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

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 21447

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

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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

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Published Papers (5 papers)

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19 pages, 5434 KiB  
Article
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://doi.org/10.3390/ijms22042004 - 18 Feb 2021
Cited by 14 | Viewed by 3856
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. [...] Read more.
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)
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21 pages, 5708 KiB  
Article
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://doi.org/10.3390/ijms21217927 - 26 Oct 2020
Cited by 26 | Viewed by 3856
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 [...] Read more.
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-kitpos/Gata4pos 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)
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18 pages, 2364 KiB  
Article
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://doi.org/10.3390/ijms21217903 - 24 Oct 2020
Cited by 21 | Viewed by 3502
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 [...] Read more.
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)
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15 pages, 2524 KiB  
Article
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://doi.org/10.3390/ijms21197215 - 29 Sep 2020
Cited by 23 | Viewed by 3533
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 [...] Read more.
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)
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Review

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21 pages, 668 KiB  
Review
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://doi.org/10.3390/ijms21207701 - 18 Oct 2020
Cited by 16 | Viewed by 6076
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 [...] Read more.
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)
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