Highlights d Chamber-like cardioids form a cavity and recapitulate heart lineage architecture d Cardioid self-organization and lineage identity is instructed by signaling d WNT-BMP signaling directs cavity formation via HAND1 d Cryoinjury initiates an in vivo-like fibronectin and collagen accumulation

SUMMARYOrganoids that self-organize into tissue-like structures have transformed our ability to model human development and disease. To date, all major organs can be mimicked using self-organizing organoids with the notable exception of the human heart. Here, we established self-organizing cardioids from human pluripotent stem cells that intrinsically specify, pattern and morph into chamber-like structures containing a cavity. Cardioid complexity can be controlled by signaling that instructs the separation of cardiomyocyte and endothelial layers, and by directing epicardial spreading, inward migration and differentiation. We find that cavity morphogenesis is governed by a mesodermal WNT-BMP signaling axis and requires its target HAND1, a transcription factor linked to human heart chamber cavity defects. In parallel, a WNT-VEGF axis coordinates myocardial self-organization with endothelial patterning and specification. Human cardioids represent a powerful platform to mechanistically dissect self-organization and congenital heart defects, serving as a foundation for future translational research.Highlights- Cardioids form cardiac-like chambers with inner endothelial lining and interact with epicardium- Cardioid self-organization and lineage complexity can be controlled by signaling- WNT-BMP signaling directs cavity formation in self-organized cardioids via HAND1- WNT-VEGF coordinate endothelial patterning with myocardial cavity morphogenesis

Signaling networks represent the molecular mechanisms controlling a cell's response to various internal or external stimuli. Most currently available signaling databases contain only a part of the complex network of intertwining pathways, leaving out key interactions or processes. Hence, we have developed SignaLink3 (http://signalink.org/), a value-added knowledge-base that provides manually curated data on signaling pathways and integrated data from several types of databases (interaction, regulation, localisation, disease, etc.) for humans, and three major animal model organisms. SignaLink3 contains over 400 000 newly added human protein-protein interactions resulting in a total of 700 000 interactions for Homo sapiens, making it one of the largest integrated signaling network resources. Next to H. sapiens, SignaLink3 is the only current signaling network resource to provide regulatory information for the model species Caenorhabditis elegans and Danio rerio, and the largest resource for Drosophila melanogaster. Compared to previous versions, we have integrated gene expression data as well as subcellular localization of the interactors, therefore uniquely allowing tissue-, or compartment-specific pathway interaction analysis to create more accurate models. Data is freely available for download in widely used formats, including CSV, PSI-MI TAB or SQL.

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The regeneration of paired appendages in certain fish and amphibian lineages is a well established and extensively studied regenerative phenomenon. The teleost fin is comprised of a proximal endoskeletal part (considered homologous to the Tetrapod limb) and a distal exoskeletal one, and these two parts form their bony elements through different ossification processes. In the past decade, a significant body of literature has been generated about the biology of exoskeletal regeneration in zebrafish. However, it is still not clear if this knowledge can be applied to the regeneration of endoskeletal parts. To address this question, we decided to compare endo- and exoskeletal regenerative capacity in zebrafish (Danio rerio) and mudskippers (Periophthalmus barbarous). In contrast to the reduced endoskeleton of zebrafish, Periophthalmus has well developed pectoral fins with a large and easily accessible endoskeleton. We performed exo- and endoskeletal amputations in both species and followed the regenerative processes. Unlike the almost flawless exoskeletal regeneration observed in zebrafish, regeneration following endoskeletal amputation is often impaired in this species. This difference is even more pronounced in Periophthalmus where we could observe no regeneration in endoskeletal structures. Therefore, regeneration is regulated differentially in the exo- and endoskeleton of teleost species.

Understanding living systems requires an in depth knowledge of the signaling networks that drive cellular homeostasis, regulate intercellular communication and contribute to cell fates during development. Several resources exist to provide high-throughput datasets or manually curated interaction information from human or invertebrate model organisms. We previously developed SignaLink, a uniformly curated, multi-layered signaling resource containing information for human and for the model organisms nematode Caenorhabditis elegans and fruit fly Drosophila melanogaster. Until now, the use of the SignaLink database for zebrafish pathway analysis was limited. To overcome this limitation we created SignaFish (http://signafish.org), a fish-specific signaling resource, built using the concept of SignaLink. SignaFish contains more than 200 curation based signaling interactions, 132 further interactions listed in other resources, and it also lists potential miRNA based regulatory connections for 7 major signaling pathways. From the SignaFish website, users can reach other web resources, such as ZFIN. SignaFish provides signaling or signaling-related interactions that can be examined for each gene, or downloaded for each signaling pathway. We believe that the SignaFish resource will serve as a novel navigating point for experimental design and evaluation for the zebrafish community and for researchers focusing on non-model fish species, such as cyclids.