Spatially Resolved Genome-wide Transcriptional Profiling Identifies BMP Signaling as Essential Regulator of Zebrafish Cardiomyocyte Regeneration

Wu, Chi; Kruse, Fabian; Vasudevarao, Mohankrishna Dalvoy; Junker, Jan Philipp; Zebrowski, David C.; Fischer, Kristin; Noël, Emily S.; Grün, Dominic; Berezikov, Eugène; Engel, Felix B.; Oudenaarden, Alexander van; Weidinger, Gilbert; Bakkers, Jeroen

doi:10.1016/j.devcel.2015.12.010

Cited by 172 publications

(180 citation statements)

References 55 publications

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“…The muscle-wound junction is of particular importance because this area corresponds to the regenerative leading edge [37, 39, 40]. To characterize the distribution of Col XII in relation to dedifferentiated cardiomyocytes, we used an antibody that detects an embryonic isoform of cardiac myosin heavy chain (embCMHC), which is re-expressed along the wound margin [37, 41].…”

Section: Resultsmentioning

confidence: 99%

Collagen XII Contributes to Epicardial and Connective Tissues in the Zebrafish Heart during Ontogenesis and Regeneration

et al. 2016

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Zebrafish heart regeneration depends on cardiac cell proliferation, epicardium activation and transient reparative tissue deposition. The contribution and the regulation of specific collagen types during the regenerative process, however, remain poorly characterized. Here, we identified that the non-fibrillar type XII collagen, which serves as a matrix-bridging component, is expressed in the epicardium of the zebrafish heart, and is boosted after cryoinjury-induced ventricular damage. During heart regeneration, an intense deposition of Collagen XII covers the outer epicardial cap and the interstitial reparative tissue. Analysis of the activated epicardium and fibroblast markers revealed a heterogeneous cellular origin of Collagen XII. Interestingly, this matrix-bridging collagen co-localized with fibrillar type I collagen and several glycoproteins in the post-injury zone, suggesting its role in tissue cohesion. Using SB431542, a selective inhibitor of the TGF-β receptor, we showed that while the inhibitor treatment did not affect the expression of collagen 12 and collagen 1a2 in the epicardium, it completely suppressed the induction of both genes in the fibrotic tissue. This suggests that distinct mechanisms might regulate collagen expression in the outer heart layer and the inner injury zone. On the basis of this study, we postulate that the TGF-β signaling pathway induces and coordinates formation of a transient collagenous network that comprises fibril-forming Collagen I and fiber-associated Collagen XII, both of which contribute to the reparative matrix of the regenerating zebrafish heart.

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Section: Resultsmentioning

confidence: 99%

Collagen XII Contributes to Epicardial and Connective Tissues in the Zebrafish Heart during Ontogenesis and Regeneration

et al. 2016

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“…These dedifferentiated cardiomyocytes re-express embryonic cardiac genes (Zhang et al, 2013; Schindler et al, 2014; Wu et al, 2016), but retain a muscular phenotype, and express myocyte markers, such as nuclear factor Mef2, myosin heavy chain (MHC), and cardiac troponin T (cTnT). Therefore, proliferation of cardiomyocytes in response to injury can be monitored by simultaneous detection of a cardiomyocyte marker and a cell cycle marker, although expression levels of these myocyte markers are reduced.…”

Section: Major Cell Types and Their Contributions To Heart Regenerationmentioning

confidence: 99%

Cell migration during heart regeneration in zebrafish

Tahara

Brush

Kawakami

2016

Developmental Dynamics

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Zebrafish possess the remarkable ability to regenerate injured hearts as adults, which contrasts the very limited ability in mammals. Although very limited, mammalian hearts do in fact have measurable levels of cardiomyocyte regeneration. Therefore, elucidating mechanisms of zebrafish heart regeneration would provide information of naturally occurring regeneration to potentially apply to mammalian studies, in addition to addressing this biologically interesting phenomenon in itself. Studies over the past 13 years have identified processes and mechanisms of heart regeneration in zebrafish. After heart injury, preexisting cardiomyocytes dedifferentiate, enter the cell cycle, and repair the injured myocardium. This process requires interaction with epicardial cells, endocardial cells, and vascular endothelial cells. Epicardial cells envelope the heart, while endocardial cells make up the inner lining of the heart. They provide paracrine signals to cardiomyocytes to regenerate the injured myocardium, which is vascularized during heart regeneration. In addition, accumulating results suggest that local migration of these major cardiac cell types have roles in heart regeneration. In this review, we summarize the characteristics of various heart injury methods used in the research community and regeneration of the major cardiac cell types. Then, we discuss local migration of these cardiac cell types and immune cells during heart regeneration.

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“…Spatially resolved RNA-seq (Tomo-seq) identified the role of BMP signalling in cardiomycote regeneration with coarse 3D mapping of a zebrafish heart, which was limited to large sample to sample collection distances. 130 On the other hand, in situ RNA sequencing approaches yield spatial distributions of molecules within a single cell or across multiple cells. [131][132][133][134] Most in situ RNA detection methods are limited to flat cellular layers; however, signal amplification methods have been developed to screen transcriptional states of cellular types in thick tissue samples.…”

Section: View Article Onlinementioning

confidence: 99%

Cellular identity at the single-cell level

2016

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A single cell creates surprising heterogeneity in a multicellular organism. While every organismal cell shares almost an identical genome, molecular interactions in cells alter the use of DNA sequences to modulate the gene of interest for specialization of cellular functions. Each cell gains a unique identity through molecular coding across the DNA, RNA, and protein conversions. On the other hand, loss of cellular identity leads to critical diseases such as cancer. Most cell identity dissection studies are based on bulk molecular assays that mask differences in individual cells. To probe cell-to-cell variability in a population, we discuss single cell approaches to decode the genetic, epigenetic, transcriptional, and translational mechanisms for cell identity formation. In combination with molecular instructions, the physical principles behind cell identity determination are examined. Deciphering and reprogramming cellular types impact biology and medicine.

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Spatially Resolved Genome-wide Transcriptional Profiling Identifies BMP Signaling as Essential Regulator of Zebrafish Cardiomyocyte Regeneration

Cited by 172 publications

References 55 publications

Collagen XII Contributes to Epicardial and Connective Tissues in the Zebrafish Heart during Ontogenesis and Regeneration

Collagen XII Contributes to Epicardial and Connective Tissues in the Zebrafish Heart during Ontogenesis and Regeneration

Cell migration during heart regeneration in zebrafish

Cellular identity at the single-cell level

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