Biology subjects

Zhao, S.

Publications and source records attributed to Zhao, S..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

Tumors mimic the niche to inhibit neighboring stem cell differentiation

Although it is well-established that stem cells maintain tissue homeostasis while tumors disrupt it, the mechanisms by which tumors influence the development of nearby stem cells remain poorly understood. Using Drosophila ovaries as a model system, here we discovered that bam or bgcn mutant germline tumors inhibit the differentiation of neighboring wild-type germline stem cells (GSCs). Mechanistically, these tumor cells mimic the stem cell niche by secreting the BMP ligands Dpp and Gbb, but at reduced levels, resulting in moderate BMP signaling activation in adjacent GSCs. Such BMP signaling activation is sufficient to repress bam transcription, thereby blocking GSC differentiation. To our knowledge, this is the first example that tumors can functionally mimic a stem cell niche to inhibit the differentiation of neighboring wild-type stem cells. Similar regulatory paradigms may operate in mammalian tissues, including humans, during tumorigenesis.

developmental biology↗

bioRxiv2025

Hic2 fast-tracks iPS cell generation by suppressing KLF4-dependent epidermal detour

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) is the most established cellular conversion by exogenous master transcription factors (TFs). A deeper understanding of this yet inefficient process is critical to extending our capability to control cellular identity for medical applications. Here we report 14 genes essential for efficient iPSC generation, but dispensable for self-renewal. Of those, overexpression of Hic2, a transcriptional suppressor highly expressed in PSCs, enhances iPSC generation [~]10-fold. This is achieved through a more direct transition towards pluripotency, bypassing an intermediate state with KLF4-dependent transient epidermal gene expression during iPSC generation. Mechanistically, HIC2 co-occupies these KLF4 targets and directly inhibits their expression. Our work demonstrates that master TFs necessary for cellular conversions can also activate obstructive genes during cellular reprogramming. We propose that identifying transcriptional suppressors against such side effects, like Hic2, can be a powerful strategy to achieve more efficient TF-mediated cell conversions.

developmental biology↗

bioRxiv2025

Sodium Selenite Alleviates Hyperglycemia-aggravated Cerebral Ischemic Injury by Mediating Apoptosis through the Fas/FasL Signaling Pathway

ObjectiveTo investigate the intervention mechanism of sodium selenite in alleviating hyperglycemia-induced cerebral ischemia/reperfusion (I/R) injury through the Fas/FasL/NF-{kappa}B/PUMA pathway. MethodsThe SD rat model of hyperglycemia-induced cerebral I/R injury and the HT22 cell model of high-glucose oxygen deprivation/reoxygenation (OD/R) were constructed to systematically evaluate the neuroprotective effect of sodium selenite and its regulatory effect on the Fas/FasL/NF-{kappa}B/PUMA pathway. ResultsThe infarct volume, neurological dysfunction, metabolic level, and apoptosis level in the HG group were significantly higher than those in the NG group. Sodium selenite improved the infarct volume, neurological dysfunction, metabolic level, and apoptosis level in the HG group, and regulated the Fas/FasL/PUMA apoptotic pathway to alleviate injury. In vitro experiments showed that sodium selenite significantly improved morphological damage caused by high-glucose OD/R, increased cell viability, and reduced the expression of apoptotic factors. The application of Fas and FasL inhibitors and knockdown of PUMA expression indicated that sodium selenite alleviated cell apoptosis by inhibiting the activation of the Fas/FasL/PUMA pathway. ConclusionSodium selenite alleviates hyperglycemia-exacerbated cerebral I/R injury by regulating the Fas/FasL/NF-{kappa}B/PUMA signaling pathway.

pathology↗

bioRxiv2025

Neutrophil-microglia interaction drives reversible motor dysfunction in neuromyelitis optica model induced by subarachnoid AQP4-IgG

Neutrophils and neutrophil extracellular traps (NETs) contribute to early neuromyelitis optica (NMO) histopathology initiated by IgG targeting astrocytic aquaporin-4 water (AQP4) channels. Yet, the mechanisms recruiting neutrophils and their pathogenic roles in disease progression remain unclear. To investigate molecular-cellular events preceding classical complement cascade activation in a mouse NMO model, we continuously infused, via spinal subarachnoid route, a non-complement-activating monoclonal AQP4-IgG. Parenchymal infiltration of netting neutrophils containing C5a ensued with microglial activation and motor impairment, but no blood-brain barrier leakage. Motor impairment and neuronal dysfunction both reversed when AQP4-IgG infusion stopped. Two-photon microscopy and electron-microscopy-based reconstructions revealed physical interaction of infiltrating neutrophils with microglia. Ablation of either peripheral neutrophils or microglia attenuated the motor deficit, highlighting their synergistic pathogenic roles. Of note, mice lacking complement receptor C5aR1 exhibited reduction in neutrophil infiltration, microglial lysosomal activation, neuronal lipid-droplet burden and motor impairment. Pharmacological inhibition of C5aR1 recapitulated this protection. Immunohistochemical analysis of an NMO patients early spinal cord lesions revealed analogous pathological findings. Our study identifies neutrophil-derived C5a signaling through microglial C5aR1 as a key early driver of reversible motor neuron dysfunction in the precytolytic phase of NMO. One Sentence SummaryNeutrophil-derived C5a coactivates microglia to drive reversible motor paresis initiated by a non-complement-activating aquaporin-4-IgG binding to astrocytes in a mouse model of neuromyelitis optica.

neuroscience↗

bioRxiv2025

Dynamic updating of spatial working memory across eye movements: a computational investigation of transsaccadic integration

The brain continuously integrates rapidly changing visual input across eye movements to maintain stable perception, yet the precise mechanisms underpinning dynamic working memory and how these break down in brain diseases remain unclear. We developed a novel eye-tracking paradigm and computational models to investigate how spatial and colour information are updated across saccades. Our findings reveal that saccades selectively impair spatial but not colour memory. Computational modelling identified that spatial representations are maintained in a dual eye-centred frame of reference which is actively updated by a noisy memory of saccades but is vulnerable to interference. Using this model, we found that specific mechanistic failures in initial encoding and memory decay, rather than the saccadic updating process itself, account for spatial working memory deficits in Alzheimers and Parkinsons disease. These results provide a mechanistic understanding of how dynamic spatial memory operates in health and its disruption in neurodegenerative disorders.

neuroscience↗

bioRxiv2025

Intracellular auto-circularizing RNA using human tRNA splicing elements

Circular RNAs (circRNAs), a type of covalently closed RNA, have emerged as crucial regulatory factors in gene expression and development across various organisms. Understanding their formation and functional mechanisms holds potential for therapeutic applications, including novel RNA vaccines against diseases such as COVID-19. However, practical challenges still exist in the preparation of circRNAs. In this study, we explored the influence of human tRNA splicing elements on circRNAs formation and identified effective sequences for intracellular auto-circularization. We developed a generic auto-circularizing RNA (acRNA) framework template, optimized various key components of circRNAs formation, and proposed a more efficient and precise intracellular auto-circularization method. This study provides novel insights into the production mechanism of circRNA and establishes a simple and effective method for intracellular auto-circularization.

cell biology↗

bioRxiv2025

Distinct neurogenic pathways shape the diversification and mosaic organization of cortical output channels

The cerebral cortex broadcasts its output to subcortical regions through the projections of diverse extratelencephalic neurons (ETs) derived from either direct (dNG-ETd) or indirect (iNG-ETi) neurogenesis, but the differential contributions of these neurogenic pathways to cortical output organization remain unknown. Establishing a lineage-based viral targeting strategy in mice, we uncover that ETi massively amplifies and diversifies ETd projections across the cortex. Whereas ETd primarily targets the forebrain and midbrain, ETi dominates the hindbrain (e.g., brainstem/spinal action centers, lemniscal sensory stations), hypothalamic, and neuromodulatory regions with cortical area-specific projections. Numerous corticofugal subpopulations derive solely from iNG-ETi. Area-specific spinal projections of ETi but not ETd emerge from the postnatal pruning of an initial cortex-wide population. In the motor cortex, ETd or ETi activation induced distinct movements: either head-trunk, or additionally, coordinated orofacial-forelimb movements, respectively. Thus, two foundational neurogenic pathways with distinct evolutionary history differentially shape the area-specific diversification of cortical output channels.

neuroscience↗

bioRxiv2025

AAV NRF2 Gene Therapy Preserves Retinal Structure and Function in Rodent Models of Oxidative Damage

Dry age-related macular degeneration is the most frequent cause of visual impairment in individuals over age 50 in developed countries. It is characterized by subretinal deposits of oxidized proteins and lipids and results in progressive loss of high acuity vision. One major risk factor is smoking, which causes oxidative stress in many tissues, including the eye. We previously showed that an adeno-associated viral vector expressing human NRF2 (AAV8/Best1-Nrf2), a transcription factor that regulates responses to oxidative damage, slowed degeneration in mouse models of another blinding disorder, retinitis pigmentosa, which also includes oxidative stress. Here, our AAV8/Best1-Nrf2 vector was tested in a model of oxidative stress wherein sodium iodate was injected systemically, as this is often used to model dry age-related macular degeneration. Sodium iodate causes acute oxidative damage to supporting cells of the retina, the retinal pigment epithelial cells, and ultimately leads to photoreceptor death. Subretinal injection of AAV8/Best1-Nrf2 led to protection of the retinal pigment epithelium and photoreceptors, as well as preservation of visual function, in rat and mouse sodium iodate models. AAV8/Best1-Nrf2 may serve as an effective gene-agnostic therapy for diseases with oxidative stress, including dry age-related macular degeneration. ETOCOxidative stress occurs in diseases that lead to vision loss, including age-related macular degeneration (AMD). AMD is commonly modeled by injection of sodium iodate (S.I.), an oxidizing agent. AAV-mediated delivery of Nrf2, a transcription factor that regulates oxidative stress, protects the eye from S.I. damage in rat and mouse models. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/663952v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@357e57org.highwire.dtl.DTLVardef@1f9986dorg.highwire.dtl.DTLVardef@186537corg.highwire.dtl.DTLVardef@1d31aad_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

Decoding Lymphangioleiomyomatosis (LAM) Niche Environment via Integrative Analysis of Single Cell Multiomics and Spatial Transcriptomics

Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease characterized by cystic destruction and metastatic growth of smooth muscle-like cells. Despite advances in understanding its genetic basis, the cellular heterogeneity, regulatory mechanisms, and microenvironmental interactions driving LAM progression remain poorly defined. In this study, we employed an integrative multi-omics approach combining single-cell RNA sequencing (scRNA-seq), single-nucleus ATAC sequencing (snATAC-seq), and high-resolution spatial transcriptomics (Visium, Visium HD, and Xenium) to decode the LAM niche in its native environment. We identified two spatially and functionally distinct LAM subtypes: LAMCORE1 and LAMCORE2. LAMCORE1 cells exhibited a uterine smooth muscle-like phenotype, expressing associated markers (ACTA2, MYH11) and were enriched in MTORC1 signaling and myogenic pathways, supporting a uterine origin. In contrast, LAMCORE2 cells displayed fibroblast-like features, with upregulated extracellular matrix (ECM) remodeling genes (COL1A1, MMP11) and epithelial-to-mesenchymal transition (EMT) pathways, suggesting a role in niche formation. Pseudotime and regulon analyses revealed dynamic transitions between these subtypes, driven by distinct transcriptional networks (e.g., HOX/PBX in LAMCORE1, TWIST/ZEB in LAMCORE2). The presence of the two distinct LAM subtypes was further validated by RNAscope and immunofluorescence microscopy. We identified LAM-associated fibroblasts (LAFs) as activated stromal cells expressing canonical markers (FAP, S100A4, VIM, IGFBP7, SPARC) and localized within LAM lesions. Subpopulations of LAFs, LAF-seed (proximal to LAMCORE1) and LAF-niche (surrounding LAM niches), exhibited unique functional profiles, including ECM deposition, TGF-{beta} signaling, and myofibroblast activation. Regulatory network analysis pinpointed EGR1 as a central hub governing LAF phenotype. Our comprehensive spatial profiling revealed niche structures dominated by LAMCORE1 cells and surrounded by lymphatic endothelial cells (LECs), LAFs, scattered LAMCORE2 cells, macrophages, and reprogrammed alveolar epithelial cells (AT2). ECM remodeling and aberrant organization of cable-like structures (-smooth muscle actin+) of the LAM niches were further validated by second harmonic generation microscopy. These findings provide a high-resolution blueprint of LAM pathogenesis, highlighting the interplay between uterine-derived LAMCORE cells, activated fibroblasts, and the remodeled lung microenvironment. They significantly enhance our understanding of the LAM niche microenvironment and offer insights into potential therapeutic targets and strategies for managing this complex disease.

genomics↗

bioRxiv2025

Human Saphenous Vein Ex Vivo Culture as a Translational Model of Intimal Hyperplasia

BACKGROUNDIntimal hyperplasia (IH) significantly limits the long-term patency of saphenous vein grafts following bypass surgery, with no human models available to fully understand its complex pathogenesis. Although animal models, primarily murine systems, have provided mechanistic insights into IH, limitations persist in translating these findings to human pathophysiology. Here, we evaluate the translational value of a static ex vivo culture model using human saphenous vein segments to study IH. METHODSHuman saphenous vein segments obtained from patients who underwent lower limb bypass surgery were cultured ex vivo for 7 days under static conditions. Histological and immunohistochemical analyses were conducted to evaluate endothelial dysfunction, vascular smooth muscle cell (VSMC) phenotype switching, extracellular matrix (ECM) remodeling, inflammation, and apoptosis. Spatial transcriptomics (GeoMx) were employed to characterize the localized transcriptional alterations, which were subsequently validated using targeted qPCR, western blotting, and additional immunostaining techniques. RESULTSCultured vein segments developed characteristic features of IH, including marked endothelial dysfunction, increased apoptosis and proliferation, ECM remodeling and neointima formation. Spatial transcriptomics revealed localized VSMC dedifferentiation and activation of inflammatory, oxidative stress, and ECM remodeling pathways. Importantly, we also observed evidence of osteochondrogenic differentiation of human VSMCs during IH, with significant upregulation of osteogenic markers such as RunX2. CONCLUSIONSOur ex vivo human saphenous vein model captures the complex molecular and cellular dynamics of IH, offering insights into endothelial dysfunction, VSMC plasticity, and osteochondrogenic transitions. This translational model holds significant promise for evaluating novel therapeutic strategies targeting graft IH.

physiology↗

bioRxiv2025

Bifidobacterium longum subsp. nexus nov., a novel subspecies isolated from infant stool

Bifidobacterium longum is a foundational, genetically diverse member of the infant gut microbiome, yet resolving its subspecies in metagenomic data remains challenging. Here, we performed a deep phylogenetic characterization of the B. longum species utilizing 4,577 fecal metagenomes from the LLNEXT mother-infant cohort alongside a global dataset of 1,220 genomes and metagenome-assembled genomes (MAGs). We identified a novel, geographically widespread lineage: Bifidobacterium longum subsp. nexti. Using a polyphasic taxonomic analysis, including average nucleotide identity and digital DNA-DNA hybridization, confirms subspecies-level divergence. Distinct from other members of the B. longum species, BL. nexti harbors -amylopullulanase and grows on soluble starch and often pullulan, consistent with -glucan utilization. Within the LLNEXT cohort, BL. nexti is enriched in formula-fed infants and shows evidence consistent with vertical transmission. Globally, while BL. nexti is geographically widespread, it usually persists at low relative abundance across diverse populations. By resolving a major fraction of previously unclassified B. longum diversity, this study provides new insights into the specialized lineages and ecological dynamics driving the assembly of the developing infant microbiome.

microbiology↗

bioRxiv2025

Swine reporter model for preclinical evaluation and characterization of gene delivery vectors

Delivery of gene therapy vectors targeted to any somatic cell remains a key barrier for the development of genetic medicines. While rodent models provide insights into vector biodistribution and cellular tropism, their anatomical and physiological differences from humans limit their translational potential and studies in large animal models are often required. In this study, we developed a swine reporter model (SRM-1) to evaluate both viral and nonviral vector delivery in a large animal system. The SRM-1 model harbors a Cre- and CRISPR-activated tdTomato reporter at the Rosa26 locus that allows for tracing of cell-specific delivery and expression of gene therapy vectors in vivo. To evaluate this model, we administered adeno-associated virus serotype 9 (AAV9) and lipid nanoparticles (LNPs) carrying mRNA systemically and found successful in vivo reporter activation across a variety of tissues. Intracerebroventricular (ICV) administration of LNP-Cre mRNA was also performed and demonstrated localized activation in cortical brain cells. In addition to biodistribution studies, this model has utility for testing safety and clinically relevant administration methods, surgical and non-surgical, of delivery vectors. Our findings support the SRM-1 model as a valuable tool for advancing gene therapies from preclinical testing to clinical application.

genetics↗

bioRxiv2025

OGDHL regulates nucleotide metabolism, tumor growth, and neuroendocrine marker expression in prostate cancer

As cancer cells evade therapeutic pressure and adopt alternate lineage identities not commonly observed in the tissue of origin, they likely adopt alternate metabolic programs to support their evolving demands. Targeting these alternative metabolic programs in distinct molecular subtypes of aggressive prostate cancer may lead to new therapeutic approaches to combat treatment-resistance. We identify the poorly studied metabolic enzyme Oxoglutarate Dehydrogenase-Like (OGDHL), named for its structural similarity to the tricarboxylic acid (TCA) cycle enzyme Oxoglutarate Dehydrogenase (OGDH), as an unexpected regulator of tumor growth, treatment-induced lineage plasticity, and DNA Damage in prostate cancer. While OGDHL has been described as a tumor-suppressor in various cancers, we find that its loss impairs prostate cancer cell proliferation and tumor formation. Loss of OGDHL profoundly alters Androgen Receptor inhibition-induced plasticity, including suppressing the neuroendocrine markers DLL3 and HES6, induces accumulation of the DNA damage response marker {gamma}H2AX, and reduces nucleotide synthesis. Our data suggest that OGDHL has minimal impact on TCA cycle activity, and that mitochondrial localization is not required for its regulation of prostate cancer plasticity and nucleotide metabolism. Finally, we demonstrate that OGDHL expression is tightly correlated with neuroendocrine differentiation in clinical prostate cancer. These findings underscore the importance of investigating poorly characterized metabolic genes as potential regulators of distinct molecular subtypes of aggressive cancer.

cancer biology↗

bioRxiv2025

Lipidomic signatures in microglial extracellular vesicles during acute inflammation: a gateway to neurological biomarkers

Extracellular vesicles (EVs) are membrane bound vesicles released from all cells throughout the body, including the central nervous system, and are known to carry both membrane-bound proteins and cargo reflective of their cell of origin. EVs show promise as neurological disease biomarkers due to their molecular makeup reflecting their parent-cell composition signature and due to their ability to cross the blood-brain barrier. To-date, the vast majority of research in this field has explored the protein profiles of EVs; however, lipids play an important role not only in the formation of EVs, but also in mediating cellular function and the pathological progression of many neurodegenerative conditions. Herein, we take a critical first step in determining the potential utility of EV lipids as biomarkers in neurological disease. In vitro we exposed BV-2 microglia to either control media or media containing lipopolysaccharides (LPS), a known pro-inflammatory stimulus, for 24 hours then isolated both the cells and their EVs and performed LC-MS/MS. For the first time, we reveal distinct lipidomic changes can differentiate resting vs. pro-inflammatory microglia and their EVs, while distinct lipids are preserved between EVs and their parent cell. Moreover, we add to current literature by demonstrating acute pro-inflammatory activation of microglia results in the activation and suppression of distinct lipidomic pathways. Finally, we demonstrate that analysis of lipid-based relationships between parent cells and their EVs may be a useful tool to infer cellular function. This study is the first of its kind to demonstrate that lipidomic analysis can not only differentiate the functional state of cells in vitro but can also differentiate their EVs. We lay the first brick in a foundation to support future research into EV lipids as novel and exciting biomarker candidates in neurological disease.

neuroscience↗

bioRxiv2025

Identification and Characterization of PLUTO-201, a Novel Long Non-Coding RNA Associated with Poor Outcomes in Prostate Cancer

Background: Despite extensive investigation, the factors promoting aggressive prostate cancer are poorly understood. In particular, despite a few prominent examples, the role of long non-coding RNAs (lncRNAs) is largely unknown. Methods: We performed a comprehensive analysis of whole-genome transcriptome data to identify differential expression across 1,567 patients with prostate cancer, then correlated differential expression with risk of metastatic recurrence. We characterized the lncRNA most associated with metastasis in vitro and in vivo to investigate the mechanism by which it promotes aggressive prostate cancer. Results: We have identified a novel lncRNA, Prostate Cancer Associated hnRNPK Interacting Transcript (PCAHIT), which is strongly associated with metastasis and poor overall survival in men with prostate cancer. We find that overexpression/knockdown of PCAHIT in pre-clinical models of prostate cancer modulates proliferation rates and markers of an aggressive phenotype through regulation of steroid biosynthesis and expression of the MHC class I complex, driving increased growth in androgen-depleted conditions and decreased susceptibility to T cell-mediated cytotoxicity. We further find that the heterogeneous nuclear ribonucleoprotein hnRNPK directly binds PCAHIT and is indispensable for its activity. Conclusions: Overall, our findings indicate that PCAHIT is a driver of aggressive prostate cancer phenotypes and poor clinical outcomes through suppression of the immune response and increased androgen-independent cancer growth. PCAHIT is a potential biomarker of aggressive disease.

cancer biology↗

bioRxiv2025

The potential of 4-Methylumbelliferone to be repurposed for treating liver fibrosis

4-Methylumbelliferone (4-MU) is the active component of hymecromone, a choleretic and antispasmodic drug with an excellent safety profile. In rodent studies, high doses of 4-MU are also used to inhibit the production of hyaluronan (HA), a biomarker of liver fibrosis. Further, 4-MU shows excellent efficacy in inhibiting liver fibrosis of different etiologies in animal studies, eliciting interest in its repurposing for this condition. However, 4-MUs mechanism of action, and whether it inhibits liver fibrosis by impeding HA synthesis, remains unclear. Using several transgenic mouse models with HA overproduction or degradation in different types of liver cells, we found that both directions of perturbation reduced liver fibrosis levels. In addition, degrading HA via hyaluronidase PH20 overexpression impaired liver function manifested by increased serum aminotransferase (ALT) activity levels. These findings challenge both the role of HA modulation in 4-MUs action and the strategy of targeting HA to treat liver fibrosis. Additional mouse models also excluded the possibility that 4-MU modulates intestinal farnesoid X receptor (FXR) to inhibit liver fibrosis. Ablation of gut microbiota partially abolishes 4-MUs anti-liver fibrosis effect. However, the anti-liver fibrosis effect of 4-MU was lost in the lower-dose group, and the high doses effect in reducing ALT disappeared over time despite its liver fibrosis-reducing effect. Based on these findings, we argue that the lack of efficacy of 4-MU at a translatable dose and lack of a clear mechanism that allows further improvement of 4-MUs efficacy make 4-MU impractical for development as an anti-liver fibrosis treatment. HighlightsO_LI4-MU inhibits MASH fibrosis. C_LIO_LIBoth HA overproduction and digestion in the liver reduce liver fibrosis. C_LIO_LIIntestinal epithelial cell FXR is not required for 4-MU to reduce liver fibrosis. C_LIO_LIThe gut microbiota is partially responsible for 4-MUs antifibrotic effect in the liver. C_LIO_LI4-MU lacks the potential to be further developed into anti-liver fibrosis treatment. C_LI

molecular biology↗

bioRxiv2025

Bona fide hematopoietic stem cells in zebrafish originate from the supra-intestinal artery

Hematopoietic stem cells (HSCs) in vertebrates are widely believed to originate from hemogenic endothelial cells (HECs) in the dorsal aorta (DA) through endothelial-to-hematopoietic transition. However, conclusive in vivo DA-specific lineage-tracing studies to confirm this origin are lacking. Here, leveraging infrared light-mediated temporospatial-resolution lineage-tracing technology, we demonstrate that in zebrafish, HSCs do not originate from the DA. Instead, following the DA hematopoiesis, which produces hematopoietic precursors with limited renewal potential, lifelong renewable HSCs emerge from the supra-intestinal artery (SIA). Remarkably, while the DA produces hematopoietic cells from unipotent HECs, the SIA generates hematopoietic cells from both unipotent HECs and bipotent vessel-resident hemangioblasts (VRHs). These VRHs undergo multiple rounds of division and budding, generating both hematopoietic cells and SIA-resident endothelial cells. The distinct characteristics of DA and SIA cells are further reinforced by single-cell transcriptomic profiling. Our findings challenge the current paradigm of HSC development, underscoring the complexity of vertebrate hematopoiesis.

developmental biology↗

bioRxiv2025

Bridging Hearts and Muscles: Genetic Insights into Cardiac Structure and Sarcopenia

BackgroundCurrently, the link between cardiovascular diseases and sarcopenia is increasingly garnering attention from researchers. However, studies exploring the association between cardiac structure and sarcopenia are sparse. This study aims to investigate the potential genetic links between cardiac structural features and sarcopenia. MethodsDuring the discovery phase, we employed Linkage Disequilibrium Score Regression (LDSC) and Mendelian Randomization (MR) to assess the genetic correlation and causality between traits related to cardiac structure and sarcopenia, with further validation of the results using validation set data. In the study, we established a scoring system to identify high-confidence trait pairs. For these pairs, we conducted sensitivity analyses to assess their heterogeneity and pleiotropy. Additionally, we undertook follow-up studies of these trait pairs, including using mediation analysis to evaluate the potential mediating effects of lipids, and enrichment analysis to explore possible shared biological pathways linking these characteristics. ResultsThe genetic correlation analyses during the discovery and validation phases identified 5 pairs (in forward analysis) and 16 pairs (in reverse analysis) of high-confidence trait pairs. As a key sarcopenia-related feature, appendicular lean mass (ALM) exhibited positive causal relationships with several cardiac structural features, including the volumes of the left and right atria. Mediation analysis suggested that certain lipids, such as phosphatidylcholine, might mediate these causal relationships. Notably, gene and pathway enrichment analyses revealed that genes associated with significant SNPs in high-confidence trait pairs were enriched in multiple key biological processes and pathways, such as tube morphogenesis, cardiac right ventricle morphogenesis, and muscle system processes in the forward analysis, as well as skeletal system development, heart development, and hemopoiesis in the reverse analysis. Cell-type enrichment analysis pointed to endothelial cells, smooth muscle cells, fibroblasts, and mesenchymal stem cells. ConclusionsThis study provides evidence for genetic relationships between cardiac structures and sarcopenia-related traits. These findings may enhance our understanding of the biological mechanisms underlying age-related diseases and provide scientific basis for developing future preventive and therapeutic strategies.

genetics↗