAR therapy , *TISSUE engineering - Abstract
Introduction Cardiovascular disease is a major cause of death worldwide. Different medical and surgical therapeutic options are well established, but a significant number of patients are not amenable to standard therapeutic options. Cell-based therapies after clinical application have shown different results in recent years. Here, we are giving a comprehensive overview on major available clinical data regarding cell therapy. Background Cell-based therapies and tissue engineering provide new promising platforms to develop upcoming therapeutic options. Initial clinical trials were able to generate promising results. A variety of different stem cell types have been used for the clinical application. Different adult cardiac stem cells and progenitor cells, including mesenchymal, CD34+ and CD133+ autologous human bone marrow-derived stem cells ( BMCs), human myoblasts, and peripheral blood-derived stem and progenitor cells ( PBSCs) have been used for the therapy for end-stage heart failure. Future experiments will show the importance of novel cell populations and clarify the mechanism causing cell therapy-mediated observed effects. Conclusion Several clinical trials have reported on sole therapy, as well as combined application of autologous adult stem cells with conventional revascularization. The reported promising findings encourage further research in the field of the translational research. [ABSTRACT FROM AUTHOR]
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- 2013
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16. USE OF STEM CELLS IN HEART FAILURE TREATMENT: WHERE WE STAND AND WHERE WE ARE GOING.
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Sánchez, Luis A., Guerrero-Beltrán, Carlos Enrique, Cordero-Reyes, Andrea M., García-Rivas, Gerardo, and Torre-Amione, Guillermo
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STEM cell treatment , *HEART failure treatment , *VENTRICULAR remodeling , *MYOCARDIAL infarction complications , *THERAPEUTICS , *CELLULAR therapy , *HEART cells - Abstract
End-stage heart failure is the final common pathway of an irreversible process associated with loss of myocardial cells. In this process, the capacity for renewal and repair of myocardial tissue is inadequate and ultimately leads to ventricular remodeling. Novel therapeutic strategies have been developed to prevent it, one being cell therapy, which has emerged as a potential approach to directly repopulate and repair the damaged heart. Here, we review the use of regenerative cell therapy for different cardiac diseases and discuss the positive effect of cell therapy mediated by paracrine factors instead of turning directly into cardiomyocytes. [ABSTRACT FROM AUTHOR]
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- 2013
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17. Human stem cell-based three-dimensional microtissues for advanced cardiac cell therapies.
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Emmert, Maximilian Y., Wolint, Petra, Wickboldt, Nadine, Gemayel, Gino, Weber, Benedikt, Brokopp, Chad E., Boni, Alessandro, Falk, Volkmar, Bosman, Alexis, Jaconi, Marisa E., and Hoerstrup, Simon P.
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STEM cells , *HEART cells , *CARDIAC surgery , *COMPARATIVE studies , *IMMUNOHISTOCHEMISTRY , *TREATMENT of cardiomyopathies , *ADIPOSE tissues - Abstract
Cardiac stem cell therapy has been proposed as a therapy option to treat the diseased myocardium. However, the low retention rate of transplanted single-cell suspensions remains a major issue of current therapy strategies. Therefore, the concept of scaffold-free cellular self-assembly into three-dimensional microtissues (3D-MTs) prior to transplantation may be beneficial to enhance retention and survival. We compared clinically relevant, human stem cell sources for their ability to generate 3D-MTs with particular regards to formation characteristics, proliferation-activity, viability and extracellular-matrix production. Single-cell suspensions of human bone marrow- and adipose tissue-derived mesenchymal stem cells (hBMMSCs and hATMSCs), Isl1+ cardiac progenitors derived from human embryonic stem cells (hESC-Isl1+ cells), and undifferentiated human induced pluripotent cells (hiPSCs) were characterized before to generate 3D-MTs using a hanging-drop culture. Besides the principal feasibility of cell-specific 3D-MT formation, a detailed head-to-head comparison between cell sources was performed using histology, immunocyto- and histo-chemistry as well as flow cytometry. Round-oval shaped and uniform 3D-MTs could be successfully generated from all cell types starting with a loose formation within the first 24 h that fully stabilized after 3 days and resulting in a mean 3D-MT diameter of 194.56 ± 18.01 μm (hBMMSCs), 194.56 ± 16.30 μm (hATMSCs), 159.73 ± 19.20 μm (hESC-Isl1+ cells) and 120.95 ± 7.97 μm (hiPSCs). While all 3D-MTs showed a homogenous cell distribution, hiPSC-derived 3D-MTs displayed a compact cell formation primarily located at the outer margin. hESC-Isl1+ and hiPSC-derived 3D-MTs maintained their proliferation-activity which was rather limited in the MSC-based 3D-MTs. All four 3D-MT types revealed a comparable viability in excess of 70% and showed a cell-specific expression profile being comparable to their single-cell counterparts. Extracellular matrix (ECM) production during 3D-MT formation was observed for all cell-specific 3D-MTs, with hiPSC-derived 3D-MTs being the fastest one. Interestingly, ECM distribution was homogenous for hATMSC- and hiPSC-based 3D-MTs, while it appeared to be primarily concentrated within in the center of hESC-Isl1+ and hBMMSC-based 3D-MTs. The results of this head-to-head comparative study indicated that 3D-MTs can be successfully generated from hESC-derived Isl1+ cells, hiPSCs and MSC lines upon hanging drop culture. Cell-specific 3D-MTs displayed sufficient viability and instant ECM formation. The concept of 3D-MT in vitro generation prior to cell transplantation may represent a promising delivery format for future strategies to enhance cellular engraftment and survival. [ABSTRACT FROM AUTHOR]
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- 2013
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18. Advanced measurement techniques of regional myocardial function to assess the effects of cardiac regenerative therapy in different models of ischaemic cardiomyopathy.
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van Slochteren, Frebus J., Teske, Arco J., van der Spoel, Tycho I.G., Koudstaal, Stefan, Doevendans, Pieter A., Sluijter, Joost P.G., Cramer, Maarten J.M., and Chamuleau, Steven A.J.
- Subjects
CELL transplantation ,MAGNETIC resonance imaging ,CARDIOMYOPATHIES ,NEOVASCULARIZATION ,HEALTH outcome assessment ,PERFUSION ,RADIONUCLIDE imaging ,STEM cells ,SINGLE-photon emission computed tomography - Abstract
Cardiac regenerative therapy is still not used in daily clinical practice. A reason for this might be the modest effect on relevant global clinical endpoints [i.e. ejection fraction (EF)] in preclinical studies. To introduce proper improvement strategies, it is important to extend the focus from clinical endpoints to more detailed local measures of cardiac function. In this review, we discuss the measurement principles of all invasive and non-invasive techniques that are used to assess the local effects of cardiac regenerative therapy in order to improve feedback to researchers unravelling the dominant pathways that lead to effective cardiac regeneration. Generally adopted mechanisms of cardiac regenerative therapy are: (i) vasculogenesis, (ii) cardiomyogenesis, and (iii) matrix-assisted myocardium stabilization. Since direct in vivo measures of these mechanisms do not exist, we discuss the measurement techniques of local microvascular resistance, myocardial perfusion, viability, fibrosis, and deformation imaging. The ability of these techniques to reflect the mechanism of cardiac regenerative therapy, and the results of applications in stem cell studies are discussed, and critically commented upon. Special attention is given to applications of deformation imaging, since this has recently been suggested and used as a potential new technique to assess local changes of cardiac biomechanics, which requires special knowledge about cardiac physiology. We conclude that besides the clinically relevant EF measurements, detailed measures of local cardiac function provide information about the local changes induced by cardiac regenerative therapy. In particular, combination of deformation imaging, by ultrasound or magnetic resonance imaging, with simultaneously measured local geometry and pressure measurements is a promising approach to assess the effects of cardiac regenerative therapy on local cardiac biomechanics. This approach provides information about local tissue contractility, stiffness, and thereby remodelling. We recommend that researchers use this comprehensive approach in future studies. [ABSTRACT FROM PUBLISHER]
- Published
- 2012
- Full Text
- View/download PDF
19. 10 Years of Intracoronary and Intramyocardial Bone Marrow Stem Cell Therapy of the Heart: From the Methodological Origin to Clinical Practice
- Author
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Strauer, Bodo-Eckehard and Steinhoff, Gustav
- Subjects
- *
CORONARY heart disease treatment , *BONE marrow cells , *STEM cell treatment , *MYOCARDIAL infarction , *CARDIAC catheterization , *ISCHEMIA , *CELL differentiation , *COST effectiveness - Abstract
Intracoronary and intramyocardial stem cell therapy aim at the repair of compromised myocardium thereby—as a causal treatment—preventing ventricular remodeling and improving overall performance. Since the first-in-human use of bone marrow stem cells (BMCs) after acute myocardial infarction in 2001, a large number of clinical studies have demonstrated their clinical benefit: BMC therapy can be performed with usual cardiac catheterization techniques in the conscious patient as well as also easily during cardiosurgical interventions. New York Heart Association severity degree of patients as well as physical activity improve in addition to (“on top” of) all other therapeutic regimens. Stem cell therapy also represents an ultimate approach in advanced cardiac failure. For acute myocardial infarction and chronic ischemia, long-term mortality after 1 and 5 years, respectively, is significantly reduced. A few studies also indicate beneficial effects for chronic dilated cardiomyopathy. The clinical use of autologous BMC therapy implies no ethical problems, when unmodified primary cells are used. With the use of primary BMCs, there are no major stem cell-related side effects, especially no cardiac arrhythmias and inflammation. Various mechanisms of the stem cell action in the human heart are discussed, for example, cell transdifferentiation, cell fusion, activation of intrinsic cardiac stem cells, and cytokine-mediated effects. New techniques allow point-of-care cell preparations, for example, within the cardiac intervention or operation theater, thereby providing short preparation time, facilitated logistics of cell transport, and reasonable cost effectiveness of the whole procedure. The 3 main indications are acute infarction, chronic ischemic heart failure, and dilated cardiomyopathy. Future studies are desirable to further elucidate the mechanisms of stem cell action and to extend the current use of intracoronary and/or intramyocardial stem cell therapy by larger and presumably multicenter and randomized trials. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
- View/download PDF
20. Cardiac stem cell therapy.
- Author
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Nesselmann, C., Kaminski, A., and Steinhoff, G.
- Abstract
Copyright of Herz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2011
- Full Text
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21. Targeted Myocardial Restoration with Injectable Hydrogels—In Search of The Holy Grail in Regenerating Damaged Heart Tissue
- Author
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Wellington Wu, Michał Kuzemczak, Engracia Loh, Theo Kofidis, and Faizus Sazzad
- Subjects
0301 basic medicine ,medicine.medical_specialty ,QH301-705.5 ,cell-based therapy ,medicine.medical_treatment ,Injectable hydrogels ,Medicine (miscellaneous) ,Review ,030204 cardiovascular system & hematology ,Hydrogel ,Extracellular matrix hydrogels ,Myocardial infarctions ,Myocardial infarction therapy ,Cardiac stem cell therapy ,Tissue engineering ,Cell-based therapy ,ch Strategy ,General Biochemistry, Genetics and Molecular Biology ,myocardial infarction therapy ,03 medical and health sciences ,0302 clinical medicine ,medicine ,biochemistry ,cardiac stem cell therapy ,Biology (General) ,Intensive care medicine ,Heart transplantation ,extracellular matrix hydrogels ,business.industry ,Treatment options ,Preclinical data ,Holy Grail ,myocardial infarctions ,Clinical Practice ,030104 developmental biology ,tissue engineering ,hydrogel ,business - Abstract
A 3-dimensional, robust, and sustained myocardial restoration by means of tissue engineering remains an experimental approach. Prolific protocols have been developed and tested in small and large animals, but, as clinical cardiac surgeons, we have not arrived at the privilege of utilizing any of them in our clinical practice. The question arises as to why this is. The heart is a unique organ, anatomically and functionally. It is not an easy target to replicate with current techniques, or even to support in its viability and function. Currently, available therapies fail to reverse the loss of functional cardiac tissue, the fundamental pathology remains unaddressed, and heart transplantation is an ultima ratio treatment option. Owing to the equivocal results of cell-based therapies, several strategies have been pursued to overcome the limitations of the current treatment options. Preclinical data, as well as first-in-human studies, conducted to-date have provided important insights into the understanding of injection-based approaches for myocardial restoration. In light of the available data, injectable biomaterials suitable for transcatheter delivery appear to have the highest translational potential. This article presents a current state-of-the-literature review in the field of hydrogel-based myocardial restoration therapy.
- Published
- 2021
22. Cardiac Function Improvement and Bone Marrow Response –
- Author
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Paula Müller, Olaf Wolkenhauer, Julia Nesteruk, Holger Hennig, Samir Sarikouch, Anna Skorska, Florian Wagner, Markus Wolfien, Günther Kundt, Jens Garbade, Jochen Börgermann, Friedrich-Wilhelm Mohr, Robert David, Joachim Lotz, Axel Haverich, Gudrun Tiedemann, Christof Stamm, Jana Große, Robert A.J. Oostendorp, Gustav Steinhoff, Alexander Kaminski, and Ulrike Ruch
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Placebo-controlled study ,lcsh:Medicine ,030204 cardiovascular system & hematology ,Placebo ,General Biochemistry, Genetics and Molecular Biology ,Cardiac repair ,03 medical and health sciences ,0302 clinical medicine ,Lnk adaptor ,Internal medicine ,Clinical endpoint ,Medicine ,Myocardial infarction ,lcsh:R5-920 ,Endothelial progenitor cell (EPC) ,Ejection fraction ,Randomised double-blinded phase III multicentre trial ,SH2B3 ,business.industry ,CD133+ ,lcsh:R ,General Medicine ,Interim analysis ,medicine.disease ,Surgery ,Cardiac stem cell therapy ,Clinical trial ,030104 developmental biology ,cardiovascular system ,Cardiology ,Angiogenesis ,lcsh:Medicine (General) ,business ,CD34+ ,Mace - Abstract
Objective The phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133 + bone marrow stem cell treatment combined with CABG for induction of cardiac repair. Design Multicentre, double-blinded, randomised placebo controlled trial. Setting The study was conducted across six centres in Germany October 2009 through March 2016 and stopped due slow recruitment after positive interim analysis in March 2015. Participants Post-infarction patients with chronic ischemia and reduced LVEF (25–50%). Interventions: Eighty-two patients were randomised to two groups receiving intramyocardial application of 5ml placebo or a suspension of 0.5–5×10 6 CD133 + . Outcome Primary endpoint was delta (∆) LVEF at 180days (d) compared to baseline measured in MRI. Findings (prespecified) Safety ( n =77): 180d survival was 100%, MACE n =2, SAE n =49, without difference between placebo and CD133 + . Efficacy ( n =58): The LVEF improved from baseline LVEF 33.5% by +9.6% at 180d, p =0.001 ( n =58). Treatment groups were not different in ∆LVEF (ANCOVA: Placebo +8.8% vs. CD133 + +10.4%, ∆CD133 + vs placebo +2.6%, p =0.4). Findings (post hoc) Responders (R) classified by ∆LVEF≥5% after 180d were 60% of the patients (35/58) in both treatment groups. ∆LVEF in ANCOVA was +17.1% in (R) vs. non-responders (NR) (∆LVEF 0%, n =23). NR were characterized by a preoperative response signature in peripheral blood with reduced CD133 + EPC (RvsNR: p =0.005) and thrombocytes ( p =0.004) in contrast to increased Erythropoeitin ( p =0.02), and SH2B3 mRNA expression ( p =0.073). Actuarial computed mean survival time was 76.9±3.32months (R) vs. +72.3±5.0months (NR), HR 0.3 [Cl 0.07–1.2]; p =0.067.Using a machine learning 20 biomarker response parameters were identified allowing preoperative discrimination with an accuracy of 80% (R) and 84% (NR) after 10-fold cross-validation. Interpretation The PERFECT trial analysis demonstrates that the regulation of induced cardiac repair is linked to the circulating pool of CD133+ EPC and thrombocytes, associated with SH2B3 gene expression. Based on these findings, responders to cardiac functional improvement may be identified by a peripheral blood biomarker signature. TRIAL REGISTRATION: ClinicalTrials.gov NCT00950274.
- Published
- 2017
23. Application of injectable hydrogels for cardiac stem cell therapy and tissue engineering
- Author
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Sanjiv Dhingra, Keshav Narayan Alagarsamy, Abhay Srivastava, Vincenzo Desiderio, Weiang Yan, Alagarsamy, K. N., Yan, W., Srivastava, A., Desiderio, V., and Dhingra, S.
- Subjects
medicine.medical_specialty ,Heart Diseases ,Cell Survival ,medicine.medical_treatment ,Cell Culture Techniques ,030204 cardiovascular system & hematology ,Cardiac tissue engineering ,Injections ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,injectable hydrogels ,Medicine ,Animals ,Humans ,Regeneration ,Myocardial infarction ,cardiac stem cell therapy ,Induced pluripotent stem cell ,Tissue Engineering ,Tissue Scaffolds ,business.industry ,Regeneration (biology) ,Myocardium ,Graft Survival ,biomaterial ,Hydrogels ,General Medicine ,Stem-cell therapy ,Recovery of Function ,medicine.disease ,Embryonic stem cell ,Transplantation ,Cardiology ,decellularized tissue ,Stem cell ,Cardiology and Cardiovascular Medicine ,business ,Adult stem cell ,Stem Cell Transplantation - Abstract
Cardiovascular diseases are responsible for approximately one-third of deaths around the world. Among cardiovascular diseases, the largest single cause of death is ischemic heart disease. Ischemic heart disease typically manifests as progressive constriction of the coronary arteries, which obstructs blood flow to the heart and can ultimately lead to myocardial infarction. This adversely affects the structure and function of the heart. Conventional treatments lack the ability to treat the myocardium lost during an acute myocardial infarction. Stem cell therapy offers an excellent solution for myocardial regeneration. Stem cell sources such as adult stem cells, embryonic and induced pluripotent stem cells have been the focal point of research in cardiac tissue engineering. However, cell survival and engraftment post-transplantation are major limitations that must be addressed prior to widespread use of this technology. Recently, biomaterials have been introduced as 3D vehicles to facilitate stem cell transplantation into infarct sites. This has shown significant promise with improved cell survival after transplantation. In this review, we discuss the various injectable hydrogels that have been tried in cardiac tissue engineering. Exploring and optimizing these cell-material interactions will guide cardiac tissue engineering towards developing stem cell based functional 3D constructs for cardiac regeneration.
- Published
- 2019
24. Targeted Myocardial Restoration with Injectable Hydrogels—In Search of The Holy Grail in Regenerating Damaged Heart Tissue.
- Author
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Sazzad, Faizus, Kuzemczak, Michał, Loh, Engracia, Wu, Wellington, and Kofidis, Theo
- Subjects
HYDROGELS ,TISSUE engineering ,REGENERATION (Biology) ,HEART transplantation ,HEART - Abstract
A 3-dimensional, robust, and sustained myocardial restoration by means of tissue engineering remains an experimental approach. Prolific protocols have been developed and tested in small and large animals, but, as clinical cardiac surgeons, we have not arrived at the privilege of utilizing any of them in our clinical practice. The question arises as to why this is. The heart is a unique organ, anatomically and functionally. It is not an easy target to replicate with current techniques, or even to support in its viability and function. Currently, available therapies fail to reverse the loss of functional cardiac tissue, the fundamental pathology remains unaddressed, and heart transplantation is an ultima ratio treatment option. Owing to the equivocal results of cell-based therapies, several strategies have been pursued to overcome the limitations of the current treatment options. Preclinical data, as well as first-in-human studies, conducted to-date have provided important insights into the understanding of injection-based approaches for myocardial restoration. In light of the available data, injectable biomaterials suitable for transcatheter delivery appear to have the highest translational potential. This article presents a current state-of-the-literature review in the field of hydrogel-based myocardial restoration therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
25. Hematopoietic stem-cell senescence and myocardial repair - Coronary artery disease genotype/phenotype analysis of post-MI myocardial regeneration response induced by CABG/CD133+ bone marrow hematopoietic stem cell treatment in RCT PERFECT Phase 3
- Author
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Olaf Wolkenhauer, Christian Ritter, Hermann Reichenspurner, Robert David, Jens Garbade, Jan Gummert, Denise Klatt, Markus Wolfien, Ralf Gaebel, Takayuki Asahara, Holger Hennig, Miki Komatsu-Horii, Ayumi Tani-Yokoyama, Julia Nesteruk, Eric Schrinner, Axel Haverich, Hiroto Iwasaki, Alexander Kaminski, Erika Akimaru, Masaaki, Christian Klopsch, Christof Stamm, Atsuhiko Kawamoto, Axel Schambach, Helmut Blum, Hiroshi Akimaru, Johannes T. Kowallick, Julia Philippou-Massier, Gustav Steinhoff, Stefan Krebs, and Amankeldi A Salybekov
- Subjects
Male ,0301 basic medicine ,Oncology ,Research paper ,Myocardial Ischemia ,lcsh:Medicine ,Stem cell factor ,Coronary Artery Disease ,Coronary artery disease ,0302 clinical medicine ,Clonal hematopoiesis of indeterminate pathology ,Angiogenesis induction ,AC133 Antigen ,Myocardial infarction ,Cellular Senescence ,Bone Marrow Transplantation ,lcsh:R5-920 ,CHIP ,SH2B3 ,Hematopoietic Stem Cell Transplantation ,Bone Marrow Stem Cell ,Hematopoietic stem cell ,Heart ,General Medicine ,Middle Aged ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Stem cell ,lcsh:Medicine (General) ,Adult ,medicine.medical_specialty ,Adolescent ,Bone Marrow Cells ,General Biochemistry, Genetics and Molecular Biology ,Young Adult ,03 medical and health sciences ,Germline mutation ,Internal medicine ,medicine ,Humans ,Regeneration ,Aged ,business.industry ,lcsh:R ,Myocardial regeneration ,Hematopoietic Stem Cells ,medicine.disease ,Cardiac stem cell therapy ,030104 developmental biology ,Bone marrow ,business - Abstract
Background: Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG). Methods: Transcriptome and variant expression analysis was studied in the phase 3 PERFECT trial post myocardial infarction CABG and CD133+ bone marrow derived hematopoetic stem cells showing difference in left ventricular ejection fraction (∆LVEF) myocardial regeneration Responders (n=14; ∆LVEF +16% day 180/0) and Non-responders (n=9; ∆LVEF -1.1% day 180/0). Subsequently, the findings have been validated in an independent patient cohort (n=14) as well as in two preclinical mouse models investigating SH2B3/LNK antisense or knockout deficient conditions. Findings: 1. Clinical: R differed from NR in a total of 161 genes in differential expression (n=23, q
- Published
- 2020
26. Exploiting AT2R to Improve CD117 Stem Cell Function In Vitro and In Vivo - Perspectives for Cardiac Stem Cell Therapy
- Author
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Gustav Steinhoff, Robert David, Christian Maschmeier, Ralf Gaebel, Cornelia A. Lux, Marion Ludwig, Anita Tölk, and Anna Skorska
- Subjects
Cardiac function curve ,medicine.medical_specialty ,Physiology ,Cell- and Tissue-Based Therapy ,Stimulation ,Cardioprotection ,Pharmacology ,Biology ,Receptor, Angiotensin, Type 2 ,Losartan ,lcsh:Physiology ,Cell Line ,lcsh:Biochemistry ,Mice ,In vivo ,Internal medicine ,Vasculogenesis ,medicine ,Animals ,Myocytes, Cardiac ,lcsh:QD415-436 ,Angiotensin II receptor type 1 ,lcsh:QP1-981 ,Angiotensin II ,Stem Cells ,Coculture Techniques ,digestive system diseases ,Mice, Inbred C57BL ,Cardiac stem cell therapy ,Proto-Oncogene Proteins c-kit ,Endocrinology ,Transient AT2R stimulation ,HL-1 cell line ,CD117+ stem cells ,Stem cell ,medicine.drug - Abstract
Background/Aims: CD117+ stem cell (SC) based therapy is considered an alternative therapeutic option for terminal heart disease. However, controversies exist on the effects of CD117+ SC implantation. In particular, the link between CD117+ SC function and angiotensin-II-type-2 receptor (AT2R) after MI is continuously discussed. We therefore asked whether 1) AT2R stimulation influences CD117+ SC properties in vitro and, 2) which effects can be ascribed to AT2R stimulation in vivo. Methods: We approached AT2R stimulation with Angiotensin II while simultaneously blocking its opponent receptor AT1 with Losartan. CD117 effects were dissected using a 2D-Matrigel assay and HL-1 co-culture in vitro. A model of myocardial infarction, in which we implanted EGFP+ CD117 SC, was further applied. Results: While we found indications for AT2R driven vasculogenesis in vitro, co-culture experiments revealed that CD117+ SC improve vitality of cardiomyocytes independently of AT2R function. Likewise, untreated CD117+ SC had a positive effect on cardiac function and acted cardioprotective in vivo. Conclusions: Therefore, our data show that transient AT2R stimulation does not significantly add to the beneficial actions of CD117+ SC in vivo. Yet, exploiting AT2R driven vasculogenis via an optimized AT2R stimulation protocol may become a promising tool for cardiac SC therapy.
- Published
- 2015
27. Cardiomyocyte Proliferation and Maturation: Two Sides of the Same Coin for Heart Regeneration.
- Author
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Zhao MT, Ye S, Su J, and Garg V
- Abstract
In the past few decades, cardiac regeneration has been the central target for restoring the injured heart. In mammals, cardiomyocytes are terminally differentiated and rarely divide during adulthood. Embryonic and fetal cardiomyocytes undergo robust proliferation to form mature heart chambers in order to accommodate the increased workload of a systemic circulation. In contrast, postnatal cardiomyocytes stop dividing and initiate hypertrophic growth by increasing the size of the cardiomyocyte when exposed to increased workload. Extracellular and intracellular signaling pathways control embryonic cardiomyocyte proliferation and postnatal cardiac hypertrophy. Harnessing these pathways could be the future focus for stimulating endogenous cardiac regeneration in response to various pathological stressors. Meanwhile, patient-specific cardiomyocytes derived from autologous induced pluripotent stem cells (iPSCs) could become the major exogenous sources for replenishing the damaged myocardium. Human iPSC-derived cardiomyocytes (iPSC-CMs) are relatively immature and have the potential to increase the population of cells that advance to physiological hypertrophy in the presence of extracellular stimuli. In this review, we discuss how cardiac proliferation and maturation are regulated during embryonic development and postnatal growth, and explore how patient iPSC-CMs could serve as the future seed cells for cardiac cell replacement therapy., (Copyright © 2020 Zhao, Ye, Su and Garg.)
- Published
- 2020
- Full Text
- View/download PDF
28. Hematopoietic stem-cell senescence and myocardial repair - Coronary artery disease genotype/phenotype analysis of post-MI myocardial regeneration response induced by CABG/CD133+ bone marrow hematopoietic stem cell treatment in RCT PERFECT Phase 3.
- Author
-
Wolfien M, Klatt D, Salybekov AA, Ii M, Komatsu-Horii M, Gaebel R, Philippou-Massier J, Schrinner E, Akimaru H, Akimaru E, David R, Garbade J, Gummert J, Haverich A, Hennig H, Iwasaki H, Kaminski A, Kawamoto A, Klopsch C, Kowallick JT, Krebs S, Nesteruk J, Reichenspurner H, Ritter C, Stamm C, Tani-Yokoyama A, Blum H, Wolkenhauer O, Schambach A, Asahara T, and Steinhoff G
- Subjects
- Adolescent, Adult, Aged, Bone Marrow Cells cytology, Cellular Senescence genetics, Coronary Artery Disease genetics, Coronary Artery Disease physiopathology, Female, Heart growth & development, Heart physiopathology, Hematopoietic Stem Cells cytology, Humans, Male, Middle Aged, Myocardial Ischemia genetics, Myocardial Ischemia pathology, Regeneration genetics, Young Adult, AC133 Antigen genetics, Bone Marrow Transplantation methods, Coronary Artery Disease therapy, Hematopoietic Stem Cell Transplantation methods, Myocardial Ischemia therapy
- Abstract
Background: Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG)., Methods: Transcriptome and variant expression analysis was studied in the phase 3 PERFECT trial post myocardial infarction CABG and CD133
+ bone marrow derived hematopoetic stem cells showing difference in left ventricular ejection fraction (∆LVEF) myocardial regeneration Responders (n=14; ∆LVEF +16% day 180/0) and Non-responders (n=9; ∆LVEF -1.1% day 180/0). Subsequently, the findings have been validated in an independent patient cohort (n=14) as well as in two preclinical mouse models investigating SH2B3/LNK antisense or knockout deficient conditions., Findings: 1. Clinical: R differed from NR in a total of 161 genes in differential expression (n=23, q<0•05) and 872 genes in coexpression analysis (n=23, q<0•05). Machine Learning clustering analysis revealed distinct RvsNR preoperative gene-expression signatures in peripheral blood acorrelated to SH2B3 (p<0.05). Mutation analysis revealed increased specific variants in RvsNR. (R: 48 genes; NR: 224 genes). 2. Preclinical:SH2B3/LNK-silenced hematopoietic stem cell (HSC) clones displayed significant overgrowth of myeloid and immune cells in bone marrow, peripheral blood, and tissue at day 160 after competitive bone-marrow transplantation into mice. SH2B3/LNK-/- mice demonstrated enhanced cardiac repair through augmenting the kinetics of bone marrow-derived endothelial progenitor cells, increased capillary density in ischemic myocardium, and reduced left ventricular fibrosis with preserved cardiac function. 3., Validation: Evaluation analysis in 14 additional patients revealed 85% RvsNR (12/14 patients) prediction accuracy for the identified biomarker signature., Interpretation: Myocardial repair is affected by HSC gene response and somatic mutation. Machine Learning can be utilized to identify and predict pathological HSC response., Funding: German Ministry of Research and Education (BMBF): Reference and Translation Center for Cardiac Stem Cell Therapy - FKZ0312138A and FKZ031L0106C, German Ministry of Research and Education (BMBF): Collaborative research center - DFG:SFB738 and Center of Excellence - DFG:EC-REBIRTH), European Social Fonds: ESF/IV-WM-B34-0011/08, ESF/IV-WM-B34-0030/10, and Miltenyi Biotec GmbH, Bergisch-Gladbach, Germany. Japanese Ministry of Health : Health and Labour Sciences Research Grant (H14-trans-001, H17-trans-002) TRIAL REGISTRATION: ClinicalTrials.gov NCT00950274., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
29. Cardiac Function Improvement and Bone Marrow Response -: Outcome Analysis of the Randomized PERFECT Phase III Clinical Trial of Intramyocardial CD133 + Application After Myocardial Infarction.
- Author
-
Steinhoff G, Nesteruk J, Wolfien M, Kundt G, Börgermann J, David R, Garbade J, Große J, Haverich A, Hennig H, Kaminski A, Lotz J, Mohr FW, Müller P, Oostendorp R, Ruch U, Sarikouch S, Skorska A, Stamm C, Tiedemann G, Wagner FM, and Wolkenhauer O
- Subjects
- Adult, Aged, Double-Blind Method, Female, Humans, Machine Learning, Male, Middle Aged, Survival Analysis, Treatment Outcome, Ventricular Function, Left, AC133 Antigen metabolism, Bone Marrow Cells immunology, Bone Marrow Transplantation, Myocardial Infarction physiopathology, Myocardial Infarction therapy
- Abstract
Objective: The phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133
+ bone marrow stem cell treatment combined with CABG for induction of cardiac repair., Design: Multicentre, double-blinded, randomised placebo controlled trial., Setting: The study was conducted across six centres in Germany October 2009 through March 2016 and stopped due slow recruitment after positive interim analysis in March 2015., Participants: Post-infarction patients with chronic ischemia and reduced LVEF (25-50%)., Interventions: Eighty-two patients were randomised to two groups receiving intramyocardial application of 5ml placebo or a suspension of 0.5-5×106 CD133+ ., Outcome: Primary endpoint was delta (∆) LVEF at 180days (d) compared to baseline measured in MRI., Findings (prespecified): Safety (n=77): 180d survival was 100%, MACE n=2, SAE n=49, without difference between placebo and CD133+ . Efficacy (n=58): The LVEF improved from baseline LVEF 33.5% by +9.6% at 180d, p=0.001 (n=58). Treatment groups were not different in ∆LVEF (ANCOVA: Placebo +8.8% vs. CD133+ +10.4%, ∆CD133+ vs placebo +2.6%, p=0.4)., Findings (post Hoc): Responders (R) classified by ∆LVEF≥5% after 180d were 60% of the patients (35/58) in both treatment groups. ∆LVEF in ANCOVA was +17.1% in (R) vs. non-responders (NR) (∆LVEF 0%, n=23). NR were characterized by a preoperative response signature in peripheral blood with reduced CD133+ EPC (RvsNR: p=0.005) and thrombocytes (p=0.004) in contrast to increased Erythropoeitin (p=0.02), and SH2B3 mRNA expression (p=0.073). Actuarial computed mean survival time was 76.9±3.32months (R) vs. +72.3±5.0months (NR), HR 0.3 [Cl 0.07-1.2]; p=0.067.Using a machine learning 20 biomarker response parameters were identified allowing preoperative discrimination with an accuracy of 80% (R) and 84% (NR) after 10-fold cross-validation., Interpretation: The PERFECT trial analysis demonstrates that the regulation of induced cardiac repair is linked to the circulating pool of CD133+ EPC and thrombocytes, associated with SH2B3 gene expression. Based on these findings, responders to cardiac functional improvement may be identified by a peripheral blood biomarker signature., Trial Registration: ClinicalTrials.govNCT00950274., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
30. UPDATE ON THE HOUSTON METHODIST DEBAKEY HEART & VASCULAR CENTER CARDIAC STEM CELL STUDIES.
- Author
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Bruckner, Brian A. and Reardon, Michael J.
- Subjects
- *
STEM cell research , *STEM cell treatment , *BONE marrow , *LEFT heart ventricle , *CORONARY artery bypass - Abstract
The article offers updates on two cardiac stem cell studies conducted at Houston Methodist DeBakey Heart & Vascular Center. The first trial involved direct injection of the patient's own bone marrow-derived stem cells into the left ventricle during a surgical procedure. Meanwhile, a phase II multicenter trial involved direct injection of the patient's stem cells into the failing myocardium during coronary artery bypass surgery.
- Published
- 2013
- Full Text
- View/download PDF
31. 10 Years of Intracoronary and Intramyocardial Bone Marrow Stem Cell Therapy of the Heart From the Methodological Origin to Clinical Practice
- Author
-
Strauer, Bodo-Eckehard and Steinhoff, Gustav
- Subjects
intramyocardial ,cardiac stem cell therapy ,intracoronary - Abstract
Intracoronary and intramyocardial stem cell therapy aim at the repair of compromised myocardium thereby—as a causal treatment—preventing ventricular remodeling and improving overall performance. Since the first-in-human use of bone marrow stem cells (BMCs) after acute myocardial infarction in 2001, a large number of clinical studies have demonstrated their clinical benefit: BMC therapy can be performed with usual cardiac catheterization techniques in the conscious patient as well as also easily during cardiosurgical interventions. New York Heart Association severity degree of patients as well as physical activity improve in addition to (“on top” of) all other therapeutic regimens. Stem cell therapy also represents an ultimate approach in advanced cardiac failure. For acute myocardial infarction and chronic ischemia, long-term mortality after 1 and 5 years, respectively, is significantly reduced. A few studies also indicate beneficial effects for chronic dilated cardiomyopathy. The clinical use of autologous BMC therapy implies no ethical problems, when unmodified primary cells are used. With the use of primary BMCs, there are no major stem cell-related side effects, especially no cardiac arrhythmias and inflammation. Various mechanisms of the stem cell action in the human heart are discussed, for example, cell transdifferentiation, cell fusion, activation of intrinsic cardiac stem cells, and cytokine-mediated effects. New techniques allow point-of-care cell preparations, for example, within the cardiac intervention or operation theater, thereby providing short preparation time, facilitated logistics of cell transport, and reasonable cost effectiveness of the whole procedure. The 3 main indications are acute infarction, chronic ischemic heart failure, and dilated cardiomyopathy. Future studies are desirable to further elucidate the mechanisms of stem cell action and to extend the current use of intracoronary and/or intramyocardial stem cell therapy by larger and presumably multicenter and randomized trials.
- Full Text
- View/download PDF
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