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The key challenge in the field of molecular and cell-based therapies for heart regeneration is controlled delivery.

An area of injured heart in zebrafish embryos repairs itself using cells from neighbouring areas. The regenerating cells seem to originate from an intermediate progenitor-cell population. See Letter p.497

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

Yao et al. observe and characterize genomic redistribution of the PBAF complexes upon PBRM1 loss, leading to sustained RELA occupancy by SMARCA4, activation of the NF-kB pathway and enhanced kidney tumourigenesis.

The mammalian heart is formed from two distinct groups of mesodermal cells, the first and second heart fields (FHF and SHF). Little is known about the progenitors giving rise to the FHF, but Chien and colleagues have now identified HCN4 (hyperpolarization-activated cyclic nucleotide-gated channel 4) as an FHF marker. They show by lineage tracing that cells expressing HCN4 primarily contribute to cardiomyogenic lineages, and use this marker to isolate FHF progenitors from differentiation cultures of human embryonic stem cells.

Chemically modified mRNA is a new approach for therapeutic protein expression that could be applied to angiogenesis. Here the authors show in a phase 1 clinical trial that a modified mRNA encoding VEGF-A is well tolerated in patients with type 2 diabetes.

Heart failure is a major cause of morbidity and mortality worldwide. Here the authors show that subcutaneous administration of antisense oligonucleotides targeting PLN is an effective strategy in preclinical models of genetic cardiomyopathy and ischemia-driven heart failure.

Studying the mechanisms underlying the diversification of human heart cell lineages has been hampered by the lack of genetic tools to purify early cardiac progenitors and define their developmental potential. By using independent transgenic and gene-targeting approaches in human embryonic stem cell lines, it has now been possible to show that populations of these primordial progenitors are capable of self-renewal and expansion prior to differentiation into the three major cell types in the heart.

Chien et al. reflect on lessons learned following the recent announcement that 31 papers from the Anversa laboratory on cardiac cell therapy are being retracted.

In this paper, a new type of cardiac progenitor, marked by the transcription factor Wt1, is shown to reside in the proepicardium and epicardium. It is shown that during normal heart development, a subset of Wt1⁺ precursors differentiated into fully functional cardiomyocytes, and they arise from Wt1 progenitors that express Nkx2-5 and Isl1, suggesting that they share a developmental origin with multipotent Nkx2 5⁺/Isl1⁺ progenitors.

Mammalian genomes are scattered with repetitive sequences, but their biology remains largely elusive. Here, the authors show that transcription can initiate from short tandem repetitive sequences, and that genetic variants linked to human diseases are preferentially found at repeats with high transcription initiation level.

Immunosuppression has been shown to induce tolerance to transplanted stem cells, but differentiation of these cells may trigger immune rejection later on. Here, Lui et al. show that a short-term immunosuppression regimen confers long-term tolerance to stem cells and their differentiated progeny.

The kinetics of DNA hybridization can be explored by measuring the conductance of a carbon nanotube that has a single strand of DNA covalently attached to a point defect.

Contrary to the view that urbanization is a major driver of the global rise in obesity, the global increase in body-mass index is shown to be mostly due to increases in the body-mass indexes of rural populations.

Cardiomyocytes generated from induced pluripotent cells hold great promise for understanding and treating heart disease. William Pu and his colleagues apply new technologies for studying such cardiomyocytes from patients with Barth syndrome to explore how the mitochondrial defects characteristic of this syndrome lead to heart dysfunction.

Epigenetic barriers need to be surmounted in order to increase the efficiency of cardiac reprogramming. A new study now reports that the histone reader PHF7 enhances cardiac reprogramming via recruiting the chromatin remodelling SWI/SNF complex and key transcription factors to the cardiac super enhancers.

A high-resolution kidney cellular atlas of 51 main cell types, including rare and previously undescribed cell populations, represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations.

Efficient, large-scale genomic analysis is facilitated on the cloud by a computational tool with error-diagnosing and self-healing capabilities.

MicroRNAs are natural, single-stranded, small RNA molecules thought to control gene expression. Four studies indicate that specific microRNA sequences can regulate heart function in development and disease.

Expression of the tumour suppressor PTEN in disseminated primary tumour cells is lost after tumour cells metastasize to the brain, with downregulation instigated by microRNAs from astrocytes, which are transferred from cell to cell by exosomes; these findings reveal the dynamic nature of metastatic cancer cells when adapting to a new tissue environment.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Mutations in the LaminA gene are the second most common inherited cause of Dilated Cardiomyopathy, a major form of heart failure. Here the authors show that disruption of the nuclear protein SUN1 in cardiomyocytes, by AAV mediated transduction of a SUN1 inhibitor, significantly suppress cardiomyopathy progression, providing a potential therapeutic route to treat this disease.

The adult human heart lacks sufficient regenerative capacity to recover after a myocardial infarction. Cell-based therapy has emerged as a potential treatment for the failing heart; however, a key issue for the success of future cell-based therapies is the ability to obtain patient-specific high-quality cardiomyocytes in a fast and efficient manner. Recent progress has been made towards this goal using reprogramming-based approaches.

The potential use of stem cells as agents of repair in human disease makes them the subject of high-profile studies. But we should be wary of prematurely pushing laboratory research into clinical practice.

The development of fully defined culture conditions for human embryonic stem cells (hESCs) should enhance experimental reproducibility, reduce unwanted contaminants and facilitate scale-up production. Rodin et al. show that a substrate made of human recombinant laminin-511 supports long-term culture of hESCs and human induced pluripotent stem cells.

Three new studies examine how a regulator of calcium homeostasis contributes to heart failure in humans and mice.

The spatially and temporally coordinated interaction between migratory cardiac precursors, endothelial cells and myogenic precursors leads to the formation of the highly differentiated cell lineages in the heart. In a new study, conditional mouse mutants are used to show that Nf1 signaling in cardiac endothelium is essential for proper heart formation.

The hyperplasia suppressor gene HSG, previously characterized for its function in mitochondrial fusion, has now been identified as a novel inhibitor of the Ras signalling pathway during smooth muscle cell proliferation. Because of the critical function of this process in atherosclerotic heart disease, these findings may have important clinical implications.

Geng et al. evaluate bone marrow stem cell (BMSC)-based system to deliver modified RNAs of BMP-2 and VEGF to enhance bone regeneration. They test its therapeutic efficacy in vivo on a rat skull defect model by inoculating these BMSCs in a collagen scaffold. This construct synergistically drives osteogenic and angiogenic pathways and can be a new approach for clinical treatment of bone injuries and defects.

mRNA therapeutics face more challenges than mRNA vaccines, but solutions are on the horizon.