scholarly journals Adhesive Stem Cell Coatings for Enhanced Retention in the Heart Tissue

2020 ◽  
Vol 3 (5) ◽  
pp. 2930-2939
Author(s):  
Pei-Jung Wu ◽  
Hsuan Peng ◽  
Cong Li ◽  
Ahmed Abdel-Latif ◽  
Brad J. Berron
Keyword(s):  
Stem Cell ◽  
Heart Tissue

scholarly journals Preclinical trial of a MAP4K4 inhibitor to reduce infarct size in the pig: does cardioprotection in human stem cell-derived myocytes predict success in large mammals?

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Maaike te Lintel Hekkert ◽  
Gary Newton ◽  
Kathryn Chapman ◽  
Rehan Aqil ◽  
Robert Downham ◽  
...  
Keyword(s):  
Stem Cell ◽  
Infarct Size ◽  
Clinical Success ◽  
Heart Tissue ◽  
Balloon Occlusion ◽  
Large Mammals ◽  
Preclinical Trial ◽  
Large Mammal ◽  
Lv Mass ◽  
Technical Issues

AbstractReducing infarct size (IS) by interfering with mechanisms for cardiomyocyte death remains an elusive goal. DMX-5804, a selective inhibitor of the stress-activated kinase MAP4K4, suppresses cell death in mouse myocardial infarction (MI), human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), and 3D human engineered heart tissue, whose fidelity to human biology is hoped to strengthen the route to clinical success. Here, DMX-10001, a soluble, rapidly cleaved pro-drug of DMX-5804, was developed for i.v. testing in large-mammal MI. Following pharmacodynamic studies, a randomized, blinded efficacy study was performed in swine subjected to LAD balloon occlusion (60 min) and reperfusion (24 h). Thirty-six animals were enrolled; 12 were excluded by pre-defined criteria, death before infusion, or technical issues. DMX-10001 was begun 20 min before reperfusion (30 min, 60 mg/kg/h; 23.5 h, 17 mg/kg/h). At all times tested, beginning 30 min after the start of infusion, DMX-5804 concentrations exceeded > fivefold the levels that rescued hPSC-CMs and reduced IS in mice after oral dosing with DMX-5804 itself. No significant reduction occurred in IS or no-reflow corrected for the area at ischemic risk, even though DMX-10001 reduced IS, expressed in grams or % of LV mass, by 27%. In summary, a rapidly cleaved pro-drug of DMX-5804 failed to reduce IS in large-mammal MI, despite exceeding the concentrations for proven success in both mice and hPSC-CMs.

scholarly journals Stem cell-derived cell sheet transplantation for heart tissue repair in myocardial infarction

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Rui Guo ◽  
Masatoshi Morimatsu ◽  
Tian Feng ◽  
Feng Lan ◽  
Dehua Chang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cell ◽  
Tissue Repair ◽  
Cardiac Tissue ◽  
Cell Sheet ◽  
Clinical Manifestations ◽  
Induced Pluripotent Stem Cell ◽  
Heart Tissue ◽  
Therapeutic Effects ◽  
Cell Sheets

AbstractStem cell-derived sheet engineering has been developed as the next-generation treatment for myocardial infarction (MI) and offers attractive advantages in comparison with direct stem cell transplantation and scaffold tissue engineering. Furthermore, induced pluripotent stem cell-derived cell sheets have been indicated to possess higher potential for MI therapy than other stem cell-derived sheets because of their capacity to form vascularized networks for fabricating thickened human cardiac tissue and their long-term therapeutic effects after transplantation in MI. To date, stem cell sheet transplantation has exhibited a dramatic role in attenuating cardiac dysfunction and improving clinical manifestations of heart failure in MI. In this review, we retrospectively summarized the current applications and strategy of stem cell-derived cell sheet technology for heart tissue repair in MI.

Global transcriptional profiling reveals similarities and differences between human stem cell-derived cardiomyocyte clusters and heart tissue

2012 ◽  
Vol 44 (4) ◽  
pp. 245-258 ◽  
Author(s):  
Jane Synnergren ◽  
Caroline Améen ◽  
Andreas Jansson ◽  
Peter Sartipy
Keyword(s):  
Stem Cell ◽  
Ion Channels ◽  
Human Heart ◽  
Embryonic Stem ◽  
Heart Tissue ◽  
Phenotypic Characterization ◽  
Adult Heart ◽  
Promising Source

It is now well documented that human embryonic stem cells (hESCs) can differentiate into functional cardiomyocytes. These cells constitute a promising source of material for use in drug development, toxicity testing, and regenerative medicine. To assess their utility as replacement or complement to existing models, extensive phenotypic characterization of the cells is required. In the present study, we used microarrays and analyzed the global transcription of hESC-derived cardiomyocyte clusters (CMCs) and determined similarities as well as differences compared with reference samples from fetal and adult heart tissue. In addition, we performed a focused analysis of the expression of cardiac ion channels and genes involved in the Ca2+-handling machinery, which in previous studies have been shown to be immature in stem cell-derived cardiomyocytes. Our results show that hESC-derived CMCs, on a global level, have a highly similar gene expression profile compared with human heart tissue, and their transcriptional phenotype was more similar to fetal than to adult heart. Despite the high similarity to heart tissue, a number of significantly differentially expressed genes were identified, providing some clues toward understanding the molecular difference between in vivo sourced tissue and stem cell derivatives generated in vitro. Interestingly, some of the cardiac-related ion channels and Ca2+-handling genes showed differential expression between the CMCs and heart tissues. These genes may represent candidates for future genetic engineering to create hESC-derived CMCs that better mimic the phenotype of the cardiomyocytes present in the adult human heart.

Assessment of Induced Pluripotent Stem Cell-Derived Cardiomyocyte Contractility Using Micropost Arrays

2013 ◽  
Author(s):  
Marita L. Rodriguez ◽  
Charles E. Murry ◽  
Nathan J. Sniadecki
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Heart Tissue ◽  
Patient Specific ◽  
Human Stem Cells ◽  
Cell Therapies ◽  
Cardiomyocyte Contractility ◽  
Induced Pluripotent ◽  
Contractile Forces

Cardiovascular stem cell therapies have shown increasing promise as a potential therapeutic means for reversing the effects of a myocardial infarction [1]. Out of the currently available sources of human stem cells, human induced pluripotent stem cells (hiPSCs) are very promising in that: the number of cell lines that can be induced to the pluripotent state is extremely vast, they serve as a potential source for patient-specific cardiomyocytes, and their use is non-controversial. However, before they can be used feasibly in a clinical setting, the functional engraftment of these cells into the host tissue must be improved [2]. It is hypothesized that the structural and functional maturity of the stem-cell derived cardiomyocytes prior to implantation, may significantly affect the ability of these cells to engraft with resident heart tissue [3]. One of the most important functional characteristics of a cardiomyocyte is its ability to produce contractile forces. However, assessing the contractile properties of single iPS-CMs is a difficult task. iPS-CMs generally have relatively unorganized cytoskeletons, with stress fibers in multiple directions. This trait renders one or two-point force assays ineffectual in determining total cell forces. Furthermore, iPS-CMs don’t spread well on tissue culture surfaces, which make two-dimensional force measurements almost impossible.

scholarly journals Improving Cell Engraftment in Cardiac Stem Cell Therapy

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Xiaofei Li ◽  
Kenichi Tamama ◽  
Xiaoyun Xie ◽  
Jianjun Guan
Keyword(s):  
Stem Cell ◽  
Cell Therapy ◽  
Cell Survival ◽  
Stem Cell Therapy ◽  
Heart Function ◽  
Immune Surveillance ◽  
Heart Tissue ◽  
Cardiac Stem Cell ◽  
Cell Retention ◽  
Cell Engraftment

Myocardial infarction (MI) affects millions of people worldwide. MI causes massive cardiac cell death and heart function decrease. However, heart tissue cannot effectively regenerate by itself. While stem cell therapy has been considered an effective approach for regeneration, the efficacy of cardiac stem cell therapy remains low due to inferior cell engraftment in the infarcted region. This is mainly a result of low cell retention in the tissue and poor cell survival under ischemic, immune rejection and inflammatory conditions. Various approaches have been explored to improve cell engraftment: increase of cell retention using biomaterials as cell carriers; augmentation of cell survival under ischemic conditions by preconditioning cells, genetic modification of cells, and controlled release of growth factors and oxygen; and enhancement of cell survival by protecting cells from excessive inflammation and immune surveillance. In this paper, we review current progress, advantages, disadvantages, and potential solutions of these approaches.

scholarly journals Gene Expression Profiling of Functional Murine Embryonic Stem Cell-Derived Cardiomyocytes and Comparison with Adult Heart: Profiling of Murine ESC-Derived Cardiomyocytes

2009 ◽  
Vol 14 (3) ◽  
pp. 239-245 ◽  
Author(s):  
Tadahiro Shinozawa ◽  
Akiko Tsuji ◽  
Kenichi Imahashi ◽  
Kosuke Nakashima ◽  
Hiroshi Sawada ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Ion Channels ◽  
Embryonic Stem Cell ◽  
Expression Profiles ◽  
Embryonic Stem ◽  
Heart Tissue ◽  
Embryoid Bodies ◽  
Efficient Production ◽  
Adult Heart

Although embryonic stem cell (ESC)—derived cardiomyocytes may be a powerful tool in drug discovery, their potential has not yet been fully explored. Nor has a detailed comparison with adult heart tissue been performed. We have developed a method for efficient production of cardiomyocyte-rich embryoid bodies (EBs) from murine ESCs. Analysis of global gene expression profiles showed that EBs on day 7 and/or 21 of differentiation (d7CMs and d21CMs, respectively) were similar to adult heart tissue for genes categorized as regulators of muscle contraction or voltage-gated ion channel activity, although d21CMs were more mature than d7CMs for contractile components related to morphological structures. Calcium and sodium channel blockers altered Ca2+ transients, and isoproterenol, a β-adrenergic compound, increased the rate of beating in d7CMs and d21CMs. Our gene analytic system therefore enabled us to identify genes that are expressed in the physiological pathways associated with ion channels and structural components in d7CMs and d21CMs. We conclude that EBs might be of use for the basic screening of drugs that might affect contractile function through ion channels. ( Journal of Biomolecular Screening 2009:239-245)

P5385Development and preclinical testing of upscaled engineered heart tissue for use in translational studies

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
R Jabbour ◽  
T Owen ◽  
M Reinsch ◽  
P Pandey ◽  
B Wang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Tissue Engineering ◽  
Stem Cell ◽  
Ex Vivo ◽  
Rabbit Model ◽  
Heart Tissue ◽  
Border Zone ◽  
Preclinical Testing ◽  
Engineered Heart Tissue

Abstract Introduction The lack of efficacy of stem cell therapy for the treatment of heart failure may be related to the poor retention rates offered by existing delivery methods (intra-coronary/ intramyocardial). Tissue engineering strategies improve cell retention in small animal models but data regarding engineered heart tissue (EHT) patches large enough for human studies are lacking. Purpose To upscale EHT to a clinically relevant size and mature the patch in-vitro. Once matured to undergo preclinical testing in a rabbit model of myocardial infarction. Methods We developed an upscaled EHT patch (3cm x 2cm x 1.5mm) able to contain up to 50 million human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM; Fig A/B). Myocardial infarction model was performed by permanent ligation. Results The patches began to beat spontaneously within 3 days of fabrication and after 28 days of dynamic culture (Late EHTs) showed the development of several mature characteristics when compared to early patches (<14 days from fabrication). For example, late EHTs contained hiPSC-CMs which were more aligned (hiPSC-CM accumulative angle change: early 2702±778 degrees [n=4] vs late 922±186 [n=5], p=0.042); showed better contraction kinetics (early peak contraction amplitude 87.9±5.8a.u. versus late 952±304a.u.; p<0.001) and faster calcium transients (time to peak: early 200.8±8.8ms [n=5] vs late 147.7±10.2ms [n=6], p=0.004; time to 75% decay: early 274±9.7ms vs late 219.9±2.7ms, p=0.0003). We then tested the EHT patch in-vivo using a rabbit model (Fig C). Patches were applied to normal (n=5) or infarcted hearts (n=8). Sham operations used non-cellular fibrin patches (n=5). The mean fraction of troponin positive cells in the graft was 27.8±10.3% at 25.2±1.7 days relative to day 0 [n=5] and KU80 (human specific marker) staining confirmed that this was of human origin. CD31 (Fig D) and KU80 staining revealed that the grafts were well vascularized and that the vasculature was not human in origin (therefore were originating from the host). Ex-vivo optical mapping revealed evidence of electrical coupling between the graft and host at 2 weeks and preliminary experiments indicated that the patch improved left ventricular function when grafted onto infarcted hearts. Telemetry recordings in vivo and arrhythmia provocation protocols (ex vivo) indicated that the patch was not proarrhythmic. Figure 1. A/B) EHT Images; C) 20x troponin T (brown) of rabbit myocardium/EHT (2 weeks after grafting), blue counterstain = haematoxylin, red lines = EHT borders; D) 63x CD31 staining (brown) rabbit/EHT border zone (2 weeks after grafting), blue stain = haematoxylin, red lines = graft/host border zones. Conclusion We successfully upscaled hiPSC-CM derived EHT to a clinically relevant size and demonstrated feasibility and integration using a rabbit model of myocardial infarction. Tissue engineering strategies may be the preferred modality of cell delivery for future cardiac regenerative medicine studies.

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