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Heart failure (HF) is a life-threatening disorder and is treated by drug therapies and surgical interventions such as heart transplantation and left ventricular assist device (LVAD). However, these treatments can lack effectiveness in the long term and are associated with issues such as donor shortage in heart transplantation, and infection, stroke, or gastrointestinal bleeding in LVADs. Therefore, alternative therapeutic strategies are still needed. In this respect, stem cell therapy has been introduced for the treatment of HF and numerous preclinical and clinical studies are employing a range of stem cell varieties. These stem cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have been shown to improve cardiac function and attenuate left ventricular remodeling. IPSCs, which have a capacity for unlimited proliferation and differentiation into cardiomyocytes, are a promising cell source for myocardial regeneration therapy. In this review, we discuss the following topics: (1) what are iPSCs; (2) the limitations and solutions for the translation of iPSC-CMs practically; and (3) the current therapeutic clinical trials.

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Irreversible myocardium infarction is one of the leading causes of cardiovascular disease (CVD) related death and its quantum is expected to grow in coming years. Pharmacological intervention has been at the forefront to ameliorate injury-related morbidity and mortality. However, its outcomes are highly skewed. As an alternative, stem cell-based tissue engineering/regenerative medicine has been explored quite extensively to regenerate the damaged myocardium. The therapeutic modality that has been most widely studied both preclinically and clinically is based on adult multipotent mesenchymal stem cells (MSC) delivered to the injured heart. However, there is debate over the mechanistic therapeutic role of MSC in generating functional beating cardiomyocytes. This review intends to emphasize the role and use of MSC in cardiac regenerative therapy (CRT). We have elucidated in detail, the various aspects related to the history and progress of MSC use in cardiac tissue engineering and its multiple strategies to drive cardiomyogenesis. We have further discussed with a focus on the various therapeutic mechanism uncovered in recent times that has a significant role in ameliorating heart-related problems. We reviewed recent and advanced technologies using MSC to develop/create tissue construct for use in cardiac regenerative therapy. Finally, we have provided the latest update on the usage of MSC in clinical trials and discussed the outcome of such studies in realizing the full potential of MSC use in clinical management of cardiac injury as a cellular therapy module.

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Stem-cell-derived extracellular vesicles (EVs) have demonstrated multiple beneficial effects in preclinical models of cardiac diseases. However, poor retention at the target site may limit their therapeutic efficacy. Cardiac extracellular matrix hydrogels (cECMH) seem promising as drug-delivery materials and could improve the retention of EVs, but may be limited by their long gelation time and soft mechanical properties. Our objective was to develop and characterize an optimized product combining cECMH, polyethylene glycol (PEG), and EVs (EVs-PEG-cECMH) in an attempt to overcome their individual limitations: long gelation time of the cECMH and poor retention of the EVs. The new combined product presented improved physicochemical properties (60% reduction in half gelation time, p < 0.001, and threefold increase in storage modulus, p < 0.01, vs. cECMH alone), while preserving injectability and biodegradability. It also maintained in vitro bioactivity of its individual components (55% reduction in cellular senescence vs. serum-free medium, p < 0.001, similar to EVs and cECMH alone) and increased on-site retention in vivo (fourfold increase vs. EVs alone, p < 0.05). In conclusion, the combination of EVs-PEG-cECMH is a potential multipronged product with improved gelation time and mechanical properties, increased on-site retention, and maintained bioactivity that, all together, may translate into boosted therapeutic efficacy.

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Background Clinical effectiveness of autologous skeletal cell-patch implantation for nonischemic dilated cardiomyopathy has not been clearly elucidated in clinical settings. This clinical study aimed to determine the feasibility, safety, therapeutic efficacy, and the predictor of responders of this treatment in patients with nonischemic dilated cardiomyopathy. Methods and Results Twenty-four nonischemic dilated cardiomyopathy patients with left ventricular ejection fraction <35% on optimal medical therapy were enrolled. Autologous cell patches were implanted over the surface of the left ventricle through left minithoracotomy without procedure-related complications and lethal arrhythmia. We identified 13 responders and 11 nonresponders using the combined indicator of a major cardiac adverse event and incidence of heart failure event. In the responders, symptoms, exercise capacity, and cardiac performance were improved postoperatively (New York Heart Association class II 7 [54%] and III 6 [46%] to New York Heart Association class II 12 [92%] and I 1 [8%], P<0.05, 6-minute walk test; 471 m [370-541 m] to 525 m [425-555 m], P<0.05, left ventricular stroke work index; 31.1 g·m2·beat [22.7-35.5 g·m2·beat] to 32.8 g·m2·beat [28-38.5 g·m2·beat], P=0.21). However, such improvement was not observed in the nonresponders. In responders, the actuarial survival rate was 90.9±8.7% at 5 years, which was superior to the estimated survival rate of 70.9±5.4% using the Seattle Heart Failure Model. However, they were similar in nonresponders (47.7±21.6% and 56.3±8.1%, respectively). Multivariate regression model with B-type natriuretic peptide, pulmonary capillary wedge pressure, and expression of histone H3K4me3 (H3 lysine 4 trimethylation) strongly predicted the responder of this treatment (B-type natriuretic peptide: odds ratio [OR], 0.96; pulmonary capillary wedge pressure: ​OR, 0.58; H3K4me3: OR, 1.35, receiver operating characteristic-area under the curve, 0.96, P<0.001). Conclusions This clinical trial demonstrated that autologous skeletal stem cell-patch implantation might promise functional recovery and good clinical outcome in selected patients with nonischemic dilated cardiomyopathy, in addition to safety and feasibility. Registration URL: http://www.umin.ac.jp/english/. Unique identifiers: UMIN000003273, UMIN0000012906 and UMIN000015892.

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Mesenchymal stem cells (MSCs) are so far the most widely researched stem cells in clinics and used as an experimental cellular therapy module, particularly in cardiac regeneration and repair. Ever since the discovery of cardiomyogenesis induction in MSCs, a wide variety of differentiation protocols have been extensively used in preclinical models. However, pre differentiated MSC-derived cardiomyocytes have not been used in clinical trials; highlighting discrepancies and limitations in its use as a source of derived cardiomyocytes for transplantation to improve the damaged heart function. Therefore, this review article focuses on the strategies used to derive cardiomyocytes-like cells from MSCs isolated from three widely used tissue sources and their differentiation efficiencies. We have further discussed the role of MSCs in inducing angiogenesis as a cellular precursor to endothelial cells and its secretory aspects including exosomes. We have then discussed the strategies used for delivering cells in the damaged heart and how its retention plays a critical role in the overall outcome of the therapy. We have also conversed about the scope of the local and systemic modes of delivery of MSCs and the application of biomaterials to improve the overall delivery efficacy and function. We have finally discussed the advantages and limitations of cell delivery to the heart and the future scope of MSCs in cardiac regenerative therapy.

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Objectives: To establish a protocol to prepare and transplant clinical-grade human induced pluripotent stem cell (hiPSC)-derived cardiac tissues (HiCTs) and to evaluate the therapeutic potential in an animal myocardial infarction (MI) model. Methods: We simultaneously differentiated clinical-grade hiPSCs into cardiovascular cell lineages with or without the administration of canonical Wnt inhibitors, generated 5- layer cell sheets with insertion of gelatin hydrogel microspheres (GHMs) (HiCTs), and transplanted them onto an athymic rat MI model. Cardiac function was evaluated by echocardiography and cardiac magnetic resonance imaging and compared with that in animals with sham and transplantation of 5-layer cell sheets without GHMs. Graft survival, ventricular remodeling, and neovascularization were evaluated histopathologically. Results: The administration of Wnt inhibitors significantly promoted cardiomyocyte (CM) (P < .0001) and vascular endothelial cell (EC) (P = .006) induction, which resulted in cellular components of 52.0 ± 6.1% CMs and 9.9 ± 3.0% ECs. Functional analyses revealed the significantly lowest left ventricular end-diastolic volume and highest ejection fraction in the HiCT group. Histopathologic evaluation revealed that the HiCT group had a significantly larger median engrafted area (4 weeks, GHM(-) vs HiCT: 0.4 [range, 0.2-0.7] mm2 vs 2.2 [range, 1.8-3.1] mm2; P = .005; 12 weeks, 0 [range, 0-0.2] mm2 vs 1.9 [range, 0.1-3.2] mm2; P = .026), accompanied by the smallest scar area and highest vascular density at the MI border zone. Conclusions: Transplantation of HiCTs generated from clinical-grade hiPSCs exhibited a prominent therapeutic potential in a rat MI model and may provide a promising therapeutic strategy in cardiac regenerative medicine.

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Heart transplantation and ventricular assist device for the patients with end-stage heart failure are limited by availability and durability due to limited donor or device-related complication. Thus, complementation or a new alternative is needed for the treatment of severe heart failure. Based on the results of basic experiments, we applied skeletal myoblast cell sheet transplantation in a clinical setting using cell-sheet methods with temperature-responsive dish for the treatment of heart failure patient from 2007. After confirming the safety of this treatment, we started a clinical trial of myoblast cell sheet transplantation as sole therapy. According to these results, in 2015, myoblast cell sheet transplantation with ischemic cardiomyopathy was approved by the Japanese government and now this treatment was covered by Japanese health insurance. Here we report our approach and future perspective of cardiac regenerative therapy using this new treatment method for severe heart failure including new strategy incorporating regenerative therapy in the conventional treatment of heart failure including VAD and heart transplantation.

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The last decade has seen impressive progress in human embryonic stem cell-derived cardiomyocytes (hESC-CMs) that makes them ideal tools to repair injured hearts. To achieve an optimal outcome, advanced molecular imaging methods are essential to accurately track these transplanted cells in the heart. Herein, we demonstrate for the first time that a class of photoacoustic nanoparticles (PANPs) incorporating semiconducting polymers (SPs) as contrast agents can be used in the photoacoustic imaging (PAI) of transplanted hESC-CMs in living mouse hearts. This is achieved by virtue of two benefits of PANPs. First, strong PA signals and specific spectral features of SPs allow PAI to sensitively detect and distinguish a small number of PANP-labeled cells (2,000) from background tissues in vivo. Second, the PANPs show a high efficiency for hESC-CM labeling without adverse effects on cell structure, function, and gene expression. Assisted by ultrasound imaging, the delivery and engraftment of hESC-CMs in living mouse hearts can be assessed by PANP-based PAI with high spatial resolution (~100 µm). In summary, this study explores and validates a novel application of SPs as a PA contrast agent to track labeled cells with high sensitivity and accuracy in vivo, highlighting the advantages of integrating PAI and PANPs to advance cardiac regenerative therapies.

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The injectable electroconductive hydrogels are desirable for the regenerative therapy of electroresponsive tissues like heart. With the present electroconductive hydrogels, the issues of cytotoxicity, biodegradability, and diffusion of the conductive element and poor water solubility limit their applications. Here, electroconductive injectable single component hydrogels, PANIE-P/PEGDA and PANIS-P/PEGDA, are prepared with fumarate-co-PEG-co-sebacate comacromer conjugated with non-sulfonated/sulfonated polyaniline and PEGDA. These hydrogels have maximum electrical conductivity of 0.351±0.043×10-3Scm-1 and 0.550±0.016×10-3Scm-1, which is comparable to the native myocardium. The hydrogels with 50% comacromer concentration coded as PE50P and PS50P retain 82.48% and 84.08% water on equilibrium swelling respectively. The hydrogels have required a porous surface for cell growth and proliferation. PS50P hydrogel has stiffness of 442kPa with elastic characteristics. The hydrogel is compatible with L929 fibroblast and H9c2 cardiomyoblast cells. PS50P hydrogel has better free radical scavenging property and protective effect over cells under oxidative stress. The hydrogel retains encapsulated cardiomyoblast cells with 98% viability under static long-term in vitro culture. Briefly, the PS50P hydrogel is electroconductive, free radical scavenging and mechanically suitable for cardiac regenerative therapy.

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Cardiac regenerative therapy includes several techniques to repair and replace damaged tissues and organs using cells, biomaterials, molecules, or a combination of these factors. Generation of heart muscle is the most important challenge in this field, although it is well known that new advances in stem cell isolation and culture techniques in bioreactors and synthesis of bioactive materials contribute to the creation of cardiac tissue regeneration in vitro. Some investigations in stem cell biology shows that stem cells are an important source for regeneration of heart muscle cells and blood vessels and can thus clinically contribute to the regeneration of damaged heart tissue. The aim of this review was to explain the principles and challenges of myocardial tissue regeneration with an emphasis on stem cells and scaffolds. J. Cell. Biochem. 118: 2454-2462, 2017. © 2017 Wiley Periodicals, Inc.

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For cardiac regenerative therapy intramyocardial catheter guided cell transplantations are targeted to the infarct border zone (IBZ) i.e. the closest region of viable myocardium in the vicinity of the infarct area. For optimal therapeutic effect this area should be accurately identified. However late gadolinium enhanced magnetic resonance imaging (LGE-MRI) is the gold standard technique to determine the infarct size and location, electromechanical mapping (EMM) is used to guide percutaneous intramyocardial injections to the IBZ. Since EMM has a low spatial resolution, we aim to develop a practical and accurate technique to fuse EMM with LGE-MRI to guide intramyocardial injections. LGE-MRI and EMM were obtained in 17 pigs with chronic myocardial infarction created by balloon occlusion of LCX and LAD coronary arteries. LGE-MRI and EMM datasets were registered using our in-house developed 3D CartBox image registration software toolbox to assess: (1) the feasibility of the 3D CartBox toolbox, (2) the EMM values measured in the areas with a distinct infarct transmurality (IT), and (3) the highest sensitivity and specificity of the EMM to assess IT and define the IBZ. Registration of LGE-MRI and EMM resulted in a mean error of 3.01 ± 1.94 mm between the LGE-MRI mesh and EMM points. The highest sensitivity and specificity were found for UV <9.4 mV and bipolar voltage <1.2 mV to respectively identify IT of ≥5 and ≥97.5 %. The 3D CartBox image registration toolbox enables registration of EMM data on pre-acquired MRI during the EMM guided procedure and allows physicians to easily guide injections to the most optimal injection location for cardiac regenerative therapy and harness the full therapeutic effect of the therapy.

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