Here we map cardiac remodeling in chronic kidney disease in two mouse models using snRNA-seq. We demonstrate the complex multicellular mechanisms drive cardiac hypertrophy, cardiac fibrosis and myoardial capillarly alterations in chronic kidney disease and that proinflammatory processes, TNFa and JAK-STAT signaling as well as uremic toxins are involved.

Here we discover a population of profibrotic Spp1+ macrophages and demonstrate that the chemokine CXCL4 drives their polarization from monocytes. In vitro and in vivo studies show that loss of Cxcl4 abrogates profibrotic Spp1 macrophage differentiation and ameliorates fibrosis after both heart and kidney injury. Moreover, we find that platelets, the most abundant source of CXCL4 in vivo, drive profibrotic Spp1 macrophage differentiation.

In this work we demonstrate that CD24+ cells are the cellular origin of tubuloids. We developed a novel lentiviral mutliplex CRISPR approach to edit the PKD1 or PKD2 gene for disase modeling of ADPKD. Gene edited tubuloids show cyst formation and various similarties to the human disease. Single nuclear RNA-seq of human healthy and ADPKD tissue and gene-edited versus control tubuloids shows a overlapping upregulation of reported ADPKD disease driving genes. Importantly, we demonstrate a response of cysts in gene-edited tubuloids to tolvaptan while cysts of gene edited iPSC do not respond.

Spatial multi-omic map of human myocardial infarction. In this study we have utilized snRNA-seq, snATAC-seq and spatial transcriptomics to map human myocardial infarction at unprecedented resolution.

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids. In this study we have demonstrated that COVID19 is associated with kidney fibrosis in patients. Furthermore, we could demonstrate that SARS-CoV2 infects kidney cells such as proximal tubule epithelium and podocytes. Infection of iPSC derived kidney organoids with SARS-CoV2 caused injury and fibrosis in a TGFb dependent manor. Importantly, we could also show that inhibition of the SARS-CoV2 protease with a novel compound developed by the COVID Moonshot Consortium can prevent iPSC derived kidneys from infection.

Mapping the cardiac vascular niche in heart failure. Using combined genetic fate tracing with confocal imaging and single-cell RNA sequencing of this niche in homeostasis and during heart failure, we unravel cell type specific transcriptomic changes in fibroblast, endothelial, pericyte and vascular smooth muscle cell subtypes.

In this study we have provided a single cell map of human kidneys in homeostasis and chronic kidney disease with the aim to unravel mechanisms that drive kidney fibrosis and functional decline. We could demonstrate that distinct pericyte and fibroblast populations are the major source of scar forming myofibroblasts and dissect their mechanisms of differentiation and cross-talk at high resolution. As a proof of concept that single cell RNA-sequencing can be utilized for target discovery we could demonstrate that Nkd2 is a novel promising therapeutic target in renal fibrosis.

We propose scOpen, a computational method for quantifying the open chromatin status of regulatory regions from single cell ATAC-seq (scATAC-seq) experiments. scOpen is based on positive-unlabelled learning of matrices and estimates the probability that a region is open at a given cell by mitigating the sparsity of scATAC-seq matrices. We demonstrate that scOpen improves all down-stream analysis steps of scATAC-seq data as clustering, visualisation and chromatin conformation. Moreover, we show the power of scOpen and single cell-based footprinting analysis (scHINT) to dissect regulatory changes in the development of fibrosis in the kidney.

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