Biology subjects

Wessely, O.

Publications and source records attributed to Wessely, O..

6 recordsLinked to original sources

bioRxiv2026

SPATIALLY PATTERNED PODOCYTE STATE TRANSITIONS COORDINATE AGING OF THE GLOMERULUS

BackgroundWith the US population living longer, the risk, incidence, prevalence and severity for chronic kidney diseases become more abundant. Glomerular diseases are the leading cause for chronic and end-stage kidney disease. Yet, the cellular responses and the underlying mechanisms of progressive glomerular disease, which ultimately leads to glomerulosclerosis and loss of kidney function with advancing age, are poorly understood. MethodsKidneys of young (4 months-old), middle-aged (20 months-old) and aged (24 months-old) mice were separated into outer cortex and juxta-medullary region and processed for single nuclei transcriptomics. Focusing on the aging glomerulus data were analyzed using a state-of-the-art analysis pipeline dissecting out the cellular age- and kidney region-specific responses. ResultsGlobal analysis of the transcriptome reveals regional-specific differences that are detectable across multiple cell types exemplified by the expression of Napsa as a bona-fide juxta-medullary marker. In contrast aging led to rather cell type-specific responses. In the glomerulus, healthy podocytes were characterized by expression of canonical podocyte genes; conversely the senescent, aged podocytes were characterized by the down-regulation of canonical podocyte genes and the emergence of inflammatory and senescent signatures. Interestingly, these senescent podocytes were primarily located in the juxtamedullary region suggesting that juxtamedullary podocytes are more sensitive. Yet, instead of aging being defined by distinct cell states, the profiles, as well as ligand-receptor and pseudotime analyses suggest that podocytes aging is selective and coordinated, not universal degeneration. This was different to the other glomerular cell types, parietal epithelial cells, glomerular endothelial cells and mesangial cells. While they also as existed in different subpopulations, they exhibited little regional-, or age-depended changes. Finally proximal tubular aging manifested itself as discrete cellular states. ConclusionsThe single nuclei transcriptomics of the aging kidney provides a mechanistic explanation for regional susceptibility of nephrons and suggests that the future therapeutic strategies need to consider the cellular and spatial complexity of the glomerulus.

bioinformatics↗

bioRxiv2026

A single cell atlas of mouse podocytes upon injury identifies kidney zone-dependent responses.

There are regional differences in the kidney in focal segmental glomerulosclerosis (FSGS) where podocyte injury is more severe in the juxta-medulla (JM) compared to the outer cortex (OC). Single nuclear RNA-sequencing was performed to determine any regional transcriptomic differences. 1055 differentially expressed genes (DEGs) were identified between healthy OC and JM podocytes. Of 53 podocyte canonical genes, only Magi1 and Mapt, and Npnt were higher in healthy OC and JM podocytes respectively. Hallmark pathway analysis showed that in normal mice, healthy JM podocytes are enriched for oxidative phosphorylation, glycolysis and fatty acid metabolism compared to OC podocytes. At day 7 in an experimental FSGS model induced in mice with a cytopathic anti-podocyte antibody, 226 and 225 DEGs were higher in OC and JM podocytes respectively, and 166 overlapped. Five podocyte subclusters were identified, of which the most severe (subcluster 4) was enriched for a senescence phenotype, including the p53 pathway. Inducing FSGS in mice in which p53 was deleted specifically in podocytes had lower glomerular injury compared to diseased wildtype mice. These results are consistent with differences in podocytes in the OC and JM, which might underlie regional differences in FSGS.

bioinformatics↗

bioRxiv2025

A poly(A) isoform-aware single-cell and spatial atlas defines fibroblast niches in the human bladder

Bladder function relies on coordinated interactions among epithelial, stromal, vascular, and neural compartments, but high-resolution molecular and spatial features remain undefined. We generated a publicly accessible, poly(A) isoform-aware single-nucleus and spatial reference of the adult human bladder spanning four anatomical regions and both sexes. Integrating 74,694 snRNA-seq profiles with 168,476 Xenium-resolved cells, we identified 22 cell types and 23,489 polyadenylation sites, with isoform usage improving stromal resolution beyond gene expression alone. Spatial mapping revealed layered fibroblast niches aligned with epithelial, vascular, and neural structures, supported by Visium data. This multimodal reference links isoform regulation to anatomical context and provides a reusable framework for cell-type annotation, cross-study integration, and analyses of bladder physiology and disease.

molecular biology↗

bioRxiv2025

Alternative polyadenylation regulates human urothelial differentiation

The urothelium is stratified into progenitor basal cells, intermediate cells, and terminally differentiated umbrella cells. Proper renewal of umbrella cells is necessary for maintaining urinary tract barrier integrity. To investigate whether mRNA alternative cleavage and polyadenylation (APA) regulates urothelial differentiation, we developed a single-cell polyadenylation site usage (scPASU) computational pipeline to map cell state-specific polyadenylation sites in single-cell RNA-seq data from 13,544 urothelial cells. Leveraging single-cell spatial imaging, we directly visualized APA events in situ, revealing their spatial specificity within the adult human ureter. APA shaped urothelial differentiation, independent of gene expression changes. Furthermore, key APA-regulated genes shared conserved motifs in their 3 UTRs, often containing Alu elements, suggesting a potential mechanism regulating poly(A) site selection. Our study establishes APA as a driver of urothelial transcriptome diversity.

systems biology↗

bioRxiv2024

BICC1 Interacts with PKD1 and PKD2 to Drive Cystogenesis in ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is primarily of adult-onset and caused by pathogenic variants in PKD1 or PKD2. Yet, disease expression is highly variable and includes very early-onset PKD presentations in utero or infancy. In animal models, the RNA-binding molecule Bicc1 has been shown to play a crucial role in the pathogenesis of PKD. To study the interaction between BICC1, PKD1 and PKD2 we combined biochemical approaches, knockout studies in mice and Xenopus, genetic engineered human kidney cells carrying BICC1 variants as well as genetic association studies in a large ADPKD cohort. We first demonstrated that BICC1 physically binds to the proteins Polycystin-1 and -2 encoded by PKD1 and PKD2 via distinct protein domains. Furthermore, PKD was aggravated in loss-of-function studies in Xenopus and mouse models resulting in more severe disease when Bicc1 was depleted in conjunction with Pkd1 or Pkd2. Finally, in a large human patient cohort, we identified a sibling pair with a homozygous BICC1 variant and patients with very early onset PKD (VEO-PKD) that exhibited compound heterozygosity of BICC1 in conjunction with PKD1 and PKD2 variants. Genome editing demonstrated that these BICC1 variants were hypomorphic in nature and impacted disease-relevant signaling pathways. These findings support the hypothesis that BICC1 cooperates functionally with PKD1 and PKD2, and that BICC1 variants may aggravate PKD severity highlighting RNA metabolism as an important new concept for disease modification in ADPKD.

genetics↗

bioRxiv2021

Upregulated PD-1 Signaling is an Important Antagonist to Glomerular Health in Aged Kidneys

Kidney aging and its contribution to disease and its underlying mechanisms are not well understood. With an aging population, kidney health becomes an important medical and socioeconomic factor. We previously showed that podocytes isolated from aged mice exhibit increased expression of Programed Cell Death Protein 1 (PD-1) surface receptor and its two ligands (PD-L1, PD-L2). PDCD1 transcript increases with age in micro-dissected human glomeruli, which correlates with lower eGFR, and higher segmental glomerulosclerosis and vascular arterial intima to lumen ratio. In vitro studies in podocytes demonstrate a critical role for PD-1 signaling in cell survival and induction of a Senescence-Associated Secretory Phenotype (SASP). To prove PD-1 signaling is critical to podocyte aging, aged mice were injected with anti-PD-1 antibody (aPD-1ab). Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life-span of podocytes, but not parietal epithelial, mesangial or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrate that anti-PD-1 treatment improved the health-span of podocytes. It restored the expression of canonical podocyte genes, transcription factors and gene regulatory networks, increased cellular metabolism signatures and lessened SASPs. These results suggest a critical contribution for increased PD-1 signaling towards both kidney and liver aging.

cell biology↗