Special Issue "Model Systems for Heart Regeneration"

A special issue of Journal of Cardiovascular Development and Disease (ISSN 2308-3425). This special issue belongs to the section "Cardiac Development and Regeneration".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 13342

Special Issue Editors

Dr. Ravi Karra
E-Mail Website
Guest Editor
Division of Cardiology, Department of Medicine, Duke University Medical Center, Box 102152, Durham, NC 27710, USA
Interests: heart regeneration; ventricular recovery; heart failure; biomarkers; myovascular interactions
Prof. Dr. Richard T. Lee
E-Mail Website
Guest Editor
1. Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, USA
2. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115, USA
Interests: cardiac regeneration; diabetes; aging; metabolism; stem cell biology

Special Issue Information

Dear Colleagues,

Innate heart regeneration is a carefully orchestrated process that requires multiple cell types to enable cardiomyocyte proliferation after injury. Prior work indicates that a heart regeneration program is conserved from zebrafish to mammals. However, while this program is active in neonatal mammals, adult mammals lack the capacity for meaningful heart regeneration. A better understanding of the signals that enable and repress heart regeneration is fundamental to realize therapeutic heart regeneration.

This Special Issue of JCDD focused on “Model Systems for Heart Regeneration” provides a critical appraisal of pre-clinical platforms for studying innate cardiac regenerative programs. We hope to capture state-of-the-art techniques for studying regeneration, including tools for tracing cell fates, deconvolving growth niches, and identifying new molecular regulators of heart regeneration. We are seeking novel discussions of regenerative models, including but not limited to zebrafish, salamanders, mice, pigs, and humans.

Dr. Ravi Karra
Prof. Dr. Richard T. Lee
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. Journal of Cardiovascular Development and Disease 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 2000 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

  • heart regeneration 
  • zebrafish
  • neonatal mouse 
  • large mammal
  • cardioid
  • cardiomyocyte proliferation

Published Papers (6 papers)

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Research

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Article
Inhibition of the NOTCH1 Pathway in the Stressed Heart Limits Fibrosis and Promotes Recruitment of Non-Myocyte Cells into the Cardiomyocyte Fate
J. Cardiovasc. Dev. Dis. 2022, 9(4), 111; https://doi.org/10.3390/jcdd9040111 - 07 Apr 2022
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Abstract
Cardiac pathologies lead to an acute or gradual loss of cardiomyocytes. Because of the limited regenerative capacity of the mammalian heart, cardiomyocytes are only replaced by fibrotic tissue. Excessive fibrosis contributes to the deterioration of cardiac function and the transition to heart failure, [...] Read more.
Cardiac pathologies lead to an acute or gradual loss of cardiomyocytes. Because of the limited regenerative capacity of the mammalian heart, cardiomyocytes are only replaced by fibrotic tissue. Excessive fibrosis contributes to the deterioration of cardiac function and the transition to heart failure, which is the leading cause of morbidity and mortality worldwide. Currently, no treatments can promote replenishment of the injured heart with newly formed cardiomyocytes. In this context, regenerative strategies explore the possibility to promote recovery through induction of cardiomyocyte production from pre-existing cardiomyocytes. On the other hand, cardiac non-myocyte cells can be directly reprogrammed into induced cardiac precursor cells and cardiomyocytes, suggesting that these cells could be exploited to produce cardiomyocytes in vivo. Here, we provide evidence that the sequential activation and inhibition of the NOTCH1 signaling pathway in the stressed heart decreases fibrosis and improves cardiac function in the stressed heart. This is accompanied by the emergence of new cardiomyocytes from non-myocyte origin. Overall, our data show how a developmental pathway such as the NOTCH pathway can be manipulated to provide therapeutic benefit in the damaged heart. Full article
(This article belongs to the Special Issue Model Systems for Heart Regeneration)
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Article
Characterizing Neonatal Heart Maturation, Regeneration, and Scar Resolution Using Spatial Transcriptomics
J. Cardiovasc. Dev. Dis. 2022, 9(1), 1; https://doi.org/10.3390/jcdd9010001 - 21 Dec 2021
Cited by 6 | Viewed by 3570
Abstract
The neonatal mammalian heart exhibits a remarkable regenerative potential, which includes fibrotic scar resolution and the generation of new cardiomyocytes. To investigate the mechanisms facilitating heart repair after apical resection in neonatal mice, we conducted bulk and spatial transcriptomic analyses at regenerative and [...] Read more.
The neonatal mammalian heart exhibits a remarkable regenerative potential, which includes fibrotic scar resolution and the generation of new cardiomyocytes. To investigate the mechanisms facilitating heart repair after apical resection in neonatal mice, we conducted bulk and spatial transcriptomic analyses at regenerative and non-regenerative timepoints. Importantly, spatial transcriptomics provided near single-cell resolution, revealing distinct domains of atrial and ventricular myocardium that exhibit dynamic phenotypic alterations during postnatal heart maturation. Spatial transcriptomics also defined the cardiac scar, which transitions from a proliferative to secretory phenotype as the heart loses regenerative potential. The resolving scar is characterized by spatially and temporally restricted programs of inflammation, epicardium expansion and extracellular matrix production, metabolic reprogramming, lipogenic scar extrusion, and cardiomyocyte restoration. Finally, this study revealed the emergence of a regenerative border zone defined by immature cardiomyocyte markers and the robust expression of Sprr1a. Taken together, our study defines the spatially and temporally restricted gene programs that underlie neonatal heart regeneration and provides insight into cardio-restorative mechanisms supporting scar resolution. Full article
(This article belongs to the Special Issue Model Systems for Heart Regeneration)
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Review

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Review
Clonal Tracing of Heart Regeneration
J. Cardiovasc. Dev. Dis. 2022, 9(5), 141; https://doi.org/10.3390/jcdd9050141 - 01 May 2022
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Abstract
Cardiomyocytes in the adult mammalian heart have a low turnover during homeostasis. After myocardial injury, there is irreversible loss of cardiomyocytes, which results in subsequent scar formation and cardiac remodeling. In order to better understand and characterize the proliferative capacity of cardiomyocytes, in [...] Read more.
Cardiomyocytes in the adult mammalian heart have a low turnover during homeostasis. After myocardial injury, there is irreversible loss of cardiomyocytes, which results in subsequent scar formation and cardiac remodeling. In order to better understand and characterize the proliferative capacity of cardiomyocytes, in vivo methods have been developed to track their fate during normal development and after injury. Lineage tracing models are of particular interest due to their ability to record cell proliferation events over a long period of time, either during development or in response to a pathological event. This paper reviews two well-studied lineage-tracing, transgenic mouse models—mosaic analysis with double markers and rainbow reporter system. Full article
(This article belongs to the Special Issue Model Systems for Heart Regeneration)
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Review
Porcine Models of Heart Regeneration
J. Cardiovasc. Dev. Dis. 2022, 9(4), 93; https://doi.org/10.3390/jcdd9040093 - 23 Mar 2022
Viewed by 1850
Abstract
Swine are popular large mammals for cardiac preclinical testing due to their similarities with humans in terms of organ size and physiology. Recent studies indicate an early neonatal regenerative capacity for swine hearts similar to small mammal laboratory models such as rodents, inspiring [...] Read more.
Swine are popular large mammals for cardiac preclinical testing due to their similarities with humans in terms of organ size and physiology. Recent studies indicate an early neonatal regenerative capacity for swine hearts similar to small mammal laboratory models such as rodents, inspiring exciting possibilities for studying cardiac regeneration with the goal of improved clinical translation to humans. However, while swine hearts are anatomically similar to humans, fundamental differences exist in growth mechanisms, nucleation, and the maturation of pig cardiomyocytes, which could present difficulties for the translation of preclinical findings in swine to human therapeutics. In this review, we discuss the maturational dynamics of pig cardiomyocytes and their capacity for proliferative cardiac regeneration during early neonatal development to provide a perspective on swine as a preclinical model for developing cardiac gene- and cell-based regenerative therapeutics. Full article
(This article belongs to the Special Issue Model Systems for Heart Regeneration)
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Review
In Vivo Methods to Monitor Cardiomyocyte Proliferation
J. Cardiovasc. Dev. Dis. 2022, 9(3), 73; https://doi.org/10.3390/jcdd9030073 - 03 Mar 2022
Cited by 1 | Viewed by 1766
Abstract
Adult mammalian cardiomyocytes demonstrate scarce cycling and even lower proliferation rates in response to injury. Signals that enhance cardiomyocyte proliferation after injury will be groundbreaking, address unmet clinical needs, and represent new strategies to treat cardiovascular diseases. In vivo methods to monitor cardiomyocyte [...] Read more.
Adult mammalian cardiomyocytes demonstrate scarce cycling and even lower proliferation rates in response to injury. Signals that enhance cardiomyocyte proliferation after injury will be groundbreaking, address unmet clinical needs, and represent new strategies to treat cardiovascular diseases. In vivo methods to monitor cardiomyocyte proliferation are critical to addressing this challenge. Fortunately, advances in transgenic approaches provide sophisticated techniques to quantify cardiomyocyte cycling and proliferation. Full article
(This article belongs to the Special Issue Model Systems for Heart Regeneration)
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Review
Leukocyte-Mediated Cardiac Repair after Myocardial Infarction in Non-Regenerative vs. Regenerative Systems
J. Cardiovasc. Dev. Dis. 2022, 9(2), 63; https://doi.org/10.3390/jcdd9020063 - 21 Feb 2022
Cited by 2 | Viewed by 2238
Abstract
Innate and adaptive leukocytes rapidly mobilize to ischemic tissues after myocardial infarction in response to damage signals released from necrotic cells. Leukocytes play important roles in cardiac repair and regeneration such as inflammation initiation and resolution; the removal of dead cells and debris; [...] Read more.
Innate and adaptive leukocytes rapidly mobilize to ischemic tissues after myocardial infarction in response to damage signals released from necrotic cells. Leukocytes play important roles in cardiac repair and regeneration such as inflammation initiation and resolution; the removal of dead cells and debris; the deposition of the extracellular matrix and granulation tissue; supporting angiogenesis and cardiomyocyte proliferation; and fibrotic scar generation and resolution. By organizing and comparing the present knowledge of leukocyte recruitment and function after cardiac injury in non-regenerative to regenerative systems, we propose that the leukocyte response to cardiac injury differs in non-regenerative adult mammals such as humans and mice in comparison to cardiac regenerative models such as neonatal mice and adult zebrafish. Specifically, extensive neutrophil, macrophage, and T-cell persistence contributes to a lengthy inflammatory period in non-regenerative systems for adverse cardiac remodeling and heart failure development, whereas their quick removal supports inflammation resolution in regenerative systems for new contractile tissue formation and coronary revascularization. Surprisingly, other leukocytes have not been examined in regenerative model systems. With this review, we aim to encourage the development of improved immune cell markers and tools in cardiac regenerative models for the identification of new immune targets in non-regenerative systems to develop new therapies. Full article
(This article belongs to the Special Issue Model Systems for Heart Regeneration)
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