Biology subjects

Wu, A.

Publications and source records attributed to Wu, A..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

NLRP10 Cleaves Oxidized DNA inhibited by OGG1 inhibitors: A Newly Identified Role in DNA Damage Processing and Senescence Regulation.

Mitochondrial DNA (mtDNA) release into the cytosol is a critical event in innate immune activation, often acting as a damage-associated molecular pattern (DAMP) that triggers inflammasome assembly. Here, we demonstrate that NLRP3 plays a direct role in cleaving and facilitating the release of D-loop mtDNA into the cytosol. We further show that NLRP3 interacts with NLRP10. NLRP10-mediated ox-DNA cleavage involves a Schiff base intermediate and is inhibited by small molecules known to inhibit glycosylases. These findings support a model where NLRP10 interaction with oxidized DNA may contribute to long-term senescence secretory phenotype and modulate inflammasome activation. Our study highlights a novel mechanism by which NLRP10 can respond to mitochondrial stress signals to influence innate immunity and suggests therapeutic potential for targeting these interactions in inflammatory diseases.

immunology↗

bioRxiv2025

Dynamic Reprogramming of Stromal Pdgfra-expressing cells during WNT-Mediated Transformation of the Intestinal Epithelium

Stromal fibroblasts regulate critical signaling gradients along the intestinal crypt-villus axis1 and provide a niche that supports adjacent epithelial stem cells. Here we report that Pdgfra-expressing fibroblasts secrete ligands that promote a regenerative-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Using a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing (RNA-seq) of mesenchyme cell populations, we revealed a dynamic reprogramming of Pdgfra+ fibroblasts that facilitates WNT-mediated tissue transformation. Functional assays of potential mediators of cell-to-cell communication between these fibroblasts and the oncogenic epithelium revealed that TGFB signaling is notably induced in Pdgfra+ fibroblasts in the presence of oncogenic epithelium, and TGFB was essential to sustain regenerative-like growth of organoids ex vivo. Genetic reduction of Cdx2 in the {beta}-catenin mutant epithelium elevated the fetal-like/regenerative transcriptome and accelerated WNT-dependent onset of oncogenic transformation of the tissue in vivo. These results demonstrate that Pdgfra+ fibroblasts are activated during WNT-driven oncogenesis to promote a regenerative state in the epithelium that precedes and facilitates formation of tumors.

cancer biology↗

bioRxiv2025

Targeted stimulation of motor cortex neural ensembles drives learned movements

During the execution of learned motor skills, the neural population in the layer 2/3 (L2/3) of the primary motor cortex (M1) expresses a reproducible spatiotemporal activity pattern. It is debated whether M1 actively participates in generating this activity pattern and whether this learned pattern causally drives the learned movement. To address these questions, we utilized in vivo two-photon calcium imaging combined with holographic optogenetic stimulation of functionally defined M1 L2/3 neuronal ensembles in mice performing a skilled lever-pressing task. A brief and synchronous stimulation of [~]20 neurons whose activity onset in voluntary trials precedes movement onsets induced movements that resembled the learned movement, while producing spatiotemporal activity patterns in other M1 neurons that resembled those during the voluntary learned movement. Moreover, trial-by-trial variability of optogenetically triggered population activity correlated with the variability in the induced movements. These trial-by-trial variabilities were predicted by the initial state of M1 population activity immediately preceding the stimulation. In some trials, the stimulation induced the learned activity without inducing overt movements, indicating that the learned activity is not simply a reflection of movements and instead can be induced internally. The stimulation failed to generate movements or learned activity when mice were disengaged from the task. Stimulation of the neurons whose activity followed voluntary movement onsets failed to induce the learned movement in task-engaged mice. Taken together, the learned activity pattern in M1 L2/3 can be generated when the M1 network is prepared at the optimal initial state and receives precise triggering inputs, supporting the active role of M1 in the generation of learned activity and learned movements.

neuroscience↗

bioRxiv2024

CRISPR-Cas supervises diverse anti-phage defense systems

A variety of bacterial anti-phage systems have recently been discovered1-3, but how these systems synergize to defend against diverse phages remains poorly understood. Here, we report that the adaptive immune system CRISPR-Cas supervises the expression of diverse immune systems by exploiting the regulatory CRISPR RNA-like RNAs (crlRNAs). The crlRNAs target and inhibit the promoters of various immune systems, including the newly characterized Nezha and Gabija, as well as eight previously unrecognized systems that feature distinct defensive domains. Notably, CRISPR regulation balances the expression level of these systems to ensure effective anti-phage activity while avoiding their autoimmunity risks. In return, the supervised immune systems trigger abortive infections when CRISPR-Cas is inhibited by viral anti-CRISPR proteins, thereby offering an anti-anti-CRISPR protection at the population level. Moreover, these systems complement CRISPR immunity with a differing anti-phage profile. These findings highlight the pivotal role of CRISPR-Cas in orchestrating a diverse range of immune systems and showcase the delicate synergy among the multilayered defense strategies in prokaryotes.

microbiology↗

bioRxiv2024

A signaling inspired synthetic toolkit for efficient production of tyrosine phosphorylated proteins

Tyrosine phosphorylation is an important post-translational modification that regulates many biochemical signaling networks in multicellular organisms. To date, 46,000 tyrosines have been observed in human proteins, but relatively little is known about the function and regulation of most of these sites. A major challenge has been producing recombinant phosphoproteins in order to test the effects of phosphorylation. Mutagenesis to acidic amino acids often fails to replicate the size and charge of a phosphorylated tyrosine residue and synthetic amino acid incorporation has high cost with relatively low yield. Here, we demonstrate an approach, inspired by how native tyrosine kinases find targets in cells - through a secondary targeting interaction, augmenting innate catalytic specificity of a tyrosine kinase, without overriding it. We engineered complementary vector systems for multiple approaches to producing high yields of phosphoprotein products in E. coli. Here, we test phosphorylation as a function of the targeting interaction (an SH3-polyproline sequence) affinity, different reaction methods across kinases of different specificity. This system presents an inexpensive and tractable system to producing phosphoproteins and phosphopeptides and we demonstrate how it can be used for testing antibody specificity on targets of EGFR and PD-1. This methodology is a generalizable approach for enhancing the enzymatic action on a recombinant protein via the flexibility of in vitro reactions and co-expression approaches. We refer to this as SISA-KiT, for Signaling Inspired Synthetically Augmented Kinase Toolkit.

molecular biology↗

bioRxiv2024

Pathway Polygenic Risk Scores (pPRS) for the Analysis of Gene-environment Interaction

A polygenic risk score (PRS) is used to quantify the combined disease risk of many genetic variants. For complex human traits there is interest in determining whether the PRS modifies, i.e. interacts with, important environmental (E) risk factors. Detection of a PRS by environment (PRS x E) interaction may provide clues to underlying biology and can be useful in developing targeted prevention strategies for modifiable risk factors. The standard PRS may include a subset of variants that interact with E but a much larger subset of variants that affect disease without regard to E. This latter subset will water down the underlying signal in former subset, leading to reduced power to detect PRS x E interaction. We explore the use of pathway-defined PRS (pPRS) scores, using state of the art tools to annotate subsets of variants to genomic pathways. We demonstrate via simulation that testing targeted pPRS x E interaction can yield substantially greater power than testing overall PRS x E interaction. We also analyze a large study (N=78,253) of colorectal cancer (CRC) where E = non-steroidal anti-inflammatory drugs (NSAIDs), a well-established protective exposure. While no evidence of overall PRS x NSAIDs interaction (p=0.41) is observed, a significant pPRS x NSAIDs interaction (p=0.0003) is identified based on SNPs within the TGF-{beta} / gonadotropin releasing hormone receptor (GRHR) pathway. NSAIDS is protective (OR=0.84) for those at the 5th percentile of the TGF-{beta}/GRHR pPRS (low genetic risk, OR), but significantly more protective (OR=0.70) for those at the 95th percentile (high genetic risk). From a biological perspective, this suggests that NSAIDs may act to reduce CRC risk specifically through genes in these pathways. From a population health perspective, our result suggests that focusing on genes within these pathways may be effective at identifying those for whom NSAIDs-based CRC-prevention efforts may be most effective. Author SummaryThe identification of polygenic risk score (PRS) by environment (PRSxE) interactions may provide clues to underlying biology and facilitate targeted disease prevention strategies. The standard approach to computing a PRS likely includes many variants that affect disease without regard to E, reducing power to detect PRS x E interactions. We utilize gene annotation tools to develop pathway-based PRS (pPRS) scores and show by simulation studies that testing pPRS x E interaction can yield substantially greater power than testing PRS x E, while also integrating biological knowledge into the analysis. We apply our method to a large study of colorectal cancer to identify a significant pPRS x NSAIDs interaction (p=0.0003) based on SNPs within the TGF-{beta} / gonadotropin releasing hormone receptor (GRHR) pathway. Our findings suggest that focusing on genetic susceptibility within biologically informed pathways may be more sensitive for identifying exposures that can be considered as part of a precision prevention approach.

genetics↗

bioRxiv2024

TTF2 promotes replisome eviction from stalled forks in mitosis

Cells entering mitosis with incompletely replicated DNA face catastrophic chromosome segregation failure. During interphase, the replisome-associated E3 ubiquitin ligase TRAIP ubiquitylates barriers in front of the fork to allow replisome progression. In mitosis, TRAIP is reprogrammed from a trans-acting to a cis-acting ligase that can ubiquitylate the replisome itself. This enables the processing of unreplicated DNA by promoting replisome disassembly, fork breakage, and joining of the broken chromosome arms. Here, we describe a mechanism for this reprogramming: the ATPase TTF2 is recruited to the replisome, where its non-catalytic N-terminal domain tethers Cyclin B-CDK1-phosphorylated TRAIP to the leading strand DNA polymerase {varepsilon} in a geometry that allows replisome ubiquitylation. Thus, a phospho-regulated architectural switch alters replisome organization in mitosis to safeguard genome integrity before chromosome segregation.

biochemistry↗

bioRxiv2024

Adiponectin Signaling Regulates Urinary Bladder Function by Blunting Smooth Muscle Purinergic Contractility

Lower urinary tract symptoms (LUTS) affect [~] 50% of the population aged >40 years and are strongly associated with obesity and metabolic syndrome. Adipose tissue plays a key role in obesity/metabolic syndrome by releasing adipokines that regulate systemic energy/lipid metabolism, insulin resistance, and inflammation. Adiponectin (ADPN), the most abundant adipokine, modulates energy/metabolism homeostasis through its insulin-sensitizing and anti-inflammatory effects. Human plasma ADPN levels are inversely associated with obesity and diabetes. The role of adipokines such as ADPN in the LUTS associated with obesity/metabolic syndrome remains unknown. We have tested such a possible role in a global ADPN knockout mouse model (Adpn-/-). Adpn-/- mice exhibited increased voiding frequency, small voids, and reduced bladder smooth muscle (BSM) contractility with absence of purinergic contraction. Molecular examination indicated significantly altered metabolic and purinergic pathways. The ADPN receptor agonist AdipoRon was found to abolish acute BSM contraction. Intriguingly, both AMPK activators and inhibitors also abolished BSM purinergic contraction. These data indicate the important contribution of a novel ADPN signaling pathway to the regulation of BSM contractility. Dysregulation of this ADPN signaling pathway might be an important mechanism leading to LUTS associated with obesity/metabolic syndrome. ARTICLE HIGHLIGHTSLower urinary tract symptom (LUTS) is strongly associated with obesity and metabolic syndrome, however, the underlying molecular mechanisms are missing. Dysregulation of adipokine signaling could be the link for this association. Whether adiponectin, the most abundant adipokine, plays a role in regulating bladder function and dysfunction. Mice null for adiponectin exhibited increased voiding frequency, small voids, and reduced bladder smooth muscle contractility, with corresponding metabolic and purinergic pathway changes. Dysregulation of adiponectin signaling might be an important mechanism leading to LUTS associated with obesity/metabolic syndrome.

physiology↗

bioRxiv2024

Suspended Tissue Open Microfluidic Patterning (STOMP)

Free-standing tissue structures tethered between pillars are powerful mechanobiology tools for studying cell contraction. To model interfaces ubiquitous in natural tissues and upgrade existing single-region suspended constructs, we developed Suspended Tissue Open Microfluidic Patterning (STOMP), a method to create multi-regional suspended tissues. STOMP uses open microfluidics and capillary pinning to pattern subregions within free-standing tissues, facilitating the study of complex tissue interfaces, such as diseased-healthy boundaries (e.g., fibrotic-healthy) and tissue-type interfaces (e.g., bone-ligament). We observed altered contractile dynamics in fibrotic-healthy engineered heart tissues compared to single-region tissues and differing contractility in bone-ligament enthesis constructs compared to single-tissue periodontal ligament models. STOMP is a versatile platform - surface tension-driven patterning removes material requirements common with other patterning methods (e.g., shear-thinning, photopolymerizable) allowing tissue generation in multiple geometries with native extracellular matrices and advanced 4D materials. STOMP combines the contractile functionality of suspended tissues with precise patterning, enabling dynamic and spatially controlled studies.

bioengineering↗

bioRxiv2024

A spatially-resolved blueprint of the developing human lung reveals a basal cell population regulated by a WNT-driven niche

Organs are composed of diverse cell types that change across space and time during development. To interrogate this diversity, we micro-dissected developing human lungs along the proximal-distal axis during the late pseudoglandular stage and generated an integrated analysis of single-nucleus sequencing and spatial transcriptomics, creating a cellularly-resolved atlas of the lung. These rich datasets revealed positional niches and cellular heterogeneity along the proximal-distal axis, including the identification of a unique population of TP63+ basal cells, the primary stem cell of the airway, marked by expression of LGR5 and LGR6. Analysis of the LGR5+ basal cell niche and functional experiments with primary organoid models suggest a tonic level of WNT pathway activity in LGR5+ basal cells that is potentiated by mesenchyme-derived R-SPONDIN. We found that basal cell self-renewal is enhanced by WNT activity, suggesting that the WNT pathway plays a previously unappreciated but critical role in airway stem cell maintenance during human development. These results enhance our fundamental understanding of the positional and cellular heterogeneity in the developing human lungs and begin to reveal unique niches that maintain homeostasis throughout the lung.

developmental biology↗

bioRxiv2024

Biomarker Identification by Proteomic Analysis of Vitreous Humor and Plasma in Diabetic Retinopathy

ImportanceIdentify detectable plasma and/or vitreous signals to potentially predict diabetic retinopathy (DR) progression for earlier disease intervention. ObjectiveTo determine the mediators and potential disease progression biomarkers of DR in vitreous humor (VH) and plasma samples using the SomaScan proteome profiling platform. DesignDifferential expression analysis was conducted on VH and plasma samples using the SomaScan Assay. SettingA non-interventional study conducted to collect and analyze VH and plasma samples from patients with diabetic retinopathy. ParticipantsSamples from DR (60 nonproliferative diabetic retinopathy/NPDR, 60 proliferative diabetic retinopathy/PDR) and 60 control patients were collected. Main outcomes and MeasuresDifferentially expressed proteins between disease and control groups were identified. Pathway enrichment analysis was conducted to identify significantly perturbed pathways in DR. Finally, a random forest model was used to identify predictive biomarkers of disease progression. ResultsSomaScan v3 is a pooled aptamer hybridization assay using 5080 SOMAmers to probe over 4100 proteoforms in VH and plasma samples from 3 groups (control, NPDR, and PDR). The most profound protein content change was observed in the VH samples of PDR patients, while minimal changes were measured in plasma samples, highlighting the regionality of PDR pathogenesis. Many key molecules and molecular pathways such as VEGF-A, erythropoietin, and inflammation-associated proteins implicated in DR were significantly affected in the VH of PDR patients. In addition to the classic pathways (hypoxia, immune response, mTORC1 signaling) known to be involved in PDR, novel signaling pathways, including HEME metabolism and adipogenesis, were identified in VH samples. Application of a machine learning algorithm identified a panel of plasma PDR predictive biomarkers and revealed SCARA5 as the top one based on the largest average Gini decrease in the model. ConclusionOur study identified profound alteration of protein expression and molecular pathways in the VH of PDR patients, supporting the key role of local pathogenic changes in DR progression compared to systemic factors. Although the systemic changes related to DR were small, a few disease progression predictive candidate biomarkers (SCARA5, PTK7, FAM3Band FAM3D) were identified, prompting further investigation. Key PointsQuestion: Are plasma/ vitreous humor (VH) proteins predictive of diabetic retinopathy (DR) progression? Findings: This study identifies substantial protein changes in the VH of proliferative diabetic retinopathy (PDR) patients, while early nonproliferative DR (NPDR) patients show minimal change. We identify multiple proteins linked to angiogenesis, inflammation, immune cells (microglia/macrophage/neutrophil), and leukostasis associated with PDR and reveal a potential plasma panel of disease progression (from NPDR to PDR) biomarkers (SCARA5, PTK7, FAM3B, FAM3D). Meaning: Identified disease progression predictive biomarkers permits potential development of prognostic tools to identify individuals most at risk for PDR progression and offering reduced disease burden by earlier intervention.

physiology↗

bioRxiv2024

Reduced ZMPSTE24 expression leads to prelamin accumulation and development of steatosis in MASLD patients.

Mutations of nuclear lamina-associated proteins LMNA and ZMPSTE24 have been associated with fatty liver. We report that the changes at the nuclear envelope we described in MASLD patients are caused by downregulation of ZMPSTE24, an enzyme that processes prelamin to mature lamin A. In addition, Zmpste24 mutant mice develop hepatic steatosis and exhibit upregulation of p53 target genes. p53 activity is also induced in genes differentially expressed in MASLD patients. Furthermore, p53 regulates genes bound by FOXA2 in these individuals, corresponding to observations in Zmpste24 mutants. In contrast, expression of glucose and insulin regulated genes is reduced in MASLD patients, suggesting altered glucose metabolism and insulin resistance, hallmarks of type 2 diabetes (T2D). Hence, our genomics data show that MASLD patients with severe steatosis but yet without MASH are already suffering from severe metabolic consequences and underscore the need for treatment at this stage of the disease.

physiology↗

bioRxiv2024

Smad4 Loss in the Mouse Intestinal Epithelium Alleviates the Pathological Fibrotic Response to Injury in the Colon

Mucosal healing is associated with better clinical outcomes in patients with inflammatory bowel diseases (IBDs). Unresolved injury and inflammation, on the other hand, increases pathological fibrosis and the predisposition to cancer. Loss of Smad4, a tumor suppressor, is known to increase colitis-associated cancer in mouse models of chronic IBD. Since common biological processes are involved in both injury repair and tumor growth, we sought to investigate the effect of Smad4 loss on the response to epithelial injury. To this end, Smad4 was knocked out specifically in the intestinal epithelium and transcriptomic and morphological changes compared between wild type mice and Smad4 knock out mice after DSS-induced injury. We find that Smad4 loss alleviates pathological fibrosis and enhances mucosal repair. The transcriptomic changes specific to epithelium indicate molecular changes that affect epithelial extracellular matrix (ECM) and promote enhanced mucosal repair. These findings suggest that the biological processes that promote wound healing alleviate the pathological fibrotic response to DSS. Therefore, these mucosal repair processes could be exploited to develop therapies that promote normal wound healing and prevent fibrosis. NEW AND NOTEWORTHYWe show that transcriptomic changes due to Smad4 loss in the colonic epithelium alleviates the pathological fibrotic response to DSS in an IBD mouse model of acute inflammation. Most notably, we find that collagen deposition in the epithelial ECM, as opposed to that in the lamina propria, correlates with epithelial changes that enhance wound healing. This is the first report on a mouse model providing alleviated fibrotic response in a DSS-IBD mouse model in vivo.

cell biology↗

bioRxiv2024

Systematic characterization of protein structural features of alternative splicing isoforms using AlphaFold 2

Alternative splicing is an important cellular process in eukaryotes, altering pre-mRNA to yield multiple protein isoforms from a single gene. However, our understanding of the impact of alternative splicing events on protein structures is currently constrained by a lack of sufficient protein structural data. To address this limitation, we employed AlphaFold 2, a cutting-edge protein structure prediction tool, to conduct a comprehensive analysis of alternative splicing for approximately 3,000 human genes, providing valuable insights into its impact on the protein structural. Our investigation employed state of the art high-performance computing infrastructure to systematically characterize structural features in alternatively spliced regions and identified changes in protein structure following alternative splicing events. Notably, we found that alternative splicing tends to alter the structure of residues primarily located in coils and beta-sheets. Our research highlighted a significant enrichment of loops and highly exposed residues within human alternatively spliced regions. Specifically, our examination of the Septin-9 protein revealed potential associations between loops and alternative splicing, providing insights into its evolutionary role. Furthermore, our analysis uncovered two missense mutations in the Tau protein that could influence alternative splicing, potentially contributing to the pathogenesis of Alzheimers disease. In summary, our work, through a thorough statistical analysis of extensive protein structural data, sheds new light on the intricate relationship between alternative splicing, evolution, and human disease.

bioinformatics↗

bioRxiv2023

Coordinated differentiation of human intestinal organoids with functional enteric neurons and vasculature

Human intestinal organoids (HIOs) derived from human pluripotent stem cells co-differentiate both epithelial and mesenchymal lineages in vitro but lack important cell types such as neurons, endothelial cells, and smooth muscle. Here, we report an in vitro method to derive HIOs with epithelium, mesenchyme, enteric neuroglial populations, endothelial cells, and organized smooth muscle in a single differentiation, without the need for co-culture. When transplanted into a murine host, these populations expand and organize to support organoid maturation and function. Functional experiments demonstrate enteric nervous system function, with HIOs undergoing peristaltic-like contractions, suggesting the development of a functional neuromuscular unit. HIOs also form functional vasculature, demonstrated in vitro using microfluidic devices to introduce vascular-like flow, and in vivo following transplantation, where HIO endothelial cells anastomose with host vasculature. Collectively, we report an in vitro model of the human gut that simultaneously co-differentiates epithelial, stromal, endothelial, neural, and organized muscle populations.

bioengineering↗

bioRxiv2023

Eugenol mimics exercise to promote skeletal muscle fiber remodeling and myokine IL-15 expression by activating TRPV1 channel

Metabolic disorders are highly prevalent in modern society. Exercise mimetics are defined as pharmacologic compounds that can produce the beneficial effects of fitness. Recently, there has been increased interest in the role of eugenol and transient receptor potential vanilloid 1 (TRPV1) in improving metabolic health. The aim of this study was to investigate whether eugenol acts as an exercise mimetic by activating TRPV1. Here, we showed that eugenol improved endurance capacity, caused the conversion of fast to slow muscle fibers, and promoted white fat browning and lipolysis in mice. Mechanistically, eugenol promoted muscle fiber type transformation by activating TRPV1-mediated CaN signaling pathway. Subsequently, we identified IL-15 as a myokine that is regulated by the CaN/Nuclear factor of activated T cells cytoplasmic 1 (NFATc1) signaling pathway. Moreover, we found that TRPV1-mediated CaN/NFATc1 signaling, activated by eugenol, controlled IL-15 levels in C2C12 myotubes. Our results suggest that eugenol may act as an exercise mimetic to improve metabolic health via activating the TRPV1-mediated CaN signaling pathway.

molecular biology↗

bioRxiv2023

Leucine alleviates cytokine storm syndrome by regulating macrophage polarization via the mTORC1/LXRα signaling pathway

Cytokine storms are associated with severe pathological damage and death in some diseases. Excessive activation of M1 macrophages and the subsequent secretion of pro-inflammatory cytokines are a major cause of cytokine storms. Therefore, promoting the polarization of M2 macrophages to restore immune balance is a promising therapeutic strategy for treating cytokine storm syndrome (CSS). This study was aimed at investigating the potential protective effects of leucine on lipopolysaccharide (LPS)-induced CSS in mice and exploring the underlying mechanisms. CSS was induced by LPS administration in mice, which were concurrently administered leucine orally. In vitro, BMDMs were polarized to M1 and M2 phenotypes with LPS and IL-4, respectively, and treated with leucine. Leucine decreased mortality in mice treated with lethal doses of LPS. Specifically, leucine decreased M1 polarization and promoted M2 polarization, thus diminishing pro-inflammatory cytokine levels and ameliorating CSS in mice. Further studies revealed that leucine induced macrophage polarization through the mechanistic target of rapamycin complex 1 (mTORC1)/liver X receptor (LXR) pathway, which synergistically enhanced the expression of the IL-4-induced M2 marker Arg1 and subsequent M2 polarization. In summary, this study revealed that leucine ameliorates CSS in LPS mice by promoting M2 polarization through the mTORC1/LXR/Arg1 signaling pathway. Our findings indicate that a fundamental link between metabolism and immunity contributes to the resolution of inflammation and the repair of damaged tissues.

immunology↗

bioRxiv2023

SpatialScope: A unified approach for integrating spatial and single-cell transcriptomics data using deep generative models

The rapid emergence of spatial transcriptomics (ST) technologies are revolutionizing our under-standing of tissue spatial architecture and their biology. Current ST technologies based on either next generation sequencing (seq-based approaches) or fluorescence in situ hybridization (image-based approaches), while providing hugely informative insights, remain unable to provide spatial characterization at transcriptome-wide single-cell resolution, limiting their usage in resolving detailed tissue structure and detecting cellular communications. To overcome these limitations, we developed SpatialScope, a unified approach to integrating scRNA-seq reference data and ST data that leverages deep generative models. With innovation in model and algorithm designs, SpatialScope not only enhances seq-based ST data to achieve single-cell resolution, but also accurately infers transcriptome-wide expression levels for image-based ST data. We demonstrate the utility of SpatialScope through comprehensive simulation studies and then apply it to real data from both seq-based and image-based ST approaches. SpatialScope provides a spatial characterization of tissue structures at transcriptome-wide single-cell resolution, greatly facilitating the downstream analysis of ST data, such as detection of cellular communication by identifying ligand-receptor interactions from seq-based ST data, localization of cellular subtypes, and detection of spatially differently expressed genes.

bioinformatics↗