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Biomolecules
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Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration
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Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 39688

Special Issue Editor

Prof. Dr. Mariann Gyöngyösi

E-Mail Website
Guest Editor
Department of Cardiology, Medical University of Vienna, Vienna, Austria
Interests: long COVID-19; post-COVID-19; multiorgan disease; cardiac regeneration; cell-based and cell-free therapies; translational animal models of cardiac diseases; ischemic heart diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cardiac regenerative medicine is regarded as one of the key technologies of the present and near future, with potential novel therapeutic opportunities for cardiovascular diseases. Revolutionary breakthroughs have been made in the last two decades, including the generation of induced pluripotent stem cells (iPS), gaining insight into fundamental regenerative mechanisms by -omics, and the development of cell-free therapuetics. Beyond using stem and progenitor cells, regenerative medicine includes the application of cell-free materials such as secretomes, cell-derived extracellular vesicles (EVs), growth factors, noncoding RNAs and gene therapies, biomaterials, and engineered tissues. In principle, regenerative medicine can be invoked by two complementary strategies: (1) stimulation of an endogenous repair mechanism by applied therapeutics (synthetic or biologically derived factors, genetic and epigenetic modifications) and (2) exogenous regeneration through use of cells, tissues or other biotechnological products (advanced therapy medicinal products, ATMPs). Despite great biological and preclinical advancements, translation to therapeutic application of regenerative cells in humans has failed so far. Although based on strongly convincing preclinical data, most of the large clinical trials with cell-based therapies in cardiovascular regenerative medicine have failed to achieve a meaningful and clinically significant benefit. According to the technical difficulties in obtainment, selection, purification, and storage of autologous stem and progenitor cells, the focus of research transposed to off-the-shelf products to use allogenous cell products and small molecules for cardiac repair.

In this Special Issue of Biomolecules called “Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration“, we invite research papers and reviews reporting cardiac regeneration achieved or failing to be achieved using small molecules, noncoding RNAs, exosomes or any other cell-free substances, or stimulating the endogenous repair mechanisms, or revealing basic mechanistic insight into cardiac reapir mechanisms, with emphasis on the translational importance of research.

Prof. Dr. Mariann Gyöngyösi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cardiac repair
  • cell-free therapies in cardiac regeneration
  • translational model of human diseases
  • ischemic and non-ischemic heart diseases
  • exosomes
  • noncoding RNAs
  • regenerative biomaterials

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 156 KiB  
Editorial
Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration
by Mariann Gyöngyösi
Biomolecules 2021, 11(2), 161; https://doi.org/10.3390/biom11020161 - 26 Jan 2021
Cited by 1 | Viewed by 1773
Abstract
In contrast with some adult human organs, such as liver or skin, the adult human heart shows very limited self-regeneration capacity, attributed to the negligible presence of resident cardiac stem cells or cardiac progenitors [...] Full article
(This article belongs to the Special Issue Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration)

Research

Jump to: Editorial, Review

43 pages, 4913 KiB  
Article
MiRNA Profiles of Extracellular Vesicles Secreted by Mesenchymal Stromal Cells—Can They Predict Potential Off-Target Effects?
by Timo Z. Nazari-Shafti, Sebastian Neuber, Ana G. Duran, Vasileios Exarchos, Christien M. Beez, Heike Meyborg, Katrin Krüger, Petra Wolint, Johanna Buschmann, Roland Böni, Martina Seifert, Volkmar Falk and Maximilian Y. Emmert
Biomolecules 2020, 10(9), 1353; https://doi.org/10.3390/biom10091353 - 22 Sep 2020
Cited by 15 | Viewed by 4111
Abstract
The cardioprotective properties of extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) are currently being investigated in preclinical studies. Although microRNAs (miRNAs) encapsulated in EVs have been identified as one component responsible for the cardioprotective effect of MSCs, their potential off-target effects [...] Read more.
The cardioprotective properties of extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) are currently being investigated in preclinical studies. Although microRNAs (miRNAs) encapsulated in EVs have been identified as one component responsible for the cardioprotective effect of MSCs, their potential off-target effects have not been sufficiently characterized. In the present study, we aimed to investigate the miRNA profile of EVs isolated from MSCs that were derived from cord blood (CB) and adipose tissue (AT). The identified miRNAs were then compared to known targets from the literature to discover possible adverse effects prior to clinical use. Our data show that while many cardioprotective miRNAs such as miR-22-3p, miR-26a-5p, miR-29c-3p, and miR-125b-5p were present in CB- and AT-MSC-derived EVs, a large number of known oncogenic and tumor suppressor miRNAs such as miR-16-5p, miR-23a-3p, and miR-191-5p were also detected. These findings highlight the importance of quality assessment for therapeutically applied EV preparations. Full article
(This article belongs to the Special Issue Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration)
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13 pages, 3078 KiB  
Article
Association between Circular RNA CDR1as and Post-Infarction Cardiac Function in Pig Ischemic Heart Failure: Influence of the Anti-Fibrotic Natural Compounds Bufalin and Lycorine
by Julia Mester-Tonczar, Johannes Winkler, Patrick Einzinger, Ena Hasimbegovic, Nina Kastner, Dominika Lukovic, Katrin Zlabinger, Andreas Spannbauer, Denise Traxler, Sandor Batkai, Thomas Thum and Mariann Gyöngyösi
Biomolecules 2020, 10(8), 1180; https://doi.org/10.3390/biom10081180 - 14 Aug 2020
Cited by 29 | Viewed by 3586
Abstract
Anti-fibrotic therapies are of increasing interest to combat cardiac remodeling and heart failure progression. Recently, anti-fibrotic circular RNAs (circRNAs) have been identified in human and rodent cardiac tissue. In vivo (rodent) experiments proved cardiac anti-fibrotic effects of the natural compounds bufalin and lycorine [...] Read more.
Anti-fibrotic therapies are of increasing interest to combat cardiac remodeling and heart failure progression. Recently, anti-fibrotic circular RNAs (circRNAs) have been identified in human and rodent cardiac tissue. In vivo (rodent) experiments proved cardiac anti-fibrotic effects of the natural compounds bufalin and lycorine by downregulating miRNA-671-5p, associated with a theoretic increase in the tissue level of circRNA CDR1as. Accordingly, we hypothesized that both anti-fibrotic drugs may inhibit focal myocardial fibrosis of the remodeled left ventricle (LV) also in a translational large animal model of heart failure (HF). Domestic pigs were repeatedly treated with subcutaneous injections of either bufalin, lycorine, or saline, (n = 5/group) between days 7–21 post acute myocardial infarction (AMI). At the 2-month follow-up, both bufalin and lycorine led to significantly reduced cardiac fibrosis. Bufalin treatment additionally led to smaller end-diastolic volumes, higher LV ejection fraction (EF), and increased expression of CDR1as of the AMI region. Elevated tissue levels of the circRNA CDR1as in the AMI region of the pig heart correlated significantly with LV and right ventricular EF, LV stroke volume, and negatively with infarct size. In conclusion, we successfully identified the circRNA CDR1as in pig hearts and show a significant association with improved LV and RV function by anti-fibrotic therapies in a translational animal model of HF. Full article
(This article belongs to the Special Issue Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration)
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Review

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21 pages, 1929 KiB  
Review
Harnessing Mechanosensation in Next Generation Cardiovascular Tissue Engineering
by Gloria Garoffolo, Silvia Ferrari, Stefano Rizzi, Marianna Barbuto, Giacomo Bernava and Maurizio Pesce
Biomolecules 2020, 10(10), 1419; https://doi.org/10.3390/biom10101419 - 7 Oct 2020
Cited by 14 | Viewed by 3177
Abstract
The ability of the cells to sense mechanical cues is an integral component of ”social” cell behavior inside tissues with a complex architecture. Through ”mechanosensation” cells are in fact able to decrypt motion, geometries and physical information of surrounding cells and extracellular matrices [...] Read more.
The ability of the cells to sense mechanical cues is an integral component of ”social” cell behavior inside tissues with a complex architecture. Through ”mechanosensation” cells are in fact able to decrypt motion, geometries and physical information of surrounding cells and extracellular matrices by activating intracellular pathways converging onto gene expression circuitries controlling cell and tissue homeostasis. Additionally, only recently cell mechanosensation has been integrated systematically as a crucial element in tissue pathophysiology. In the present review, we highlight some of the current efforts to assess the relevance of mechanical sensing into pathology modeling and manufacturing criteria for a next generation of cardiovascular tissue implants. Full article
(This article belongs to the Special Issue Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration)
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19 pages, 1061 KiB  
Review
Large Animal Models of Cell-Free Cardiac Regeneration
by Andreas Spannbauer, Julia Mester-Tonczar, Denise Traxler, Nina Kastner, Katrin Zlabinger, Ena Hašimbegović, Martin Riesenhuber, Noemi Pavo, Georg Goliasch and Mariann Gyöngyösi
Biomolecules 2020, 10(10), 1392; https://doi.org/10.3390/biom10101392 - 29 Sep 2020
Cited by 11 | Viewed by 4097
Abstract
The adult mammalian heart lacks the ability to sufficiently regenerate itself, leading to the progressive deterioration of function and heart failure after ischemic injuries such as myocardial infarction. Thus far, cell-based therapies have delivered unsatisfactory results, prompting the search for cell-free alternatives that [...] Read more.
The adult mammalian heart lacks the ability to sufficiently regenerate itself, leading to the progressive deterioration of function and heart failure after ischemic injuries such as myocardial infarction. Thus far, cell-based therapies have delivered unsatisfactory results, prompting the search for cell-free alternatives that can induce the heart to repair itself through cardiomyocyte proliferation, angiogenesis, and advantageous remodeling. Large animal models are an invaluable step toward translating basic research into clinical applications. In this review, we give an overview of the state-of-the-art in cell-free cardiac regeneration therapies that have been tested in large animal models, mainly pigs. Cell-free cardiac regeneration therapies involve stem cell secretome- and extracellular vesicles (including exosomes)-induced cardiac repair, RNA-based therapies, mainly regarding microRNAs, but also modified mRNA (modRNA) as well as other molecules including growth factors and extracellular matrix components. Various methods for the delivery of regenerative substances are used, including adenoviral vectors (AAVs), microencapsulation, and microparticles. Physical stimulation methods and direct cardiac reprogramming approaches are also discussed. Full article
(This article belongs to the Special Issue Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration)
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Graphical abstract

20 pages, 1768 KiB  
Review
Cellular and Molecular Mechanism of Cardiac Regeneration: A Comparison of Newts, Zebrafish, and Mammals
by Lousanne de Wit, Juntao Fang, Klaus Neef, Junjie Xiao, Pieter A. Doevendans, Raymond M. Schiffelers, Zhiyong Lei and Joost P.G. Sluijter
Biomolecules 2020, 10(9), 1204; https://doi.org/10.3390/biom10091204 - 19 Aug 2020
Cited by 15 | Viewed by 6042
Abstract
Cardiovascular disease is the leading cause of death worldwide. Current palliative treatments can slow the progression of heart failure, but ultimately, the only curative treatment for end-stage heart failure is heart transplantation, which is only available for a minority of patients due to [...] Read more.
Cardiovascular disease is the leading cause of death worldwide. Current palliative treatments can slow the progression of heart failure, but ultimately, the only curative treatment for end-stage heart failure is heart transplantation, which is only available for a minority of patients due to lack of donors’ hearts. Explorative research has shown the replacement of the damaged and lost myocardium by inducing cardiac regeneration from preexisting myocardial cells. Lower vertebrates, such as the newt and zebrafish, can regenerate lost myocardium through cardiomyocyte proliferation. The preexisting adult cardiomyocytes replace the lost cells through subsequent dedifferentiation, proliferation, migration, and re-differentiation. Similarly, neonatal mice show complete cardiac regeneration post-injury; however, this regenerative capacity is remarkably diminished one week after birth. In contrast, the adult mammalian heart presents a fibrotic rather than a regenerative response and only shows signs of partial pathological cardiomyocyte dedifferentiation after injury. In this review, we explore the cellular and molecular responses to myocardial insults in different adult species to give insights for future interventional directions by which one can promote or activate cardiac regeneration in mammals. Full article
(This article belongs to the Special Issue Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration)
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15 pages, 1172 KiB  
Review
The Hippo Pathway in Cardiac Regeneration and Homeostasis: New Perspectives for Cell-Free Therapy in the Injured Heart
by Mingjie Zheng, Joan Jacob, Shao-Hsi Hung and Jun Wang
Biomolecules 2020, 10(7), 1024; https://doi.org/10.3390/biom10071024 - 10 Jul 2020
Cited by 19 | Viewed by 5288
Abstract
Intractable cardiovascular diseases are leading causes of mortality around the world. Adult mammalian hearts have poor regenerative capacity and are not capable of self-repair after injury. Recent studies of cell-free therapeutics such as those designed to stimulate endogenous cardiac regeneration have uncovered new [...] Read more.
Intractable cardiovascular diseases are leading causes of mortality around the world. Adult mammalian hearts have poor regenerative capacity and are not capable of self-repair after injury. Recent studies of cell-free therapeutics such as those designed to stimulate endogenous cardiac regeneration have uncovered new feasible therapeutic avenues for cardiac repair. The Hippo pathway, a fundamental pathway with pivotal roles in cell proliferation, survival and differentiation, has tremendous potential for therapeutic manipulation in cardiac regeneration. In this review, we summarize the most recent studies that have revealed the function of the Hippo pathway in heart regeneration and homeostasis. In particular, we discuss the molecular mechanisms of how the Hippo pathway maintains cardiac homeostasis by directing cardiomyocyte chromatin remodeling and regulating the cell-cell communication between cardiomyocytes and non-cardiomyocytes in the heart. Full article
(This article belongs to the Special Issue Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration)
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30 pages, 1274 KiB  
Review
Novel Applications of Mesenchymal Stem Cell-Derived Exosomes for Myocardial Infarction Therapeutics
by Sho Joseph Ozaki Tan, Juliana Ferreria Floriano, Laura Nicastro, Costanza Emanueli and Francesco Catapano
Biomolecules 2020, 10(5), 707; https://doi.org/10.3390/biom10050707 - 2 May 2020
Cited by 63 | Viewed by 7402
Abstract
Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity globally, representing approximately a third of all deaths every year. The greater part of these cases is represented by myocardial infarction (MI), or heart attack as it is better known, which occurs [...] Read more.
Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity globally, representing approximately a third of all deaths every year. The greater part of these cases is represented by myocardial infarction (MI), or heart attack as it is better known, which occurs when declining blood flow to the heart causes injury to cardiac tissue. Mesenchymal stem cells (MSCs) are multipotent stem cells that represent a promising vector for cell therapies that aim to treat MI due to their potent regenerative effects. However, it remains unclear the extent to which MSC-based therapies are able to induce regeneration in the heart and even less clear the degree to which clinical outcomes could be improved. Exosomes, which are small extracellular vesicles (EVs) known to have implications in intracellular communication, derived from MSCs (MSC-Exos), have recently emerged as a novel cell-free vector that is capable of conferring cardio-protection and regeneration in target cardiac cells. In this review, we assess the current state of research of MSC-Exos in the context of MI. In particular, we place emphasis on the mechanisms of action by which MSC-Exos accomplish their therapeutic effects, along with commentary on the current difficulties faced with exosome research and the ongoing clinical applications of stem-cell derived exosomes in different medical contexts. Full article
(This article belongs to the Special Issue Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration)
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23 pages, 383 KiB  
Review
Reviewing the Limitations of Adult Mammalian Cardiac Regeneration: Noncoding RNAs as Regulators of Cardiomyogenesis
by Robin Verjans, Marc van Bilsen and Blanche Schroen
Biomolecules 2020, 10(2), 262; https://doi.org/10.3390/biom10020262 - 10 Feb 2020
Cited by 10 | Viewed by 3387
Abstract
The adult mammalian heart is incapable of regeneration following cardiac injury, leading to a decline in function and eventually heart failure. One of the most evident barriers limiting cardiac regeneration is the inability of cardiomyocytes to divide. It has recently become clear that [...] Read more.
The adult mammalian heart is incapable of regeneration following cardiac injury, leading to a decline in function and eventually heart failure. One of the most evident barriers limiting cardiac regeneration is the inability of cardiomyocytes to divide. It has recently become clear that the mammalian heart undergoes limited cardiomyocyte self-renewal throughout life and is even capable of modest regeneration early after birth. These exciting findings have awakened the goal to promote cardiomyogenesis of the human heart to repair cardiac injury or treat heart failure. We are still far from understanding why adult mammalian cardiomyocytes possess only a limited capacity to proliferate. Identifying the key regulators may help to progress towards such revolutionary therapy. Specific noncoding RNAs control cardiomyocyte division, including well explored microRNAs and more recently emerged long noncoding RNAs. Elucidating their function and molecular mechanisms during cardiomyogenesis is a prerequisite to advance towards therapeutic options for cardiac regeneration. In this review, we present an overview of the molecular basis of cardiac regeneration and describe current evidence implicating microRNAs and long noncoding RNAs in this process. Current limitations and future opportunities regarding how these regulatory mechanisms can be harnessed to study myocardial regeneration will be addressed. Full article
(This article belongs to the Special Issue Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration)
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