Biology subjects

Schuh, M. P.

Publications and source records attributed to Schuh, M. P..

4 recordsLinked to original sources

bioRxiv2026

Megalin (LRP2), prenatal betamethasone, and injury susceptibility in the developing kidney

Preterm infants undergo postnatal nephrogenesis and are often exposed to gentamicin (gent). Mothers at risk of preterm birth receive betamethasone (beta) to accelerate fetal lung development. Gent cytotoxicity occurs in proximal tubules (PT) after megalin (LRP2)-mediated endocytosis and accumulation. The objective of this study was to evaluate the impact of proximal tubular maturation, impacted by both age and prenatal beta, on injury susceptibility and nephron number in rats. Pups were given toxic gent dosing (100mg/kg) or saline intraperitoneal for 5 days during nephrogenesis (P0-4) or tubular maturation (P6-10). This was repeated with maternal exposure to beta to evaluate impact of beta on injury. Quantitative proteomics analysis revealed significantly higher levels of LRP2 at P10 as compared to P4, correlating with increased injury to gent exposure from P6-10 relative to P0-4. P10 pups exposed to prenatal beta had significantly more LRP2 protein relative to controls, which correlated to more injury after gent exposure at P6-10. Only those exposed to prenatal beta with P6-10 gent demonstrated ~50% nephron reduction. This study supports that tubular maturation is a critical period of vulnerability to gentamicin correlating to LRP2 protein abundance. Prenatal corticosteroids increase the severity of acute and chronic injury in this highest risk exposure group.

developmental biology↗

bioRxiv2026

Single nucleus RNA sequencing of juvenile dermatomyositis skeletal muscle identifies altered angiogenic signaling

Juvenile dermatomyositis (JDM) is a chronic multisystem vasculopathy and inflammatory myopathy characterized by proximal muscle weakness, distinct rash, and risk of complications such as calcinosis cutis, skin ulceration, and mortality. Molecular insight from diagnostic muscle biopsy histology is limited, and the mechanistic pathoetiology of JDM remains poorly defined. We used single nuclei transcriptomics to assess muscle samples from patients with newly diagnosed treatment-naive JDM. As a control, we assessed muscle samples from patients with congenital (nemaline) myopathy (CM), a non-inflammatory disorder. A total of 25,794 high quality nuclei were analyzed and clustered into various muscle-resident or infiltrating cellular populations. JDM tissue was characterized by an enriched interferon (IFN) response signature across endothelial, stromal, and immune cell compartments. Endothelial and perivascular populations showed increased inflammatory and angiogenic programs. Intercellular communication inference analysis identified dysregulated vascular endothelial growth factor (VEGF)-related signaling involving endothelial, stromal, and myonuclear populations as a possible mechanism for myonuclear-driven modulation of the muscle microvasculature. Spatial RNA in situ hybridization supported increased expression of selected IFN responsive and angiogenesis signaling genes in JDM tissue. Collectively, these data provide a cell type-resolved view of treatment-naive JDM muscle and highlight vascular and IFN pathways for follow-up in larger cohorts.

genomics↗

bioRxiv2025

Bridging the gap of late-gestation nephrogenesis using a non-human primate model

BackgroundHuman nephrogenesis is complete at 34-36 weeks gestation, with 60% of nephrons forming during the third trimester through lateral branch nephrogenesis (LBN). Currently, no mechanism exists for LBN as there are no late gestation human kidney transcriptional datasets. We hypothesized that a differentiated but dividing population of nephron progenitor cells (NPCs) would contribute to the amplification of nephrons in late gestation. We used the rhesus macaque, an established model of LBN, to help identify potential mechanisms. MethodsSingle-cell RNA-sequencing (scRNA-Seq) was performed on cortically-enriched fetal rhesus kidneys (n=9) from late second trimester and third trimester during LBN. This data was integrated with publicly available human scRNA-seq datasets from 8-18 weeks gestation kidneys (n=8) using state-of-the-art bioinformatics pipelines. Differentially expressed genes and ligand-receptor interactions were assessed and validated using RNAScopeTM on human and rhesus archival tissue. ResultsscRNA-Seq of 64,782 rhesus cells revealed 37 transcriptionally distinct cell populations, including 7,879 rhesus NPCs. Pseudotime analyses identified a late gestation-specific lineage branch of differentiated NPC in rhesus that was not observed in mid-gestation humans. Differential expression analyses identified increased SFRP1, FZD4, and TLE2 and decreased FZD7, SHISA2, SHISA3, and TLE4 within the late-gestation rhesus NPC compared to mid-gestation human NPC and increased SEMA3D within the rhesus ureteric bud (UB) tip, suggesting a compositional shift in WNT and SEMA signaling components within the naive NPC population during LBN. ConclusionThe rhesus macaque uniquely enables molecular studies of late-gestation primate nephrogenesis. Our study suggests the hypothesis that a transitional state of self-renewing NPCs supported by compositional shifts in key pathways may underlie the switch from branching phase nephrogenesis to lateral branch nephrogenesis and support ongoing nephron formation in late gestation. Translational statementNo transcriptional data exists for the late-gestation human kidney, during which 60% of the nephron endowment is formed through a primate-specific process called lateral branch nephrogenesis (LBN). In this study, we used single-cell RNA sequencing the late gestation rhesus macaque as a model for this developmental stage. Our findings suggest a potential mechanism for LBN, in which a transitional state of self-renewing nephron progenitor cells (NPCs) is supported by compositional shifts in key pathways, allowing for continued nephron formation in late gestation.

developmental biology↗

bioRxiv2019

Single Cell Profiling of Acute Kidney Injury Reveals Novel Transcriptional Signatures, Mixed Identities and Epithelial-to-Stromal Crosstalk

Acute kidney injury (AKI) is a rapid decline of renal function, with an incidence of up to 67% of intensive care unit patients. Current treatments are merely supportive, emphasizing the need for deeper understanding that could lead to improved therapies. We used single cell RNA sequencing, in situ hybridization and protein expression analyses to create comprehensive renal cell specific transcriptional profiles of multiple AKI stages. We revealed that AKI induces marked dedifferentiation, renal developmental gene activation and mixed identities in injured renal tubules. Moreover, we identified potential pathologic crosstalk between epithelial and stromal cells, and several novel genes involved in AKI. We also demonstrated the definitive effects of age on AKI outcome, and showed that renal developmental genes hold a potential as novel AKI markers. Moreover, our study provides the resource power which will aid in unraveling the molecular genetics of AKI.

developmental biology↗