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Backgound Aims: This meta-analysis aims at summarizing the whole body of research on cell therapies for acute myocardial infarction (MI) in the mouse model to bring forward ongoing research in this field of regenerative medicine. Despite rather modest effects in clinical trials, pre-clinical studies continue to report beneficial effects of cardiac cell therapies for cardiac repair following acute ischemic injury. Results: The authors' meta-analysis of data from 166 mouse studies comprising 257 experimental groups demonstrated a significant improvement in left ventricular ejection fraction of 10.21% after cell therapy compared with control animals. Subgroup analysis indicated that second-generation cell therapies such as cardiac progenitor cells and pluripotent stem cell derivatives had the highest therapeutic potential for minimizing myocardial damage post-MI. Conclusions: Whereas the vision of functional tissue replacement has been replaced by the concept of regional scar modulation in most of the investigated studies, rather basic methods for assessing cardiac function were most frequently used. Hence, future studies will highly benefit from integrating methods for assessment of regional wall properties to evolve a deeper understanding of how to modulate cardiac healing after acute MI. The graphical abstract was created with BioRender.com. [Display omitted] [ABSTRACT FROM AUTHOR]

We review the history of cardiac cell therapy, highlighting lessons learned from initial adult stem cell (ASC) clinical trials. We present pluripotent stem cell–derived cardiomyocytes (PSC-CMs) as a leading candidate for robust regeneration of infarcted myocardium but identify several issues that must be addressed before successful clinical translation. We conducted an unstructured literature review of PubMed-listed articles, selecting the most comprehensive and relevant research articles, review articles, clinical trials, and basic or translation articles in the field of cardiac cell therapy. Articles were identified using the search terms adult stem cells , pluripotent stem cells , cardiac stem cell , and cardiac regeneration or from references of relevant articles, Articles were prioritized and selected based on their impact, originality, or potential clinical applicability. Since its inception, the ASC therapy field has been troubled by conflicting preclinical data, academic controversies, and inconsistent trial designs. These issues have damaged perceptions of cardiac cell therapy among investors, the academic community, health care professionals, and, importantly, patients. In hindsight, the key issue underpinning these problems was the inability of these cell types to differentiate directly into genuine cardiomyocytes, rendering them unable to replace damaged myocardium. Despite this, beneficial effects through indirect paracrine or immunomodulatory effects remain possible and continue to be investigated. However, in preclinical models, PSC-CMs have robustly remuscularized infarcted myocardium with functional, force-generating cardiomyocytes. Hence, PSC-CMs have now emerged as a leading candidate for cardiac regeneration, and unpublished reports of first-in-human delivery of these cells have recently surfaced. However, the cardiac cell therapy field's history should serve as a cautionary tale, and we identify several translational hurdles that still remain. Preclinical solutions to issues such as arrhythmogenicity, immunogenicity, and poor engraftment rates are needed, and next-generation clinical trials must draw on robust knowledge of mechanistic principles of the therapy. The clinical transplantation of functional stem cell–derived heart tissue with seamless integration into native myocardium is a lofty goal. However, considerable advances have been made during the past 2 decades. Currently, PSC-CMs appear to be the best prospect to reach this goal, but several hurdles remain. The history of adult stem cell trials has taught us that shortcuts cannot be taken without dire consequences, and it is essential that progress not be hurried and that a worldwide, cross-disciplinary approach be used to ensure safe and effective clinical translation. [ABSTRACT FROM AUTHOR]

Limited data are available on the effects of stem cells in non-ischemic dilated cardiomyopathy (DCM). Since the diffuse nature of the disease calls for a broad distribution of cells, this study investigated the scaffold-based delivery of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) in a mouse model of DCM. Nanofibrous scaffolds were produced using a clinical grade atelocollagen which was electrospun and cross-linked under different conditions. As assessed by scanning electron microscopy and shearwave elastography, the optimum crosslinking conditions for hiPS-CM colonization proved to be a 10% concentration of citric acid crosslinking agent and 150 min of post-electrospinning baking. Acellular collagen scaffolds were first implanted in both healthy mice and those with induced DCM by a cardiac-specific invalidation of serum response factor (SRF). Seven and fourteen days after implantation, the safety of the scaffold was demonstrated by echocardiography and histological assessments. The subsequent step of implantation of the scaffolds seeded with hiPS-CM in DCM induced mice, using cell-free scaffolds as controls, revealed that after fourteen days heart function decreased in controls while it remained stable in the treated mice. This pattern was associated with an increased number of endothelial cells, in line with the greater vascularity of the scaffold. Moreover, a lesser degree of fibrosis consistent with the upregulation of several genes involved in extracellular matrix remodeling was observed. These results support the interest of the proposed hiPS-CM seeded electrospun scaffold for the stabilization of the DCM outcome with potential for its clinical use in the future. [ABSTRACT FROM AUTHOR]

Synergy between micro-nanotechnology and regenerative medicine can lead to new tools for health improvement. In this study, we investigate the efficacy of electrospun scaffolds – fabricated using clinically approved collagen – as supports for cardiomyoblast culture. The scaffolds were prepared using non-toxic solvents and crosslinking agents and characterized by scanning electron microscopy and contact angle measurements. Among different types of collagen samples, we found that atelocollagen can produce better quality of electrospun fibers than acid and basic fibrous collagen. Our results also show that the cell culture performance can be improved by adjusting the crosslinking conditions. Typically, increasing the concentration of citric acid of the cross-link agents from 5% to 10% w/w and the post-crosslink baking time from 1.5 to 2.5 h led to significant increases of the cellular colonization of the scaffold, showing three-dimensional growth of cardiac cells due to the specific morphology of the fibrous scaffolds. Finally, in vivo tests of the biocompatibility of the fabricated scaffolds have been done using a mouse model of dilated cardiomyopathy. As expected, the biocompatibility of the scaffold was found excellent and no visible inflammation was observed after the implantation up to two weeks. However, 5% citric acid electrospun collagen scaffolds was less resistant in vivo, proving again the importance of the processing parameter optimization of the electrospun scaffolds. [ABSTRACT FROM AUTHOR]

Abstract: Ischemic Heart Disease (IHD) still represents the “Number One Killer” worldwide accounting for the death of numerous patients. However the capacity for self-regeneration of the adult heart is very limited and the loss of cardiomyocytes in the infarcted heart leads to continuous adverse cardiac-remodeling which often leads to heart-failure (HF). The concept of regenerative medicine comprising cell-based therapies, bio-engineering technologies and hybrid solutions has been proposed as a promising next-generation approach to address IHD and HF. Numerous strategies are under investigation evaluating the potential of regenerative medicine on the failing myocardium including classical cell-therapy concepts, three-dimensional culture techniques and tissue-engineering approaches. While most of these regenerative strategies have shown great potential in experimental studies, the translation into a clinical setting has either been limited or too rapid leaving many key questions unanswered. This review summarizes the current state-of-the-art, important challenges and future research directions as to regenerative approaches addressing IHD and resulting HF. [Copyright &y& Elsevier]

Autologous cardiac cell therapy is a promising treatment for combating the right ventricular heart failure (RVHF) that can occur in patients with congenital heart disease (CHD). However, autologous cell therapies suffer from low cell retention following injection and patient-to-patient variability in cell quality. Here, we demonstrate how computational methods can be used to identify mechanisms of cardiac-derived c-Kit+ cell (CPC) reparative capacity and how biomaterials can be designed to improve cardiac patch performance by engaging these mechanisms. Computational modeling revealed the integrin subunit α V (ITGAV) as an important mediator of repair in CPCs with inherently low reparative capacity (CPCslow). We could engage ITGAV on the cell surface and improve reparative capacity by culturing CPCs on electrospun polycaprolactone (PCL) patches coated with fibronectin (PCL + FN). We tested CPCs from 4 different donors and found that only CPCslow with high ITGAV expression (patient 956) had improved anti-fibrotic and pro-angiogenic paracrine secretion on PCL + FN patches. Further, knockdown of ITGAV via siRNA led to loss of this improved paracrine secretion in patient 956 on PCL + FN patches. When implanted in rat model of RVHF, only PCL + FN + 956 patches were able to improve RV function, while PCL +956 patches did not. In total, we demonstrate how cardiac patches can be designed in a patient-specific manner to improve in vitro and in vivo outcomes. [Display omitted] • Statistical methods reveal ITGAV as a mediator of patient-derived CPC function. • CPCs with increased ITGAV have improved function on FN-coated cardiac patches. • Patient-specific cardiac patches improve RV function in rat models of RVHF. [ABSTRACT FROM AUTHOR]

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Abstract: Successful implementation of cardiac cell transplantation for treating damaged myocardium relies on the development of improved injectable biomaterials. A novel biomaterial technology using PEGylated fibrinogen has been developed with controllable physicochemical properties based on the poly(ethylene glycol) (PEG) constituent. In addition, the fibrinogen backbone of the material confers inherent bioactivity to cells. The purpose of this investigation was to explore by in vitro techniques the use of this biomaterial as a scaffold for cardiac tissue regeneration. To this end neonatal rat cardiomyocytes were cultivated in PEGylated fibrinogen constructs. The cell-seeding density and biomaterial composition were optimized to obtain maximum spontaneous contraction of the constructs. Quantitative characterization of the contraction pattern was accomplished by video image analysis. It was possible to demonstrate an inverse correlation between the material stiffness and the amplitude of contraction of the tissue constructs by changing the modulus of the matrix using different compositions of PEG and fibrinogen. The relationship between matrix stiffness, cell density and tissue contraction also provided some insight into the mechanism of cellular remodeling that ultimately leads to synchronized contraction of the constructs. These findings indicate that PEGylated fibrinogen hydrogels can be used as a scaffold for cardiomyocytes, and offer the possibility of controlling cellular remodeling via simple compositional modifications to the matrix. [Copyright &y& Elsevier]