Biology subjects

Nie, Y.

Publications and source records attributed to Nie, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Matrix stiffness shapes immunometabolic states and response to PD-1 blockade in gastric cancer

The extracellular matrix of solid tumors exhibits spatially heterogeneous stiffness, yet how matrix stiffness shapes antitumor immunity in gastric cancer (GC) remains unclear. Here, we integrated anti-PD-1 clinical cohorts, GC specimens, single-cell and spatial transcriptomic analyses, a syngeneic mouse model, and tunable-stiffness hydrogels to clarify the immunological consequences of matrix stiffness. High matrix stiffness was associated with collagen accumulation and immune exclusion, while higher stiffness-associated transcriptional scores were related to poorer response to PD-1 blockade. Matrix softening markedly reshaped the immune microenvironment and enhanced the efficacy of PD-1 blockade. Mechanistically, stiff matrices promoted F-actin remodeling and YAP nuclear enrichment, driving LDHA-dependent glycolytic reprogramming in GC cells that further impaired the effector function of CD8 T cells. Intriguingly, matrix softening was accompanied by enhanced IFN-{gamma}-responsive PD-L1 expression in GC cells, consistent with adaptive immune resistance that may contribute to the limited antitumor effects of matrix softening alone. These findings suggest that matrix remodeling alleviates spatial and metabolic constraints on antitumor immunity, providing a preclinical rationale for combining matrix softening with PD-1 blockade in GC.

cancer biology↗

bioRxiv2026

Single-cell Transcriptomics Analyses Reveal Specialized Microglial Subsets with Oligodendrocyte-like Signatures

BackgroundMicroglial heterogeneity is a fundamental feature of brain homeostasis and pathology. The purpose of this study was to investigate the complexity of microglial plasticity by characterizing specialized oligodendrocyte-like microglial subsets. MethodsThe study was performed utilizing single-cell transcriptomics analyses and immunofluorescence staining to identify and profile microglial subpopulations. Additionally, spatial transferring and morphological analyses were conducted to determine the anatomical distribution and structural features of these specific cells. ResultsWe identified a distinct microglial subset termed dual-phenotype microglia (DPM), which co-expresses microglial and oligodendrocyte markers. DPM consisted of two subtypes with distinct functions: myelin-associated DPM (mDPM) and neuron-associated DPM (nDPM). Spatial and morphological evaluations revealed that mDPMs were sparsely distributed across the whole brain and exhibited a highly ramified architecture, whereas nDPMs were enriched in the hippocampal dentate gyrus. Mechanistically, we found that mDPM function was driven by the Sox10 regulon to modulate myelin maintenance and axonal ensheathment, while nDPM was orchestrated by Glis2, facilitating essential neuron-glia crosstalk and synaptic regulation. Furthermore, we demonstrated that nDPM and mDPM were predicted to undergo significant alterations in multiple sclerosis and Alzheimers disease. Notably, mDPMs were selectively enriched in active multiple sclerosis lesions, revealing that DPM were closely related to neuropsychiatric disorders. ConclusionsBy comprehensively characterizing the morphology, molecular signatures, and spatial logic of these oligodendrocyte-like microglial subsets, our study elucidated the complexity of microglial plasticity. These findings provided new insights into their diverse roles in central nervous system health and disease. Graphical abstractIdentification, Molecular Profiling, and Functional Modeling of Dual-Phenotype Microglia (DPM). (1) Discovery: Identification of the dual-phenotype microglia (DPM) population through single-cell transcriptomics. (2) Molecular Signatures: The transcriptomic identity of DPM subtypes is governed by specific regulatory networks. (3) Distribution & Pathology: Spatial mapping reveals divergent anatomical logic and disease relations for DPM subtypes. (4) Mechanism/Theory: A proposed functional model of mDPMs as "metabolic relay" and support units. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/724239v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@b7db1dorg.highwire.dtl.DTLVardef@9265e7org.highwire.dtl.DTLVardef@1605d82org.highwire.dtl.DTLVardef@19b048f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Ketone body beta-hydroxybutyrate restores neuronal Tau proteostasis via ketolysis-independent mechanism

Metabolic interventions that induce ketosis, including ketogenic diets, caloric restriction, intermittent fasting, and exercise, show promise in the treatment of Alzheimers disease (AD) and related tauopathies. {beta}-hydroxybutyrate ({beta}HB), the primary ketone body produced during ketosis, reproduces key features of these metabolic interventions, but the molecular mechanism underlying its neuroprotective properties is not fully understood. Here, we demonstrate that a {beta}HB precursor diet is sufficient to ameliorate Tau pathophysiology in a tauopathy mouse model. Furthermore, across in vitro, ex vivo, and in vivo models, we find that {beta}HB enhances neuronal Tau proteostasis and reduces Tau aggregation and secretion. Importantly, these effects are independent of {beta}HBs oxidation for ATP production, as its ketolysis-resistant enantiomer reproduces these benefits, indicating that ketolysis is dispensable for these effects. Overall, these data position {beta}HB as a novel therapeutic avenue for AD and tauopathy and elucidate a novel mechanism of action of metabolic interventions in neurodegenerative disease.

neuroscience↗

bioRxiv2026

Fezf2 regulates differentiation of Aire-expressing and post-Aire mimetic epithelial populations maintaining thymic homeostasis

Fezf2 has been proposed to serve principally as a transcriptional regulator of broad self-antigen expression in medullary thymic epithelial cells (mTECs). Here, we demonstrate an additional function for Fezf2 as a developmental regulator of TEC lineage commitment. Fezf2 deficiency in the thymus led to a relative expansion of lung mimetic and Ccl21+ immature mTECs at the expense of MHCII-hi Aire-expressing and all other mimetic populations. Consistent with this, the disruption of mTEC development had functional consequences, including alterations in tuft-associated iNKT polarization and microfold-associated B-cell class switching. In addition, high-resolution transcriptomics revealed that Fezf2 and Aire regulate distinct transcriptional programs, with Fezf2 driving both activation and repression of a more limited set of tissue-restricted genes compared to the broad gene activation program observed for Aire. Pure transcriptional repression at Fezf2 target loci was sufficient to partially rescue mTEC development in global Fezf2-/- (tKO) mice, potentially through suppression of Lifr expression and modulation of downstream Stat3 signaling tone. These results expand our understanding of Fezf2 in mTEC biology, highlighting transcriptional repression as a required functional facet for adult steady-state lineage patterning across the mTEC compartment.

immunology↗

bioRxiv2025

Perturbational single-cell profiling of patient tumors defines lineage- and context-specific programs of innate immune resistance

AbstractDespite promise in preclinical models, most immuno-oncology drug candidates fail in clinical trials. These failures reflect limitations in our ability to directly model the response of human tumor and immune cells to immunotherapies. To address this gap and test the effect of innate immune agonists, we developed PERCEPT, an approach that uses ex vivo perturbational single-cell RNA sequencing to compare the response of immunomodulatory treatments with unstimulated controls directly in patient samples. Using PERCEPT, we tested cytokines and innate immune agonists in melanoma and Merkel cell carcinoma (MCC) and identified the dsRNA mimetic, RIG-I agonist, Stem Loop RNA (SLR) 14 as a powerful inducer of anti-viral states and enhancer of T cell activation. We compared transcriptional responder and non-responder patient samples and identified midkine (MDK), a multifunctional cytokine, as a potent repressor of IFN signaling in both tumor and immune cells. MDK expression dampened MHC-I presentation in human tumor cells and reduced activation of antigen-presenting cells, disrupting tumor immunity at multiple levels. In contrast to prior studies, we identified MDK as specifically enriched in neuroendocrine cancers such as MCC and small cell lung cancer compared with melanoma, suggesting the importance of lineage- and context-specific targeting. Our results demonstrate the utility of high-dimensional controlled perturbation of patient samples to identify mechanisms of innate immune response and resistance and demonstrate an actionable path towards clinical development of MDK-inhibiting therapies including FDA-approved ALK inhibitors in neuroendocrine cancers.

cancer biology↗

bioRxiv2025

Longitudinal analysis of bacterial community dynamics in normal hospital ward following patient occupancy

The hospital microbiome significantly influences patient recovery and clinical outcomes. However, the dynamics of microbial colonization and transmission following initial patient occupancy remain poorly understood. Here, we employed 16S rRNA gene amplicon sequencing to investigate bacterial community dynamics on surfaces within neurosurgery ward and patients as a new hospital became operational. Our results showed that bacterial colonization in hospital wards follows distinct site-specific patterns, after hospital opening, alpha diversity was significantly increased on floors and drawer handles but decreased on bedrails and faucet handles compared to preopening. Beta diversity analysis showed that surfaces frequently contacted by patients exhibited the greatest compositional turnover, such as bedrails, drawer handles, and faucet handles, bacterial communities in after-opening were more homogeneous across sites than preopening, indicating potential bacterial transmission. Moreover, we found following patient admission, patient hand-derived microbiomes exert a significant influence on the bacterial communities in hospital wards, with a particularly pronounced impact on bedrails. Additionally, the potential disease risk of bedrails in post-opening was significantly higher than preopening. Taken together, these findings underscore the critical role of human contact in shaping hospital microbiomes and highlight the importance of targeted infection control strategies to mitigate pathogen transmission.

bioinformatics↗

bioRxiv2025

Understanding Foundation Models in Digital Pathology: Performance, Trade-offs, and Model-Selection Recommendations

The rapid proliferation of digital pathology foundation models (FMs), spanning widely in architectural scales and pre-training datasets, poses a significant challenge in selecting the optimal model for a specific clinical application. To systematically evaluate these performance trade-offs, we conducted a comprehensive benchmark of five FMs, stratified from small to huge scales, across a diverse suite of whole slide image (WSI) and region of interest (ROI) tasks. Our findings demonstrate that model superiority is strongly task-specific, challenging the assumption that a larger scale universally offers an advantage. For instance, while the huge-scale Virchow2 model excelled at WSI metastasis detection, the small-scale Lunit model was superior for fine-grained lung subtype classification. This trend was even more pronounced in survival analysis, where smaller models outperformed their massive-scale counterparts, a phenomenon we hypothesize is linked to potential information bottlenecks within downstream aggregation models. Notably, the base-scale Kaiko model consistently provided a compelling balance, delivering competitive accuracy, superior stability in prognostic tasks, and higher computational efficiency. Our analysis suggests that the optimal FM is not necessarily the largest, but one whose scale, data composition, and training strategy are best aligned with the specific task. This work offers a practical, evidence-based framework for balancing performance, stability, and real-world deployment costs in computational pathology.

pathology↗

bioRxiv2025

Total variation of quantitative phase map reveals cellular Young's modulus

Collective cell migration is a fundamental physiological process involved in wound healing, development, and tissue regeneration. Though the role of the environmental stiffness in collective cell migration has been extensively investigated, the effects of cellular stiffness have been less studied due to the lack of high-throughput in situ methods for characterizing cellular stiffness. Here, we characterize the cellular Youngs modulus in situ with a large field of view and in real time using use quantitative phase microscopy. We found that standard deviation and total variation of the phase are inversely related to the cellular Youngs modulus, while the total variation of phase has finer mechanical resolution. Integrating the total variation of phase with cell segmentation algorithms, we efficiently analyzed the cellular Youngs modulus for cells in a monolayer. Using this system, we found the cells at the wound frontier are much softer than that of the cells in the inner region of monolayer in in vitro wound healing assay. At single cellular level, the Youngs modulus of leader cells, boundary cells, and inner cells are significantly distinct from each other. To conclude, our method would help elucidate the essential role of cellular stiffness in collective cell migration and has the potential to further benefit the progress of mechanobiology.

biophysics↗

bioRxiv2025

A complete and near-perfect rhesus macaque reference genome: lessons from subtelomeric repeats and sequencing bias

A truly complete, telomere-to-telomere (T2T), and error-free reference genome remains a foundational resource--and long-standing goal--for unbiased comparative and functional genomics. While recent T2T assemblies of humans and other primates have made substantial progress, most still contain thousands of base-level errors, particularly within highly repetitive regions. Here, we present T2T-MMU8v2.0, a near-perfect T2T assembly of the rhesus macaque (Macaca mulatta), representing the highest base-level accuracy reported in a primate genome to date. By employing an optimized ONT-only assembly strategy, we identify subtelomeric satellite-rich regions as the principal bottleneck to improving assembly quality, owing to technological biases in long-read platforms and limitations in current hybrid assembly frameworks. We discover 268 previously unannotated repeat families and resolve [~]8 Mbp of SATR satellite arrays, with over 99-fold enrichment in historically misassembled subtelomeric regions. These satellites form four distinct genomic architectures, each with unique SATR satellite composition, segmental duplication organization, and epigenetic signatures, distinct from the subtelomeric architectures observed in hominid genomes. Notably, in contrast to the largely gene-poor subtelomeric regions in African hominids, the SATR architectures in macaques harbor 58 actively transcribed genes, supported by open chromatin and expression data, suggesting gene innovation within these repetitive regions. Functionally, T2T-MMU8v2.0 improves read mappability and accuracy across sequencing platforms, and results in a 19% improvement of transcription start site enrichment scores and 5,821 additional chromatin accessibility peaks on average, thereby enhancing variant detection, regulatory annotation, and transcriptomic resolution in population genetics or single-nucleus studies. Together, this work establishes a new benchmark for genomics, offers a roadmap for resolving complex repetitive regions, and reveals previously unrecognized features of subtelomeric genome structure and evolution.

genomics↗

bioRxiv2025

Genomic Touchstone: Benchmarking Genomic Language Models in the Context of the Central Dogma

The emergence of genomic language models (gLMs) has revolutionized the analysis of genomic sequences, enabling robust capture of biologically meaningful patterns from DNA sequences for an improved understanding of human genome-wide regulatory programs, variant pathogenicity and therapeutic discovery. Given that DNA serves as the foundational blueprint within the central dogma, the ultimate evaluation of a gLM is its ability to generalize across this entire biological cascade. However, existing evaluations lack this holistic and consistent framework, leaving researchers uncertain about which model best translates sequence understanding into downstream biological prediction. Here we present Genomic Touchstone, a comprehensive benchmark designed to evaluate gLMs across 36 diverse tasks and 88 datasets structured along the central dogmas modalities of DNA, RNA, and protein, encompassing 5.34 billion base pairs of genomic sequences. We evaluate 34 representative models encompassing transformers and convolutional neural networks, as well as emerging efficient architectures such as Hyena and Mamba. Our analysis yield four key insights. First, gLMs achieve comparable or superior performance on RNA and protein tasks compared to models pretrained on these molecules. Second, transformer-based models continue to lead in overall performance, yet efficient sequence models show promising task-specific capabilities and deserve further exploration. Third, the scaling behavior of gLMs remains incompletely understood. While longer input sequences and more diverse pretraining data consistently improve performance, increases in model size do not always translate into better results. Fourth, pretraining strategies, including the choice of training objectives and the composition of pretraining corpora, exert substantial influence on downstream generalization across different genomic contexts. Genomic Touchstone establishes a unified evaluation framework tailored to human genomics. By spanning multiple molecular modalities and biological tasks, it offers a valuable foundation for guiding future gLM design and understanding model generalizability in complex biological contexts.

bioinformatics↗

bioRxiv2025

Allosteric modulation of dimeric GPR3 by ligands in the dimerization interface

Class C G-protein coupled receptors (GPCRs) are widely recognized to function as a dimer, whereas the existence, molecular mechanisms and functional importance of dimerization in class A GPCRs remain poorly explored. GPR3, GPR6 and GPR12 are closely related to cannabinoid receptors, and are associated with neurogenerative diseases such as Parkinsons and Alzheimers diseases. Here, we determined cryo-EM structures of GPR3-Gs complex in the active state and GPR3 alone in the inactive state. We observe that GPR3 forms symmetric dimers in both states, with the dimerization interface primarily involving TM5 and TM6. Upon activation, GPR3 undergoes an outward movement of TM6 and an inward movement of TM7, alongside stabilization of helix 8, which is disordered in the inactive state. Functionally, GPR3 dimerization attenuates Gs signaling. Furthermore, we identify AF64394 as a negative allosteric modulator that targets the GPR3 dimerization interface and allosterically shifts the -helical structure of ICL2 into a random coil structure, thereby impairing Gs coupling. Our findings provide structural and mechanistic insights into class A GPCR dimerization, offering potential therapeutic strategies targeting the dimerization interface of these receptors.

biochemistry↗

bioRxiv2025

Metagenomics reveals potential interactions between CPR bacteria and their phages in groundwater ecosystems

Candidate phyla radiation (CPR) is a vast lineage composed of bacteria with ultra-small size, streamlined genomes, notable defects in core metabolic potential and symbiotic lifestyle, which are widely detected in groundwater ecosystems. Increasing attention has focused on the physiological and ecological significance of CPR bacteria, while the potential interactions between CPR bacteria and their phages still need more exploration. Here, we collected 82 groundwater metagenomic datasets and further derived 1,162 phages with the potential to infect 2,439 groundwater CPR metagenome-assembled genomes (MAGs). Notably, the groundwater CPR MAGs were predominantly infected by temperate phages, and the abundance profiles of phage-CPR interactions in groundwater ecosystems supported the Piggybacking the Winner (PtW) hypothesis, suggesting that lysogenic infection was a strategy co-evolved by CPR bacteria and their phages in groundwater ecosystems. Intriguingly, the groundwater CPR phages encoded various auxiliary metabolic genes (AMGs) that might promote symbiotic lifestyle and metabolic potential of host CPR MAGs. These included AMGs associated with concanavalin A-like lectin/glucanases superfamily and O-Antigen nucleotide sugar biosynthesis, which could enhance surface adhesion of host CPR MAGs. Moreover, AMGs related to ABC transport system and P-type transporter could strengthen metabolic exchange and uptake of essential nutrients from surroundings. Additionally, AMGs involved in various metabolic pathways might alleviate metabolic deficiencies in host CPR MAGs. This study elucidated the mechanisms of phage-CPR interactions and the potential roles of phages in modulating the physiology and ecology of CPR bacteria within groundwater ecosystems.

microbiology↗

bioRxiv2024

Incomplete lineage sorting of segmental duplications defines the human chromosome 2 fusion site early during African great ape speciation

All great apes differ karyotypically from humans due to the fusion of chromosomes 2a and 2b, resulting in human chromosome 2. Yet, the structure, function, and evolutionary history of the genomic regions associated with this fusion remain poorly understood. Here, we analyze finished telomere-to-telomere chromosomes in great apes and macaques to show that the fusion was associated with multiple pericentric inversions, segmental duplications (SDs), and the rapid turnover of subterminal repetitive DNA. We characterized the fusion site at single-base-pair resolution and identified three distinct SDs that originated more than 5 million years ago. These three distinct SDs were differentially distributed among African great apes as a result of incomplete lineage sorting (ILS) and lineage-specific duplication. Most conspicuously, one of these SDs shares homology to a hypomethylated SD spacer sequence present in hundreds of copies in the subterminal heterochromatin of chimpanzees and bonobos. The fusion in human was accompanied by a systematic degradation of the three divergent -satellite arrays representing the ancestral centromere creating five distinct structural haplotypes in humans. CRISPR/Cas9-mediated depletion of the fusion site in human cell lines significantly alters the expression of 108 genes, indicating a potential regulatory consequence to this human-specific karyotypic change.

evolutionary biology↗

bioRxiv2024

Unraveling SARS-CoV-2 Host-Response Heterogeneity through Longitudinal Molecular Subtyping

Hospitalized COVID-19 patients exhibit diverse immune responses during acute infection, which are associated with a wide range of clinical outcomes. However, understanding these immune heterogeneities and their links to various clinical complications, especially long COVID, remains a challenge. In this study, we performed unsupervised subtyping of longitudinal multi-omics immunophenotyping in over 1,000 hospitalized patients, identifying two critical subtypes linked to mortality or mechanical ventilation with prolonged hospital stay and three severe subtypes associated with timely acute recovery. We confirmed that unresolved systemic inflammation and T-cell dysfunctions were hallmarks of increased severity and further distinguished patients with similar acute respiratory severity by their distinct immune profiles, which correlated with differences in demographic and clinical complications. Notably, one critical subtype (SubF) was uniquely characterized by early excessive inflammation, insufficient anticoagulation, and fatty acid dysregulation, alongside higher incidences of hematologic, cardiac, and renal complications, and an elevated risk of long COVID. Among the severe subtypes, significant differences in viral clearance and early antiviral responses were observed, with one subtype (SubC) showing strong early T-cell cytotoxicity but a poor humoral response, slower viral clearance, and greater risks of chronic organ dysfunction and long COVID. These findings provide crucial insights into the complex and context-dependent nature of COVID-19 immune responses, highlighting the importance of personalized therapeutic strategies to improve both acute and long-term outcomes.

immunology↗

bioRxiv2024

Singular Odorant Receptor Expression Orchestrated by Promoter Activation Specificity in Apis Mellifera Olfactory Sensory Neurons

Honeybee, positioned as an outgroup of flies and mosquitos, have exhibited intriguing duplications and expansions of OR genes in genomic studies. However, little is known about how the OR genes are expressed and regulated in honeybee olfactory sensory neurons (OSNs). In this study, we utilized a single-cell multi-omics approach to profile the transcriptome and chromatin accessibility in Apis mellifera antennal nuclei, aiming to elucidate OR gene expression and its underlying regulatory mechanisms. Our systematical analysis unveiled a similar singular expression pattern of ligand-specific receptors in Apis mellifera OSNs, parallel with those observed in Drosophila melanogaster. Mechanistically, we discovered that promoter activation of OR genes orchestrates receptor expression patterns. For instance, although multiple adjacent OR genes are co-expressed with a single active promoter through polycistronic transcription, only the first OR gene could produce functional receptor protein, as supported by transcriptome quantification in OSNs. Additionally, we found that co-expression of receptor proteins might occur only when co-expressed OR genes possess multiple accessible promoters. This scenario is less common than expected, considering the number and evolutionary age of OR genes in Apis mellifera, suggesting a selection favoring the specialization of rapidly expanded OR genes in Apis mellifera. Overall, our study provides significant insights into the insect olfaction system and the regulatory mechanisms of OR genes expression.

neuroscience↗

bioRxiv2024

Nuclear speckle rejuvenation alleviates proteinopathies at the expense of YAP1

Current treatments targeting individual protein quality control pathways have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common druggable target capable of global proteostasis modulation. Building upon our prior research establishing nuclear speckles as pivotal membrane-less organelles for transcriptional control of proteostasis, we aim to alleviate proteinopathies through nuclear speckle rehabilitation. We identified pyrvinium pamoate as a nuclear speckle rehabilitator that enhances protein quality control gene expression and suppresses YAP1 transcriptional activity via decreasing the surface/interfacial tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, nanomolar pyrvinium pamoate protected against retinal degeneration and tauopathy mainly by promoting autophagy and ubiquitin-proteasome activity in a SON-dependent manner without causing stress. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity were observed in human tauopathies. Our study provides proof-of-principle of targeting nuclear speckles to ameliorate proteinopathies.

cell biology↗

bioRxiv2024

Restricted intake of sulfur-containing amino acids reversed the hepatic injury induced by excess Desulfovibrio through gut-liver axis

Gut-liver axis has been a study focus for liver diseases. Diet is a key player in influencing the gut microbiota. However, the effect of different dietary patterns on gut microbiota and liver functions remains unclear. Here, we used mouse standard chow and purified diet to mimic two common human dietary patterns: healthy grain and planted-based diet and Western style diet, respectively and explored their impacts on the gut microbiota and liver. Gut microbiota experienced a great shift with notable increase in Desulfovibrio, gut bile acid (BA) concentration elevated significantly, and liver inflammation was observed in mice fed with the purified diet. Liver inflammation due to translocation of toxic lipopolysaccharides (LPS) and hydrophobic BAs from the damaged gut barrier was also observed in mice fed with the chow diet after receiving Desulfovibrio desulfuricans ATCC 29577 (DSV). Restricted intake of sulfur-containing amino acids reversed the liver injury due to excess Desulfovibrio through lowering the gut BA concentration and enhancing the hepatic antioxidant and detoxifying ability. Ex vivo fermentation of human fecal microbiota with primary BAs also demonstrated that DSV enhanced production of secondary BAs. Germ-free mice had higher concentration of both conjugated and unconjugated primary BAs in their gut after receiving DSV.

microbiology↗

bioRxiv2023

Pharmacologically inducing regenerative cardiac cells by small molecule drugs

Adult mammals, unlike some lower organisms, lack the ability to regenerate damaged hearts through cardiomyocytes (CMs) dedifferentiation into cells with regenerative capacity. Developing conditions to induce such naturally unavailable cells with potential to proliferate and differentiate into CMs, i.e., regenerative cardiac cells (RCCs), in mammals will provide new insights and tools for heart regeneration research. In this study, we demonstrate that a two-compound combination, CHIR99021 and A-485 (2C), effectively induces RCCs from human embryonic stem cell (hESC)-derived TNNT2+ CMs in vitro, as evidenced by lineage tracing experiments. Functional analysis shows that these RCCs express a broad spectrum of cardiogenesis genes and have the potential to differentiate into functional CMs, endothelial cells (ECs), and smooth muscle cells (SMCs). Importantly, similar results were observed in neonatal rat CMs both in vitro and in vivo. Remarkably, administering 2C in adult mouse hearts significantly enhances survival and improves heart function post-myocardial infarction. Mechanistically, CHIR99021 is crucial for the transcriptional and epigenetic activation of genes essential for RCC development, while A-485 primarily suppresses H3K27Ac and particularly H3K9Ac in CMs. Their synergistic effect enhances these modifications on RCC genes, facilitating the transition from CMs to RCCs. Therefore, our findings demonstrate the feasibility and reveal the mechanisms of pharmacological induction of RCCs from endogenous CMs, which could offer a promising regenerative strategy to repair injured hearts.

cell biology↗