Cardiomyocyte heterogeneity during zebrafish development and regeneration

Tsedeke, Ayele Taddese; Allanki, Srinivas; Gentile, Alessandra; Jiménez-Amilburu, Vanesa; Rasouli, S. Javad; Guenther, Stefan; Lai, Shih-Lei; Stainier, Didier Y.R.; Marín-Juez, Rubén

doi:10.1016/j.ydbio.2021.03.014

Cited by 12 publications

(13 citation statements)

References 63 publications

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“…This adaptive process is based on the suppression of adult and reactivation of foetal gene profile as a result of cardiac disease promoting the reversion of the contractile machinery to a more compliant foetal one ( van der Pol et al, 2020 ). As reported in literature TNNC2, TPM1 and MYL2 are markers expressed at early developmental stages during cardiogenesis ( Sheikh et al, 2015 ; England et al, 2017 ; Tsedeke et al, 2021 ). Furthermore, Cetinkaya et al states that the ACTN1 expression in adult myocytes implies the activation of fetal pathways in patients affected by dilated cardiomyopathy ( Cetinkaya et al, 2020 ).…”

Section: Discussionsupporting

confidence: 53%

Long-term culture of patient-derived cardiac organoids recapitulated Duchenne muscular dystrophy cardiomyopathy and disease progression

Marini

Marino

Aliberti

et al. 2022

Front. Cell Dev. Biol.

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Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disease which to date is incurable. The major cause of death is dilated cardiomyopathy however, its pathogenesis is unclear as existing cellular and animal models do not fully recapitulate the human disease phenotypes. In this study, we generated cardiac organoids from patient-derived induced pluripotent stem cells (DMD-COs) and isogenic-corrected controls (DMD-Iso-COs) and studied if DMD-related cardiomyopathy and disease progression occur in the organoids upon long-term culture (up to 93 days). Histological analysis showed that DMD-COs lack initial proliferative capacity, displayed a progressive loss of sarcoglycan localization and high stress in endoplasmic reticulum. Additionally, cardiomyocyte deterioration, fibrosis and aberrant adipogenesis were observed in DMD-COs over time. RNA sequencing analysis confirmed a distinct transcriptomic profile in DMD-COs which was associated with functional enrichment in hypertrophy/dilated cardiomyopathy, arrhythmia, adipogenesis and fibrosis pathways. Moreover, five miRNAs were identified to be crucial in this dysregulated gene network. In conclusion, we generated patient-derived cardiac organoid model that displayed DMD-related cardiomyopathy and disease progression phenotypes in long-term culture. We envision the feasibility to develop a more complex, realistic and reliable in vitro 3D human cardiac-mimics to study DMD-related cardiomyopathies.

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Section: Discussionsupporting

confidence: 53%

Long-term culture of patient-derived cardiac organoids recapitulated Duchenne muscular dystrophy cardiomyopathy and disease progression

Marini

Marino

Aliberti

et al. 2022

Front. Cell Dev. Biol.

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“…Notably, the immense datasets generated via single-cell and single-nucleus genomic analyses can require a prohibitively large amount of computer memory, so a number of recent studies ( Wang and Gu, 2018 ; Eraslan et al, 2019 ; Tran et al, 2021 ) have reduced the dimensionality of the input data before the autoencoding procedure is initiated. However, the transcriptional heterogeneity of cardiac cells is exceptionally high ( Nahrendorf and Swirski, 2013 ; Vidal et al, 2019 ; Tsedeke et al, 2021 ) and likely to be exacerbated by the physiological changes that occur in response to AR surgery and MI induction. Thus, since any attempt to reduce the dimensionality of the input data before autoencoding could mask this complexity, the input layer used for the studies reported here included the complete list of 14,753 genes (i.e., 14,753 dimensions) with at least 1,000 UMIs in our dataset.…”

Section: Methodsmentioning

confidence: 99%

Cardiomyocyte Cell-Cycle Regulation in Neonatal Large Mammals: Single Nucleus RNA-Sequencing Data Analysis via an Artificial-Intelligence–Based Pipeline

Nguyen

Wei²,

Nakada³

et al. 2022

Front. Bioeng. Biotechnol.

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Adult mammalian cardiomyocytes have very limited capacity to proliferate and repair the myocardial infarction. However, when apical resection (AR) was performed in pig hearts on postnatal day (P) 1 (ARP1) and acute myocardial infarction (MI) was induced on P28 (MIP28), the animals recovered with no evidence of myocardial scarring or decline in contractile performance. Furthermore, the repair process appeared to be driven by cardiomyocyte proliferation, but the regulatory molecules that govern the ARP1-induced enhancement of myocardial recovery remain unclear. Single-nucleus RNA sequencing (snRNA-seq) data collected from fetal pig hearts and the hearts of pigs that underwent ARP1, MIP28, both ARP1 and MI, or neither myocardial injury were evaluated via autoencoder, cluster analysis, sparse learning, and semisupervised learning. Ten clusters of cardiomyocytes (CM1–CM10) were identified across all experimental groups and time points. CM1 was only observed in ARP1 hearts on P28 and was enriched for the expression of T-box transcription factors 5 and 20 (TBX5 and TBX20, respectively), Erb-B2 receptor tyrosine kinase 4 (ERBB4), and G Protein-Coupled Receptor Kinase 5 (GRK5), as well as genes associated with the proliferation and growth of cardiac muscle. CM1 cardiomyocytes also highly expressed genes for glycolysis while lowly expressed genes for adrenergic signaling, which suggested that CM1 were immature cardiomyocytes. Thus, we have identified a cluster of cardiomyocytes, CM1, in neonatal pig hearts that appeared to be generated in response to AR injury on P1 and may have been primed for activation of CM cell-cycle activation and proliferation by the upregulation of TBX5, TBX20, ERBB4, and GRK5.

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“…11 In addition, we observed a decrease in the expression levels of cxcr4a and apln (Figure S1F), two genes that have been shown to regulate coronary regeneration in zebrafish. 12 During cardiac regeneration, cardiomyocytes dedifferentiate and proliferate to replenish the injured tissue, [36][37][38][39] and this process is regulated in part by cECs. 11,12 Hence, we reasoned that altering revascularization by blocking Vegfc signaling could lead to defects in cardiomyocyte regeneration.…”

Section: Vegfc Signaling Promotes Cec Proliferation After Cardiac Cry...mentioning

confidence: 99%

A Vegfc-Emilin2a-Cxcl8a Signaling Axis Required for Zebrafish Cardiac Regeneration

El-Sammak

Yang

Guenther

et al. 2022

Circulation Research

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Background: Ischemic heart disease following the obstruction of coronary vessels leads to the death of cardiac tissue and the formation of a fibrotic scar. In contrast to adult mammals, zebrafish can regenerate their heart after injury, enabling the study of the underlying mechanisms. One of the earliest responses following cardiac injury in adult zebrafish is coronary revascularization. Defects in this process lead to impaired cardiomyocyte repopulation and scarring. Hence, identifying and investigating factors that promote coronary revascularization holds great therapeutic potential. Methods: We used whole mount imaging, immunohistochemistry and histology to assess various aspects of zebrafish cardiac regeneration. Deep transcriptomic analysis allowed us to identify targets and potential effectors of Vegfc (vascular endothelial growth factor C) signaling. We used newly generated loss- and gain-of-function genetic tools to investigate the role of Emilin2a and Cxcl8a-Cxcr1 signaling in cardiac regeneration. Results: We first show that regenerating coronary endothelial cells upregulate vegfc upon cardiac injury in adult zebrafish and that Vegfc signaling is required for their proliferation during regeneration. Notably, blocking Vegfc signaling also significantly reduces cardiomyocyte dedifferentiation and proliferation. Using transcriptomic analyses, we identified emilin2a as an effector of Vegfc signaling and found that manipulation of emilin2a expression can modulate coronary revascularization as well as cardiomyocyte proliferation. Mechanistically, Emilin2a induces the expression of the chemokine gene cxcl8a in epicardium-derived cells, while cxcr1 , the Cxcl8a receptor gene, is expressed in coronary endothelial cells. We further show that Cxcl8a-Cxcr1 signaling is also required for coronary endothelial cell proliferation during cardiac regeneration. Conclusions: These data show that after cardiac injury, coronary endothelial cells upregulate vegfc to promote coronary network reestablishment and cardiac regeneration. Mechanistically, Vegfc signaling upregulates epicardial emilin2a and cxcl8a expression to promote cardiac regeneration. These studies aid in understanding the mechanisms underlying coronary revascularization in zebrafish, with potential therapeutic implications to enhance revascularization and regeneration in injured human hearts.

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Cardiomyocyte heterogeneity during zebrafish development and regeneration

Cited by 12 publications

References 63 publications

Long-term culture of patient-derived cardiac organoids recapitulated Duchenne muscular dystrophy cardiomyopathy and disease progression

Long-term culture of patient-derived cardiac organoids recapitulated Duchenne muscular dystrophy cardiomyopathy and disease progression

Cardiomyocyte Cell-Cycle Regulation in Neonatal Large Mammals: Single Nucleus RNA-Sequencing Data Analysis via an Artificial-Intelligence–Based Pipeline

A Vegfc-Emilin2a-Cxcl8a Signaling Axis Required for Zebrafish Cardiac Regeneration

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