Kidney fibrosis is the hallmark of chronic kidney disease progression, however, currently no antifibrotic therapies exist. This is largely because the origin, functional heterogeneity and regulation of scar-forming cells during human kidney fibrosis remains poorly understood. Here, using single cell RNA-seq, we profiled the transcriptomes of proximal tubule and non-proximal tubule cells in healthy and fibrotic human kidneys to map the entire human kidney in an unbiased approach. This enabled mapping of all matrix-producing cells at high resolution, revealing distinct subpopulations of pericytes and fibroblasts as the major cellular sources of scar forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single cell RNA-seq and ATAC-seq experiments in mice, and spatial transcriptomics in human kidney fibrosis to functionally interrogate these findings, shedding new light on the origin, heterogeneity and differentiation of human kidney myofibroblasts and their fibroblast and pericyte precursors at unprecedented resolution. Finally, we used this strategy to facilitate target discovery, identifying Nkd2 as a myofibroblast-specific target in human kidney fibrosis.

Myocardial infarction is a leading cause of death worldwide 1 . Although advances have been made in acute treatment, an incomplete understanding of remodelling processes has limited the effectiveness of therapies to reduce late-stage mortality 2 . Here we generate an integrative high-resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium from patients with myocardial infarction and controls. Multi-modal data integration enabled us to evaluate cardiac cell-type compositions at increased resolution, yielding insights into changes of the cardiac transcriptome and epigenome through the identification of distinct tissue structures of injury, repair and remodelling. We identified and validated disease-specific cardiac cell states of major cell types and analysed them in their spatial context, evaluating their dependency on other cell types. Our data elucidate the molecular principles of human myocardial tissue organization, recapitulating a gradual cardiomyocyte and myeloid continuum following ischaemic injury. In sum, our study provides an integrative molecular map of human myocardial infarction, represents an essential reference for the field and paves the way for advanced mechanistic and therapeutic studies of cardiac disease.

Highlights d m 6 A and m 6 Am methylomes of brain tissues are highly specific d m 6 A and m 6 Am are partially correlated with their writers and erasers d SNPs are enriched in m 6 A-containing regions d Species rather than tissue type is the primary determinant of methylome

Human TRAP/Mediator is a key coactivator for many transcription factors that act through direct interactions with distinct subunits, and MED1/TRAP220 is the main subunit target for various nuclear receptors. Remarkably, the current study shows that MED1/TRAP220 only exists in a TRAP/Mediator subpopulation (less then 20% of the total) that is greatly enriched in specific TRAP/Mediator subunits and is tightly associated with a near stoichiometeric level of RNA polymerase II. Importantly, this MED1/TRAP220-containing holoenzyme supports both basal- and activator-dependent transcription in an in vitro system lacking additional RNA polymerase II. Furthermore, chromatin immunoprecipitation experiments demonstrate an activator-selective recruitment of MED1/TRAP220-containing versus MED1/TRAP220-deficient TRAP/Mediator complexes to estrogen receptor (ER) and p53 target genes, respectively. Finally, RNAi studies show that MED1/TRAP220 is required for ER-mediated transcription and estrogen-dependent breast cancer cell growth. These observations have significant implications for our current understanding of the composition, heterogeneity, and functional specificity of TRAP/Mediator complexes.

Boron-containing polymers have many applications resulting from their prominent properties. Organoboron species with reversible B–O bonds have been successfully employed for the fabrication of various self-healing/healable and reprocessable polymers. However, the application of the polymers containing boronic ester or boroxine linkages is limited because of their instability to water. Herein, we report the hydrolytic stability and dynamic covalent chemistry of the nitrogen-coordinating cyclic boronic diester (NCB) linkages, and a new class of vitrimers based on NCB linkages is developed through the chemical reactions of reactive hydrogen with isocyanate. Thermodynamic and kinetic studies demonstrated that NCB linkages exhibit enhanced water and heat resistance, whereas the exchange reactions between NCB linkages can take place upon heating without any catalyst. The model compounds of NCBC-X1 and NCBC-X2 containing a urethane group and urea group, respectively, also showed higher hydrolytic stability compared to that of conventional boronic esters. Polyurethane vitrimers and poly­(urea-urethane) vitrimers based on NCB linkages exhibited excellent solvent resistance and mechanical properties like general thermosets, which can be repaired, reprocessed, and recycled via the transesterification of NCB linkages upon heating. Especially, vitrimers based on NCB linkages presented improved stability to water and heat compared to those through conventional boronic esters because of the existence of N → B internal coordination. We anticipate that this work will provide a new strategy for designing the next generation of sustainable materials.