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Abstract Human cardiac and other organoids have recently emerged as a groundbreaking tool for advancing our understanding the developmental biology of human organs. A recent paper from Sasha Mendjan’s laboratory published in the journal Cell on December 7, 2023, reported the generation of multi-chamber cardioids from human pluripotent stem cells, a transformative technology in the field of cardiology. In this short highlight paper, we summarize their findings. Their cardioids remarkably recapitulate the complexity of the human embryonic heart, including tissue architecture, cellular diversity, and functionality providing an excellent in vitro model for investigation of human heart development, disease modeling, precision medicine, and regenerative medicine. Thus, generating cardioids is an important step forward for understanding human heart development and developing potential therapies for heart diseases.

Abstract Whole-body regeneration is a multifaceted process that reinstates a body to its initial three-dimension size and structure after resection injury. It is well-known that signaling waves such as calcium and extracellular signal-related kinase (ERK) signaling waves can efficiently transmit information between tissues or cells. However, the mechanisms responsible for coordinating wound responses over long distances are largely unexplored. A recent study has reported that the propagation of ERK signaling waves via longitudinal body-wall muscles play an essential role in wound response and whole-body regeneration in planarians, underscoring the significance of feedback interactions between spatially distinct tissues during whole-body regeneration over long distances. These findings not only address the central questions of regenerative biology but also have potential implications for regenerative medicine.

Abstract Ischemia–reperfusion injury occurs after reperfusion treatment for patients suffering myocardial infarction, however the underlying mechanisms are incompletely understood and effective pharmacological interventions are limited. Here, we report the identification and characterization of the FDA-approved drug disulfiram (DSF) as a cardioprotective compound. By applying high-throughput chemical screening, we found that DSF decreased H2O2-induced cardiomyocyte death by inhibiting Gasdermin D, but not ALDH1, in cardiomyocytes. Oral gavage of DSF decreased myocardial infarct size and improved heart function after myocardial ischemia–reperfusion injury in rats. Therefore, this work reveals DSF as a potential therapeutic compound for the treatment of ischemic heart disease.

Abstract Myocardial Brg1 is essential for heart regeneration in zebrafish, but it remains unknown whether and how endothelial Brg1 plays a role in heart regeneration. Here, we found that both brg1 mRNA and protein were induced in cardiac endothelial cells after ventricular resection and endothelium-specific overexpression of dominant-negative Xenopus Brg1 (dn-xbrg1) inhibited myocardial proliferation and heart regeneration and increased cardiac fibrosis. RNA-seq and ChIP-seq analysis revealed that endothelium-specific overexpression of dn-xbrg1 changed the levels of H3K4me3 modifications in the promoter regions of the zebrafish genome and induced abnormal activation of Notch family genes upon injury. Mechanistically, Brg1 interacted with lysine demethylase 7aa (Kdm7aa) to fine-tune the level of H3K4me3 within the promoter regions of Notch family genes and thus regulated notch gene transcription. Together, this work demonstrates that the Brg1-Kdm7aa-Notch axis in cardiac endothelial cells, including the endocardium, regulates myocardial proliferation and regeneration via modulating the H3K4me3 of the notch promoters in zebrafish.

Dusp6, an ERK specific phosphatase, was identified as a regenerative repressor during zebrafish heart regeneration. Here, the authors show that Dusp6 deficiency improves post infarctional cardiac repair by predominantly attenuating neutrophil-mediated myocardial damage in mammalian hearts.

Abstract Rheumatoid arthritis (RA) is chronic systemic disease that can cause joint damage, disability and destructive polyarthritis. Current diagnosis of RA is based on a combination of clinical and laboratory features. However, RA diagnosis can be difficult at its disease onset on account of overlapping symptoms with other arthritis, so early recognition and diagnosis of RA permit the better management of patients. In order to improve the medical diagnosis of RA and evaluate the effects of different clinical features on RA diagnosis, we applied an artificial neural network (ANN) as the training algorithm, and used fivefold cross-validation to evaluate its performance. From each sample, we obtained data on 6 features: age, sex, rheumatoid factor, anti-citrullinated peptide antibody (CCP), 14-3-3η, and anti-carbamylated protein (CarP) antibodies. After training, this ANN model assigned each sample a probability for being either an RA patient or a non-RA patient. On the validation dataset, the F1 for all samples by this ANN model was 0.916, which was higher than the 0.906 we previously reported using an optimal threshold algorithm. Therefore, this ANN algorithm not only improved the accuracy of RA diagnosis, but also revealed that anti-CCP had the greatest effect while age and anti-CarP had a weaker on RA diagnosis.

Summary: Discovery of small molecules promoting cardiomyocyte proliferation is important for heart regeneration and related heart disease. Here, we describe a protocol to isolate neonatal rat and mouse cardiomyocytes, infect cardiomyocytes with Tnnt2-mAG-hGeminin (1/110) or Tnnt2-Cre adenovirus, and identify small molecules that promote cardiomyocyte proliferation by high-content microscopy. This protocol can be modified to investigate other pro-proliferation factors in cardiomyocytes and other cell types.For complete details on the use and execution of this protocol, please refer to Du et al. (2022).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Organ regeneration is an important, fascinating, and old topic while much remains unknown in spite of extensive investigations for decades. From March 25th to 27th, 2021, the Third Chinese Symposium on Organ Regeneration took place in the beautiful ocean city of Zhoushan, Zhejiang, China. This biennial conference attracted ~ 300 academic attendees: students, postdoctoral fellows, and principal investigators, in addition to few industrial investigators. The mixed live and virtual talks covered the broad field of organ regeneration from different animal organisms to human organoids, and concluded with some impressive advances on inflammatory signaling, regenerative signaling mechanisms, new technologies, and applications for organ regeneration.

Cardiac looping and trabeculation are key processes during cardiac chamber maturation. However, the underlying mechanisms remain incompletely understood. Here, we report the isolation, cloning and characterization of the proprotein convertase furina from the cardiovascular mutant loft in zebrafish. loft is an ethylnitrosoureainduced mutant and has evident defects in the cardiac outflow tract, heart looping and trabeculation, the craniofacial region and pharyngeal arch arteries. Positional cloning revealed that furina mRNA was barely detectable in loft mutants, and loft failed to complement the TALEN-induced furina mutant pku338, confirming that furina is responsible for the loft mutant phenotypes. Mechanistic studies demonstrated that Notch reporter Tg(tp1:mCherry) signals were largely eliminated in mutant hearts, and overexpression of the Notch intracellular domain partially rescued the mutant phenotypes, probably due to the lack of Furina-mediated cleavage processing of Notch1b proteins, the only Notch receptor expressed in the heart. Together, our data suggest a potential post-translational modification of Notch1b proteins via the proprotein convertase Furina in the heart, and unveil the function of the Furina-Notch1b axis in cardiac looping and trabeculation in zebrafish, and possibly in other organisms. [ABSTRACT FROM AUTHOR]