Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Adult Cardiac Stem Cells Revisited: Their Potential Is Unfulfilled but Remains

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 18363

Share This Special Issue

Special Issue Editors

Dr. Daniele Torella

E-Mail Website
Guest Editor

Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
Interests: cardiac stem cells

Dr. Bernardo Nadal Ginard

E-Mail Website
Co-Guest Editor

Molecular Cellular Cardiology, Department of Medical, Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy

Special Issue Information

Dear Colleagues,

The demonstration that new cardiomyocytes are produced in the adult mammalian myocardium, albeit in limited amounts, generated a flurry of interest in harnessing this adult neo-cardiomyogensis to foster adult myocardial regeneration and repair in order to ameliorate the devastating impact of myocardial damage and heart failure in an aging human population. This paradigmatic change, together with the identification and characterization of adult cardiac stem cells, gave birth to the bourgeoning field of adult myocardial regeneration. Unfortunately, since its inception, myocardial regeneration in the adult has been hotly debated and controversial. The present crisis started with the publication of research questioning the existence, nature, and role of the adult cardiac stem cells together with a number of papers claiming the replication of adult and terminally differentiated myocytes as the main/sole source of adult neo-cardiomyogenesis. This controversy has been further fostered by a recent scandal followed by retractions of a number of publications by a former leader of the field. Together, these three events have brought the field of adult myocardial regeneration/repair to its current state of disarray. The disappointing situation of a field expected to play an important role in charting the future of cardiovascular biology and medicine is, at least in part, due to the current tendency to “throw away the baby with the bathwater” and to overlook and/or ignore the data accumulated over the past two decades on adult cardiac cell biology and stem/progenitor cells together with an uncritical confidence on inadequately controlled technologies of cell-fate mapping applied to the myocardium.

To address the present situation, this Special Issue aims to review and advance the present state of the field of adult myocardial cell biology, with a particular emphasis on the role of the cardiac stem cells on myocardial cell homeostasis and repair, as well as other sources of cardiomyogenesis. We are welcoming critical and unbiased reviews on the present knowledge of myocardial cell homeostasis and regeneration in the adult, the existence, detection, and quantification of bona fide adult, differentiated cardiomyocyte division, novel experimental model systems to address the main questions in the field, as well as to foster the conversation and knowledge, and methods and technology sharing not only among the contributors but with the scientific audience at large. Furthermore, we also welcome original and methodological/technical contributions addressing the topic detailed above from the biology to the therapeutic perspective.

We expect that this Special Issue will help to move the conversation on myocardial regeneration in the adult to a productive, open-minded and enlightened avenue and away from the controversies which have mired recent years. The following keywords describe only some of the potential topics to be covered in this Special Issue

Dr. Daniele Torella
Dr. Bernardo Nadal Ginard
Guest Editors

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

Cardiovascular diseases
Cardiac regeneration
Cardiac stem cells
Cardiovascular progenitors
Cardiovascular disease
Pluripotent stem cells
ESCs
iPSCs
Adult stem cells
Cell replacement
Direct reprogramming
Tissue engineering
Nanotechnology

Published Papers (5 papers)

Download All Papers

Research

Jump to: Review

19 pages, 5434 KiB

Open AccessArticle

Deciphering the Role of Wnt and Rho Signaling Pathway in iPSC-Derived ARVC Cardiomyocytes by In Silico Mathematical Modeling

by Elvira Immacolata Parrotta, Anna Procopio, Stefania Scalise, Claudia Esposito, Giovanni Nicoletta, Gianluca Santamaria, Maria Teresa De Angelis, Tatjana Dorn, Alessandra Moretti, Karl-Ludwig Laugwitz, Francesco Montefusco, Carlo Cosentino and Giovanni Cuda

Int. J. Mol. Sci. 2021, 22(4), 2004; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042004 - 18 Feb 2021

Cited by 14 | Viewed by 3303

Abstract

Arrhythmogenic Right Ventricular cardiomyopathy (ARVC) is an inherited cardiac muscle disease linked to genetic deficiency in components of the desmosomes. The disease is characterized by progressive fibro-fatty replacement of the right ventricle, which acts as a substrate for arrhythmias and sudden cardiac death. The molecular mechanisms underpinning ARVC are largely unknown. Here we propose a mathematical model for investigating the molecular dynamics underlying heart remodeling and the loss of cardiac myocytes identity during ARVC. Our methodology is based on three computational models: firstly, in the context of the Wnt pathway, we examined two different competition mechanisms between β-catenin and Plakoglobin (PG) and their role in the expression of adipogenic program. Secondly, we investigated the role of RhoA-ROCK pathway in ARVC pathogenesis, and thirdly we analyzed the interplay between Wnt and RhoA-ROCK pathways in the context of the ARVC phenotype. We conclude with the following remark: both Wnt/β-catenin and RhoA-ROCK pathways must be inactive for a significant increase of PPARγ expression, suggesting that a crosstalk mechanism might be responsible for mediating ARVC pathogenesis. Full article

(This article belongs to the Special Issue Adult Cardiac Stem Cells Revisited: Their Potential Is Unfulfilled but Remains)

► Show Figures

Figure 1

21 pages, 5708 KiB

Open AccessArticle

Statins Stimulate New Myocyte Formation After Myocardial Infarction by Activating Growth and Differentiation of the Endogenous Cardiac Stem Cells

by Eleonora Cianflone, Donato Cappetta, Teresa Mancuso, Jolanda Sabatino, Fabiola Marino, Mariangela Scalise, Michele Albanese, Alessandro Salatino, Elvira Immacolata Parrotta, Giovanni Cuda, Antonella De Angelis, Liberato Berrino, Francesco Rossi, Bernardo Nadal-Ginard, Daniele Torella and Konrad Urbanek

Int. J. Mol. Sci. 2020, 21(21), 7927; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217927 - 26 Oct 2020

Cited by 25 | Viewed by 3290

Abstract

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert pleiotropic effects on cardiac cell biology which are not yet fully understood. Here we tested whether statin treatment affects resident endogenous cardiac stem/progenitor cell (CSC) activation in vitro and in vivo after myocardial infarction (MI). Statins (Rosuvastatin, Simvastatin and Pravastatin) significantly increased CSC expansion in vitro as measured by both BrdU incorporation and cell growth curve. Additionally, statins increased CSC clonal expansion and cardiosphere formation. The effects of statins on CSC growth and differentiation depended on Akt phosphorylation. Twenty-eight days after myocardial infarction by permanent coronary ligation in rats, the number of endogenous CSCs in the infarct border zone was significantly increased by Rosuvastatin-treatment as compared to untreated controls. Additionally, commitment of the activated CSCs into the myogenic lineage (c-kit^pos/Gata4^pos CSCs) was increased by Rosuvastatin administration. Accordingly, Rosuvastatin fostered new cardiomyocyte formation after MI. Finally, Rosuvastatin treatment reversed the cardiomyogenic defects of CSCs in c-kit haploinsufficient mice, increasing new cardiomyocyte formation by endogenous CSCs in these mice after myocardial infarction. In summary, statins, by sustaining Akt activation, foster CSC growth and differentiation in vitro and in vivo. The activation and differentiation of the endogenous CSC pool and consequent new myocyte formation by statins improve myocardial remodeling after coronary occlusion in rodents. Similar effects might contribute to the beneficial effects of statins on human cardiovascular diseases. Full article

(This article belongs to the Special Issue Adult Cardiac Stem Cells Revisited: Their Potential Is Unfulfilled but Remains)

► Show Figures

Figure 1

18 pages, 2364 KiB

Open AccessArticle

The Microenvironment of Decellularized Extracellular Matrix from Heart Failure Myocardium Alters the Balance between Angiogenic and Fibrotic Signals from Stromal Primitive Cells

by Immacolata Belviso, Francesco Angelini, Franca Di Meglio, Vittorio Picchio, Anna Maria Sacco, Cristina Nocella, Veronica Romano, Daria Nurzynska, Giacomo Frati, Ciro Maiello, Elisa Messina, Stefania Montagnani, Francesca Pagano, Clotilde Castaldo and Isotta Chimenti

Int. J. Mol. Sci. 2020, 21(21), 7903; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217903 - 24 Oct 2020

Cited by 18 | Viewed by 3016

Abstract

Cardiac adverse remodeling is characterized by biological changes that affect the composition and architecture of the extracellular matrix (ECM). The consequently disrupted signaling can interfere with the balance between cardiogenic and pro-fibrotic phenotype of resident cardiac stromal primitive cells (CPCs). The latter are important players in cardiac homeostasis and can be exploited as therapeutic cells in regenerative medicine. Our aim was to compare the effects of human decellularized native ECM from normal (dECM-NH) or failing hearts (dECM-PH) on human CPCs. CPCs were cultured on dECM sections and characterized for gene expression, immunofluorescence, and paracrine profiles. When cultured on dECM-NH, CPCs significantly upregulated cardiac commitment markers (CX43, NKX2.5), cardioprotective cytokines (bFGF, HGF), and the angiogenesis mediator, NO. When seeded on dECM-PH, instead, CPCs upregulated pro-remodeling cytokines (IGF-2, PDGF-AA, TGF-β) and the oxidative stress molecule H₂O₂. Interestingly, culture on dECM-PH was associated with impaired paracrine support to angiogenesis, and increased expression of the vascular endothelial growth factor (VEGF)-sequestering decoy isoform of the KDR/VEGFR2 receptor. Our results suggest that resident CPCs exposed to the pathological microenvironment of remodeling ECM partially lose their paracrine angiogenic properties and release more pro-fibrotic cytokines. These observations shed novel insights on the crosstalk between ECM and stromal CPCs, suggesting also a cautious use of non-healthy decellularized myocardium for cardiac tissue engineering approaches. Full article

(This article belongs to the Special Issue Adult Cardiac Stem Cells Revisited: Their Potential Is Unfulfilled but Remains)

► Show Figures

Figure 1

15 pages, 2524 KiB

Open AccessArticle

Cardiac Fibroblast-Induced Pluripotent Stem Cell-Derived Exosomes as a Potential Therapeutic Mean for Heart Failure

by Efrat Kurtzwald-Josefson, Naama Zeevi-Levin, Victor Rubchevsky, Neta Bechar Erdman, Orna Schwartz Rohaker, Ortal Nahum, Edith Hochhauser, Ben Ben-Avraham, Joseph Itskovitz-Eldor, Dan Aravot and Yaron D. Barac

Int. J. Mol. Sci. 2020, 21(19), 7215; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197215 - 29 Sep 2020

Cited by 20 | Viewed by 2903

Abstract

The limited regenerative capacity of the injured myocardium leads to remodeling and often heart failure. Novel therapeutic approaches are essential. Induced pluripotent stem cells (iPSC) differentiated into cardiomyocytes are a potential future therapeutics. We hypothesized that organ-specific reprogramed fibroblasts may serve an advantageous source for future cardiomyocytes. Moreover, exosomes secreted from those cells may have a beneficial effect on cardiac differentiation and/or function. We compared RNA from different sources of human iPSC using chip gene expression. Protein expression was evaluated as well as exosome micro-RNA levels and their impact on embryoid bodies (EBs) differentiation. Statistical analysis identified 51 genes that were altered (p ≤ 0.05), and confirmed in the protein level, cardiac fibroblasts-iPSCs (CF-iPSCs) vs. dermal fibroblasts-iPSCs (DF-iPSCs). Several miRs were altered especially miR22, a key regulator of cardiac hypertrophy and remodeling. Lower expression of miR22 in CF-iPSCs vs. DF-iPSCs was observed. EBs treated with these exosomes exhibited more beating EBs p = 0.05. vs. control. We identify CF-iPSC and its exosomes as a potential source for cardiac recovery induction. The decrease in miR22 level points out that our CF-iPSC-exosomes are naïve of congestive heart cell memory, making them a potential biological source for future therapy for the injured heart. Full article

(This article belongs to the Special Issue Adult Cardiac Stem Cells Revisited: Their Potential Is Unfulfilled but Remains)

► Show Figures

Figure 1

Review

Jump to: Research

21 pages, 668 KiB

Open AccessReview

Cardiac Stem Cell-Loaded Delivery Systems: A New Challenge for Myocardial Tissue Regeneration

by Antonia Mancuso, Antonella Barone, Maria Chiara Cristiano, Eleonora Cianflone, Massimo Fresta and Donatella Paolino

Int. J. Mol. Sci. 2020, 21(20), 7701; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207701 - 18 Oct 2020

Cited by 16 | Viewed by 5288

Abstract

Cardiovascular disease (CVD) remains the leading cause of death in Western countries. Post-myocardial infarction heart failure can be considered a degenerative disease where myocyte loss outweighs any regenerative potential. In this scenario, regenerative biology and tissue engineering can provide effective solutions to repair the infarcted failing heart. The main strategies involve the use of stem and progenitor cells to regenerate/repair lost and dysfunctional tissue, administrated as a suspension or encapsulated in specific delivery systems. Several studies demonstrated that effectiveness of direct injection of cardiac stem cells (CSCs) is limited in humans by the hostile cardiac microenvironment and poor cell engraftment; therefore, the use of injectable hydrogel or pre-formed patches have been strongly advocated to obtain a better integration between delivered stem cells and host myocardial tissue. Several approaches were used to refine these types of constructs, trying to obtain an optimized functional scaffold. Despite the promising features of these stem cells’ delivery systems, few have reached the clinical practice. In this review, we summarize the advantages, and the novelty but also the current limitations of engineered patches and injectable hydrogels for tissue regenerative purposes, offering a perspective of how we believe tissue engineering should evolve to obtain the optimal delivery system applicable to the everyday clinical scenario. Full article

(This article belongs to the Special Issue Adult Cardiac Stem Cells Revisited: Their Potential Is Unfulfilled but Remains)

► Show Figures