Biology subjects

Rabb, H.

Publications and source records attributed to Rabb, H..

4 recordsLinked to original sources

bioRxiv2025

STcompare: comparative spatial transcriptomics data analysis of structurally matched tissues to characterize differentially spatially patterned genes

MotivationComparative analysis of spatial transcriptomics (ST) data is needed to identify genes that spatially change in their expression patterns between conditions, such as in diseased versus healthy tissues. Existing methods generally fail to distinguish changes in spatial patterning by focusing only on changes in gene expression magnitude for methods adapted from non-spatial data or on changes in significance of spatial variability for methods focusing on spatially-resolved data. ResultsTo address these limitations, we develop STcompare, a statistical framework for comparative analysis of ST data by testing for differences in spatial correlation and spatial fold-change across structurally matched locations. Using simulated data, we demonstrate how STcompare provides distinct insights from bulk differential gene expression analysis and spatially variable gene expression analysis as well as other spatial comparison methods. STcompare further robustly controls for false positives even in the presence of spatial autocorrelation common in ST data. We apply STcompare to real ST data of biological replicates of mouse brains to confirm high spatial correspondence of gene expression patterns across samples. We apply STcompare to identify genes that spatially change in mouse kidneys with acute kidney injury compared to a healthy control, revealing tissue compartment-specific molecular dysregulation. Overall, the application of this spatially-aware comparative analysis will enable the discovery of differential spatially patterned genes across various physiological and technological axes of interest. Availability and ImplementationSTcompare is implemented as an open-source R package at https://github.com/JEFworks-Lab/STcompare with additional documentation and tutorials available at https://jef.works/STcompare/.

bioinformatics↗

bioRxiv2025

Spatiotemporal transcriptomic analysis during cold ischemic injury to the murine kidney reveals compartment-specific changes

BackgroundKidney transplantation is the preferred treatment strategy for end-stage kidney disease. Deceased donor kidneys usually undergo cold storage until kidney transplantation, leading to cold ischemia injury that may contribute to poor graft outcomes. However, the molecular characterization of potential mechanisms of cold ischemia injury remains incomplete. ResultsTo bridge this knowledge gap, we leveraged the 10x Visium spatial transcriptomic technology to perform full transcriptome profiling of murine kidneys subject to varying durations of cold ischemia typical in a deceased donor kidney transplant setting. We developed a computational workflow to identify and compare spatiotemporal transcriptomic changes that accompany the injury pathophysiology in a tissue compartment-specific manner. We identified proportional enrichment of oxidative phosphorylation (OXPHOS) genes with increasing duration of cold ischemia injury within the oxygen-lean inner medulla region, suggestive of atypical metabolic presentation. This was distinct in cold ischemia injury tissue compared to warm ischemia-reperfusion kidney injury tissue. Spatiotemporal trends were validated by qPCR and immunofluorescence in a larger cohort of mice. We provide an interactive online browser at https://jef.works/CellCarto-ColdIschemia/ to facilitate exploration of our results by the broader scientific and clinical community. ConclusionsAltogether, our spatiotemporal transcriptomic analysis identified coordinated molecular changes within metabolic pathways such as OXPHOS deep within the cold ischemic kidney, highlighting the need for increased attention to the inner medulla and potential opportunities for new insights beyond those available from superficial biopsy-focused tissue examinations.

bioinformatics↗

bioRxiv2025

Microbes regulate glomerular filtration rate in health and chronic kidney disease in mice

Microbes are implicated in a variety of host physiological and pathophysiological processes. In this study, we tested the hypothesis that microbes modulate glomerular filtration rate (GFR). Microbiota were depleted in mice using oral antibiotics (ABX; a mixture of ampicillin, neomycin, and vancomycin). GFR was significantly increased in ABX-treated mice. To confirm that the increase in GFR was due to decreased microbes, we also measured GFR in germ-free (GF) mice. GFR was increased in GF mice as compared to both conventional and conventionalized GF (CGF) mice. We next used the murine adenine diet model to ask if suppressing gut microbes with ABX also increases GFR in a setting of chronic kidney disease (CKD), where GFR is impaired. In females on an adenine diet, ABX increased GFR versus adenine alone on weeks 4 and 6. In males, ABX elevated GFR on week 2. Adenine diet significantly increased plasma creatinine and kidney fibrosis; this was suppressed by ABX in both sexes. To explore the mechanism of this increase, we tested the hypothesis that altered tubuloglomerular feedback (TGF) contributes to elevated GFR using the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA); EMPA impairs Na+ reabsorption in the proximal tubule, altering TGF. We found that EMPA impaired ABX-induced GFR increases on week 3 but not week 5, suggesting that altered TGF contributes to the initial increase in GFR. In conclusion, the microbiome plays a key role in setting baseline GFR by a mechanism which partially involves TGF, and, suppressing gut microbes can elevate GFR even in CKD. Translational StatementThis study reports that GFR is elevated when gut microbes are absent or suppressed in mice, indicating a role for commensal microbes to help establish baseline GFR in health. Likewise, suppressing gut microbes also elevates GFR in a chronic kidney disease model. These data suggest a future possibility of modulating the commensal microbes to elevate GFR in a clinical setting.

physiology↗

bioRxiv2025

Inhibition of methylthioadenosine phosphorylase provides protection from experimental acute kidney injury

Acute kidney injury (AKI) increases mortality risk and predisposes individuals to chronic kidney disease. Metabolic pathways play a crucial role in AKI pathophysiology. Here, we investigate the potential of methylthioadenosine phosphorylase (MTAP) inhibition as a novel renoprotective strategy in AKI. Using AKI mouse models, we demonstrate that a small molecule MTAP inhibitor significantly reduces kidney injury markers and improves renal histology. RNA sequencing reveals that MTAP inhibition modulates pathways associated with inflammation, oxidative phosphorylation, and cell survival. Additionally, analysis of human single-cell RNA sequencing data links MTAP expression to kidney injury marker in AKI. This study provides evidence of MTAP inhibition as a potential therapeutic strategy for AKI, highlighting metabolic dysregulation as a target for future clinical interventions.

pathology↗