Biology subjects

Arana, C.

Publications and source records attributed to Arana, C..

5 recordsLinked to original sources

bioRxiv2025

The gut microbiota directs vitamin A flux to regulate intestinal T cell development

The intestinal microbiota shapes adaptive immunity, but the mechanisms remain incompletely defined. Here, we show that the microbiota initiates the movement of retinoids--dietary vitamin A derivatives including retinol and retinoic acid--through a sequential pathway from epithelial cells to myeloid cells and ultimately to T cells in the mesenteric lymph nodes (mLNs). This cellular axis is traversed over three days. Microbe-associated molecular patterns (MAMPs) initiate retinoid flux by inducing expression of serum amyloid A (SAA) proteins. These epithelial retinol-binding proteins are necessary and sufficient for epithelial-to-myeloid cell retinoid transfer and for myeloid cell migration to the mLNs. In the mLNs, microbial antigen drives retinoid transfer from myeloid cells to developing T cells, culminating in T cell retinoid uptake and transcriptional programming. This pathway is activated during postnatal development, when gut adaptive immunity is first established. These findings reveal that the microbiota programs intestinal adaptive immunity by regulating immune cell access to a nutrient-derived developmental signal. HighlightsO_LIThe gut microbiota enables vitamin A flux to developing intestinal CD4 T cells. C_LIO_LIMicrobiota-induced SAA initiates vitamin A flux along a gut myeloid-T cell axis. C_LIO_LIMicrobial molecular patterns and antigen drive distinct steps of vitamin A flux. C_LIO_LIMicrobiota-driven vitamin A flux programs intestinal T cell homing and maturation. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/674524v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@13b3906org.highwire.dtl.DTLVardef@11ceee3org.highwire.dtl.DTLVardef@87913forg.highwire.dtl.DTLVardef@50c9a0_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Enhanced Kidney Targeting and Distribution of Tubuloids During Normothermic Perfusion

Tubuloids have become a promising tool for kidney disease model and regeneration, although their ability for integration and regeneration in vivo is not well documented. Here we establish, characterize and compare human tubuloids using two optimized protocols, which added a prior isolation of tubular cells (Crude tubuloids) and proximal tubular cells (F4 tubuloids). Secondly, using this protocol, healthy rat-derived tubuloids were established. Finally, we compared two strategies to deliver GFP tubuloids in a kidney host: 1) subcapsular/intracortical injection and 2) tubuloid infusion during normothermic preservation in a rat transplantation model and a human discarded kidney. F4 tubuloids achieved a more differentiation state compared to Crude tubuloids. When analyzing tubuloid delivery to the kidney, normothermic perfusion was more efficient compared to in vivo injection, observing fully-developed tubules in the host parenchyma after 1 week and 1 month. Normothermic perfusion also successfully delivered kidney tubuloids to a discarded human kidney for transplantation. These results suggest that tubuloids administered during normothermic perfusion represent a potential strategy to enhance the translatability of kidney regenerative therapies to the clinical practice to condition kidney grafts and to treat kidney diseases.

bioengineering↗

bioRxiv2024

Glomerular Elasticity and Gene Expression Patterns Define Two Phases of Alport Nephropathy

Alport syndrome (AS), caused by COL4A3,4,5 mutations, leads to progressive glomerular disease and eventual kidney failure. In Col43-/- mice (C57BL/6 background), we found that increased glomerular capillary deformability (reduced Youngs modulus, E) appears 2-3 months before detectable proteinuria or elevated serum creatinine. This early change indicates that podocyte injury precedes traditional clinical markers of disease and corresponds to reduced podocyte adhesion and loss. Bulk and podocyte-enriched RNA-seq data, obtained from deconvoluting bulk RNA sequencing data, showed that starting at 4 months, endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) steadily rise while extracellular matrix remodeling, inflammation, epithelial-mesenchymal transition, and maladaptive repair begin. By 7 months, pathology shifts toward widespread parenchymal fibrosis, interleukin, cytokine, and chemokine signaling, cytoskeleton disruption, metabolic failure, and podocyte dedifferentiation. Notably, administration of the chemical chaperone Tauro-Urso-Deoxcycholic Acid (TUDCA) from weaning reduced ER stress, preserved glomerular stiffness, minimized podocyte detachment and loss, normalized inflammatory, injury, and fibrotic gene expression, and halved proteinuria and serum creatinine at 7 months, preserving kidney structure. Differentially expressed podocyte enriched genes from 4-month Col43-/- (vs WT) mice were mapped to human orthologs in the NEPTUNE cohort. Four genes (CRB2, GPC6, NKD1, STX11) were associated with End Stage Renal Disease or 40% loss of eGFR (ESRD40). Collectively, our results identify these four genes and ER stress/UPR as key and treatable drivers of podocyte injury and disease progression in Alport syndrome, well before overt proteinuria, and highlight UPR activation and several genes as promising targets for disease-modifying therapies.

cell biology↗

bioRxiv2021

JAK-STAT Signaling Enables Lineage Plasticity-driven AR Targeted Therapy Resistance

Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic aberrations correlate with lineage plasticity-driven resistance, the molecular mechanisms of acquiring lineage plasticity have not been fully elucidated. Through integrated transcriptomic and single cell RNA-Seq (scRNA-Seq) analysis of more than 80,000 cells, we reveal for the first time that the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is a crucial executor in promoting lineage plasticity-driven AR targeted therapy resistance in prostate cancer. Ectopic activation of JAK-STAT signaling is specifically required for the AR targeted therapy resistance of subclones expressing multilineage, stem-like and epithelial-to-mesenchymal transition (EMT) lineage transcriptional programs and represents a potential therapeutic target for overcoming AR targeted therapy resistance. One-Sentence SummaryJAK-STAT signaling is a crucial executor in promoting lineage plasticity-driven AR therapy resistance in prostate cancer.

cancer biology↗

bioRxiv2020

Impact of bead-beating intensity on microbiome recovery in mouse and human stool: Optimization of DNA extraction

DNA extraction methods play an important role in the acquisition of accurate and reproducible 16S sequencing data in microbiome studies. In this study, we assessed the impact of bead-beating intensity during DNA extraction on microbiome recovery in mouse and human stool. We observed a higher DNA yield, better DNA integrity, higher Shannons entropy and Simpsons index in samples beaten for 4 and 9 minutes as compared to unbeaten samples. 16S sequencing data showed that bead beating has a statistically-significant (p<0.05) impact on the recovery of many clinically relevant microbes that live in the mouse and human gut, including Bifidobacterium, Sutterella and Veillonella. It was observed that 4 minutes of bead beating promotes recovery of about 70% of OTUs in mouse and human stool, while the remaining 30% requires longer bead beating. In conclusion, our study indicates adjustments in bead beating treatment based on the composition of the specimen and the targeted bacteria.

microbiology↗