Biology subjects

Tata, A.

Publications and source records attributed to Tata, A..

14 recordsLinked to original sources

bioRxiv2026

A tonic PDGFA-dependent niche organizer maintains alveolar homeostasis

Tissue homeostasis requires mechanisms that preserve quiescence while allowing rapid activation after injury, but how tissues actively restrain injury responses during homeostasis remains poorly understood. Here we identify alveolar type 1 (AT1) cells as organizers of the distal lung niche through tonic expression of PDGFA, which maintains alveolar fibroblast identity and restrains myofibroblast activation. Cell type-specific ablation revealed that loss of AT1s, but not other major alveolar cell populations, was sufficient to evoke spontaneous fibroblast activation and tissue-wide responses that recapitulate injury. In silico ligand-receptor analysis, ex vivo screening, and conditional genetic models identified AT1-derived PDGFA as a key homeostatic signal. Loss of AT1-derived PDGFA caused spontaneous myofibroblast induction and tissue remodeling, whereas increasing PDGFA promoted fibroblast proliferation while suppressing myofibroblast differentiation. Integrated phosphoproteomic, transcriptomic, and chromatin accessibility analyses showed that PDGFA engages SHP2-ERK signaling, suppresses MRTFA-associated SRF programs, and promotes E2F-associated cell-cycle programs, thereby opposing the pro-fibrotic effects of TGF{beta}-driven fibroblast activation. Restoring PDGFA signaling abrogates myofibroblast features from human idiopathic pulmonary fibrotic lungs and attenuated fibrotic remodeling in vivo. These findings define a tonic AT1-derived PDGFA signal that maintains alveolar homeostasis and offers a therapeutic target to prevent or revert lung fibrosis.

cell biology↗

bioRxiv2026

Alveolar Cytochrome P450 Mediates Butylated Hydroxytoluene-Induced Electrophilic Injury and Apoptosis

Butylated hydroxytoluene (BHT) is a synthetic phenolic antioxidant utilized as a preservative in many products from foods to cosmetics. Population-based studies have detected BHT in the vast majority (>90%) of human specimens (serum, urine, fingernails) as well as home dust samples. Thus, BHT constitutes a ubiquitous environmental contaminant without obvious adverse health effects to humans. In contrast, exposure of mice to a single intraperitoneal dose of BHT triggers distal epithelial damage including loss of gas-exchanging alveolar type 1 epithelial cells, thus providing an invaluable tool to study alveolar repair and transient fibrosis. Presently, the molecular basis of BHT lung toxicity remains unknown. To address this, mouse lung single cell transcriptomic data were used to identify cytochrome P450 2B10 (CYP2B10) in AT1 cells as a BHT-activating enzyme. In cell culture systems, expression of CYP2B10 leads to marked BHT sensitization consistent with bioactivation of BHT into a toxic quinone methide. Targeted and proteome-wide experiments identify BHT-induced protein alkylation, DNA damage response, stress kinase activation and intrinsic apoptosis in a CYP2B10-dependent manner. Structure-activity relationship studies reveal the necessity of para-methyl and ortho-t-butyl groups necessary for BHT bioactivation. Our findings elucidate the molecular basis by which BHT is converted from an innocuous antioxidant into a highly toxic quinone methide and identify the first mammalian enzyme known to catalyze BHT bioactivation. Further, CYP2B10-catalyzed BHT bioactivation may provide a strategy for future targeted cell ablation technologies or environmental remediation of BHT.

molecular biology↗

bioRxiv2026

TP53-mediated bidirectional lineage plasticity drives alveolar epithelial cell extrusion and tissue remodeling

Cell extrusion contributes to epithelial homeostasis, but its dysregulation can lead to tumorigenesis or degeneration. A fine balance in this process is therefore essential for tissue integrity. Yet the cell types and states vulnerable to extrusion, and the mechanisms that drive it, remain elusive. Here, using spatial maps of cell states in human idiopathic pulmonary fibrosis (IPF) we find that aberrant TP53 activation in alveolar epithelial cells drives cell extrusion. Genetic modulation of TP53 specifically in alveolar epithelial type 1 cells (AT1) was sufficient to induce plasticity and subsequent extrusion as demonstrated by lineage tracing and live imaging. Strikingly, single cell and bulk transcriptome profiling revealed aberrant TP53 drives AT1 cells to acquire a transitional state mirroring AT2-derived regeneration associated intermediate states. Critically, loss of AT1 derived transitional state triggers a compensatory AT2-derived regenerative response, establishing a bidirectional transitional state that activates myofibroblasts and remodels the alveolus. Together, our study implicates AT1 plasticity and their reversion as an unrecognized driver of epithelial cell loss and establishes bidirectional transitional state as a central mechanism underlying progression of fibrotic remodeling.

Cell Biology↗

bioRxiv2025

Distinct dermal fibroblasts direct mechano-chemical signaling to the epidermis during pregnancy

Dermal fibroblasts alter extracellular matrix (ECM) and tissue mechanics dynamically in wound healing and fibrosis, however, are understudied in healthy skin remodeling across life stages. Here, by conducting spatio-temporal transcriptomics, we identified Cdh4+ dermal fibroblast subpopulation that remodels ECM and converts mechano-to-chemical signals to promote epidermal stem cell proliferation in expanding abdominal skin of pregnant mice. Mechanistically, Cdh4+ fibroblasts produce a pregnancy-responsive matrisome, resulting in denser and stiffer dermal fibrils. These fibroblasts then sense the stiffened substrate and convert the mechanical input into a chemical output via the YAP1-TGF{beta}2 axis, leading to the proliferation of epidermal stem cells via TGF{beta} receptor in the expanding skin. Thus, Cdh4+ fibroblasts fine-tune the dermal mechanofield and act as a mechanical-to-chemical signal conversion hub in healthy skin expansion.

developmental biology↗

bioRxiv2025

Ferret model of bleomycin-induced lung injury shares features of human idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with limited therapeutic options. The development of effective therapies has been hindered by the lack of models that recapitulate key features of human disease. Here we report a bleomycin-induced ferret PF model characterized by an irreversible decrease in pulmonary compliance and an increase of opacification, accompanied by "honeycomb cyst-like" structures and "proximalization" of distal lung epithelium. Cellular and molecular analysis by single-nucleus RNA sequencing revealed a significant shift in distal lung epithelium towards proximal epithelial phenotype. Importantly, a histopathological pattern of bronchiolization encompassing divergent atypical epithelial cells and KRT17+/TP63+/KRT5low "basaloid-like" cells was present in the distal fibrotic lung lesions. Trajectory analysis revealed AT2 cells transition through multiple cell-states in bleomycin injured ferret lungs, particularly AT2 to KRT8high/KRT7low/SOX4+ and eventually to KRT8high/KRT7high/SFN+/TP63+/KRT5low "basaloid-like" cells. Further, immunofluorescence analyses demonstrated KRT7 and KRT8 populations reside overlaying the ACTA2-positive myofibroblasts in fibrotic foci, implying their pro-fibrogenic activity similar to human IPF lungs. Collectively, our results provide evidence that bleomycin-induced lung injury in ferrets recapitulates pathophysiological, cellular, and molecular features of human IPF, suggesting that they may be a reliable model for understanding mechanisms of IPF pathogenesis and for testing therapeutic strategies for treatment of IPF. Take Home MessageBleomycin-induced acute lung injury in the ferret recapitulates pathophysiological, cellular, and molecular features of human IPF; thus the ferret may be a reliable species for studying mechanisms of IPF pathogenesis and testing therapeutic strategies.

pathology↗

bioRxiv2025

Evaluation of Prostaglandin Receptor Agonists and Eupatilin in the Context of Nephronophthisis

BackgroundPrimary cilia are sensory antennas that are present on the majority of quiescent vertebrate cells where they mediate key signaling during development and in response to environmental stimuli. Defects in primary cilia result in a group of heterogeneous inherited disorders with overlapping phenotypes, called ciliopathies. Nephronophthisis is an autosomal recessive tubulo-interstitial kidney ciliopathy with more than 25 identified genes called NPHP. Presently, no treatment exists beyond supportive care and kidney transplant, underscoring the need for novel therapies. MethodsUsing a phenotypic screening approach in cultured cell lines, we previously identified prostaglandin analogues as candidate therapeutic molecules based on their ability to rescue ciliogenesis defects in kidney tubular cells from NPHP1 patients. Here, we have investigated the potential beneficial effects of ROCK inhibitors and Eupatilin, similarly identified by other groups in different NPHP contexts, in kidney cells from NPHP1 and IQCB1/NPHP5 patients as well as in a zebrafish NPHP mutant line (traf3ip1/ift54). ResultsEupatilin partially rescued NPHP1-associated ciliogenesis defects. Transcriptomic analyses pointed out that cell cycle progression was inhibited by Eupatilin, likely explaining its broad effects on cilia assembly. Interestingly, while ciliary defects also observed in NPHP5 patient cells were rescued by both prostaglandins and Eupatilin, only prostaglandin analogues were able to reduce pronephric cysts size in the used nphp zebrafish model. ConclusionOur study indicates that these molecules can show beneficial effects across genetic contexts and shed light on their potential as therapeutic interventions for nephronophthisis.

cell biology↗

bioRxiv2024

Analysis of Protein Cysteine Acylation Using a Modified Suspension Trap (Acyl-Trap)

Proteins undergo reversible S-acylation via a thioester linkage in vivo. S-palmitoylation, modification by C16:0 fatty acid, is a common S-acylation that mediates critical protein-membrane and protein-protein interactions. The most widely used S-acylation assays, including acyl-biotin exchange and acyl resin-assisted capture, utilize blocking of free Cys thiols, hydroxylamine-dependent cleavage of the thioester and subsequent labeling of nascent thiol. These assays generally require >500 micrograms of protein input material per sample and numerous reagent removal and washing steps, making them laborious and ill-suited for high throughput and low input applications. To overcome these limitations, we devised "Acyl-Trap", a suspension trap-based assay that utilizes a thiol-reactive quartz to enable buffer exchange and hydroxylamine-mediated S-acyl enrichment. We show that the method is compatible with protein-level detection of S-acylated proteins (e.g. H-Ras) as well as S-acyl site identification and quantification using "on trap" isobaric labeling and LC-MS/MS from as little as 20 micrograms of protein input. In mouse brain, Acyl-Trap identified 279 reported sites of S-acylation and 1298 previously unreported putative sites. Also described are conditions for long-term hydroxylamine storage, which streamlines the assay. More generally, Acyl-Trap serves as a proof-of-concept for PTM-tailored suspension traps suitable for both traditional protein detection and chemoproteomic workflows. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/586403v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@16d595aorg.highwire.dtl.DTLVardef@55acforg.highwire.dtl.DTLVardef@18cf92eorg.highwire.dtl.DTLVardef@3b5fb4_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2024

A split-GAL4 driver line resource for Drosophila CNS cell types

Techniques that enable precise manipulations of subsets of neurons in the fly central nervous system have greatly facilitated our understanding of the neural basis of behavior. Split-GAL4 driver lines allow specific targeting of cell types in Drosophila melanogaster and other species. We describe here a collection of 3060 lines targeting a range of cell types in the adult Drosophila central nervous system and 1373 lines characterized in third-instar larvae. These tools enable functional, transcriptomic, and proteomic studies based on precise anatomical targeting. NeuronBridge and other search tools relate light microscopy images of these split-GAL4 lines to connectomes reconstructed from electron microscopy images. The collections are the result of screening over 77,000 split hemidriver combinations. Previously published and new lines are included, all validated for driver expression and curated for optimal cell type specificity across diverse cell types. In addition to images and fly stocks for these well-characterized lines, we make available 300,000 new 3D images of other split-GAL4 lines.

neuroscience↗

bioRxiv2022

Transgenic porcine model reveals two roles for LGR5 during lung development and homeostasis

Cells expressing LGR5 play a pivotal role in homeostasis, repair, and regeneration in multiple organs including skin and gastrointestinal tract, yet little is known about their role in the lung. Findings from mice, a widely used animal model, suggest that lung LGR5 expression differs from that of humans. In this work, using a new transgenic pig model, we identify two main populations of LGR5+ cells in the lung that are conserved in human, but not mouse lungs. Using RNA sequencing, 3D imaging and organoid models, we determine that in the fetal lung, epithelial LGR5 expression is transient in a subpopulation of SOX9+/ETV+/SFTPC+ progenitor lung tip cells. In contrast, epithelial LGR5 expression is absent from postnatal lung, but is reactivated in bronchioalveolar organoids derived from basal airway cells. We also describe a separate population of mesenchymal LGR5+ cells that surrounds developing and mature airways, lies adjacent to airway basal cells, and is closely associated with nerve fibers. Transcriptionally, mesenchymal LGR5+ cells include a subset of peribronchial fibroblasts (PBF) that express unique patterns of SHH, FGF, WNT and TGF-{beta} signaling pathway genes. These results support distinct roles for LGR5+ cells in the lung and describe a physiologically relevant animal model for further studies on the function of these cells in repair and regeneration.

cell biology↗

bioRxiv2021

Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair

Overwhelming lipid peroxidation induces ferroptotic stress and ferroptosis, a non-apoptotic form of regulated cell death that has been implicated in maladaptive renal repair in mice and humans. Using single-cell transcriptomic and mouse genetic approaches, we show that proximal tubular (PT) cells develop a molecularly distinct, pro-inflammatory state following injury. While these inflammatory PT cells transiently appear after mild injury and return to their original state without inducing fibrosis, they accumulate and contribute to persistent inflammation after severe injury. This transient inflammatory PT state significantly downregulates glutathione metabolism genes, making them vulnerable to ferroptotic stress. Genetic induction of high ferroptotic stress in these cells after mild injury leads to the accumulation of the inflammatory PT cells, enhancing inflammation and fibrosis. Our study broadens the roles of ferroptotic stress from being a trigger of regulated cell death to include the promotion and accumulation of proinflammatory cells that underlie maladaptive repair.

cell biology↗

bioRxiv2020

SRSF protein kinases 1 and 2 are essential host factors for human coronaviruses including SARS-CoV-2

While vaccines are vital for preventing COVID-19 infections, it is critical to develop new therapies to treat patients who become infected. Pharmacological targeting of a host factor required for viral replication can suppress viral spread with a low probability of viral mutation leading to resistance. In particular, host kinases are highly druggable targets and a number of conserved coronavirus proteins, notably the nucleoprotein (N), require phosphorylation for full functionality. In order to understand how targeting kinases could be used to compromise viral replication, we used a combination of phosphoproteomics and bioinformatics as well as genetic and pharmacological kinase inhibition to define the enzymes important for SARS-CoV-2 N protein phosphorylation and viral replication. From these data, we propose a model whereby SRPK1/2 initiates phosphorylation of the N protein, which primes for further phosphorylation by GSK-3/{beta} and CK1 to achieve extensive phosphorylation of the N protein SR-rich domain. Importantly, we were able to leverage our data to identify an FDA-approved kinase inhibitor, Alectinib, that suppresses N phosphorylation by SRPK1/2 and limits SARS-CoV-2 replication. Together, these data suggest that repurposing or developing novel host-kinase directed therapies may be an efficacious strategy to prevent or treat COVID-19 and other coronavirus-mediated diseases.

microbiology↗

bioRxiv2020

A dendritic-like microtubule network is organized from swellings of the basal fiber in neural progenitors

Neurons of the neocortex are generated by neural progenitors called radial glial cells. These polarized cells extend a short apical process towards the ventricular surface and a long basal fiber that acts as a scaffold for neuronal migration. How the microtubule cytoskeleton is organized in these cells to support long-range transport in unknown. Using subcellular live imaging within brain tissue, we show that microtubules in the apical process uniformly emanate for the pericentrosomal region, while microtubules in the basal fiber display a mixed polarity, reminiscent of the mammalian dendrite. We identify acentrosomal microtubule organizing centers localized in swellings of the basal fiber. We characterize their distribution and demonstrate that they accumulate the minus end stabilizing factor CAMSAP3 and TGN-related membranes, from which the majority of microtubules grow. Finally, using live imaging of human fetal cortex, we show that this organization is conserved in basal radial glial (bRG) cells, a highly abundant progenitor cell population associated with human brain size expansion.

cell biology↗

bioRxiv2019

The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M2 receptor subtype

Triple negative tumors are more aggressive than other breast cancer subtypes and there is a lack of specific therapeutic targets on them. Since muscarinic receptors have been linked to tumor progression, we investigated the effect of metronomic therapy employing a traditional anti-cancer drug, paclitaxel plus muscarinic agonists at low doses on this type of tumor. We observed that MDA-MB231 tumor cells express muscarinic receptors, while they are absent in the non-tumorigenic MCF-10A cell line, which was used as control. The addition of carbachol or arecaidine propargyl ester, a non-selective or a selective subtype 2 muscarinic (M2) receptor agonist respectively, plus paclitaxel reduces cell viability involving a down-regulation in the expression of ATP "binding cassette" G2 drug transporter and epidermal growth factor receptor. We also detected an inhibition of tumor cell migration and anti-angiogenic effects produced by those drug combinations in vitro and in vivo (in NUDE mice) respectively. Our findings provide substantial evidence about M2 receptors as therapeutic target for the treatment of triple negative tumors.

pharmacology and toxicology↗

bioRxiv2019

Persistence of a novel regeneration-associated transitional cell state in pulmonary fibrosis

Stem cell senescence is often seen as an age associated pathological state in which cells acquire an abnormal and irreversible state. Here, we show that alveolar stem cell differentiation during lung regeneration involves a unique previously uncharacterized transitional state that exhibits cardinal features normally associated with cell senescence. Specifically, using organoid cultures, multiple in vivo injury models coupled with single cell transcriptomics and lineage tracing analysis, we find that alveolar stem cell differentiation involves a novel, pre-alveolar type-1 transitional state (PATS) en route to their terminal maturation. PATS can be distinguished based on their unique transcriptional signatures, including enrichment for TP53, TGF{beta}, and DNA damage repair signaling, and cellular senescence in both in vivo and ex vivo regenerating tissues. Significantly, PATS undergo extensive cell stretching, which makes them vulnerable to DNA damage, a feature commonly associated with most degenerative lung diseases. Importantly, we find enrichment of PATS-like state in human fibrotic lung tissues, suggesting that persistence of such transitional states underlies the pathogenesis of pulmonary fibrosis. Our study thus redefines senescence as a state that can occur as part of a normal tissue maintenance program, and can be derailed in human disease, notably fibrosis.

cell biology↗