Biology subjects

Wong, S. Y.

Publications and source records attributed to Wong, S. Y..

8 recordsLinked to original sources

bioRxiv2025

Von Willebrand Factor Deficiency Impairs Vascular Morphogenesis via Angiopoietin-2: Relevance for Gut Angiodysplasia

Management of recurrent gastrointestinal (GI) bleeding is a clinical unmet need for patients with Von Willebrand disease (VWD) and is linked to the presence of gut vascular malformations (angiodysplasia). We previously demonstrated that von Willebrand factor (VWF) regulates angiogenesis and vascular integrity, the likely mechanism underlying angiodysplasia. VWF controls the storage of the angiogenesis regulator Angiopoietin-2 (Angpt-2) in endothelial cells (EC), suggesting a candidate for the genesis of angiodysplasia; however, no direct evidence of the role of Angpt-2 in VWF-dependent angiogenesis is available. Here we use VWF-deficient HUVEC, and endothelial colony forming cells (ECFCs) from severe VWD patients and find that loss of VWF in EC results in increased Angpt-2 expression through a positive feedback loop via the Angpt-2-TIE2-AKT-FOXO1 pathway. We also show an imbalance of the Angpt/Tie2 pathway in vivo. In the gut of VWF-deficient mice, Angpt-2 expression is increased whilst Angpt-1 expression is decreased; this correlates with reduced expression of the pericyte marker NG2. These data suggest that VWF regulates the Angpt/Tie2 balance in the gut. To investigate the functional defects caused by loss of VWF, we use a fibrin bead assay and show that VWF-deficient HUVEC present increased sprouting. We develop a microfluidic model of 3D vasculogenesis/angiogenesis and find that ECFCs from VWD patients exhibit defective remodeling and abnormal lumen formation compared to healthy controls. Importantly, inhibition of Angpt-2 reduces sprouting in VWF-deficient HUVEC and normalises vascular networks in ECFCs from severe VWD, suggesting Angpt-2 inhibitors may be effective in VWD patients with GI bleeding and angiodysplasia. Key pointsO_LIEndothelial VWF regulates multiple steps of angiogenesis, including sprouting and lumen formation. C_LIO_LIVWF regulates Angpt-2 storage and expression, and Angpt-2 blockade normalises defective angiogenesis in VWD ECFCs. C_LI Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/675051v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@150eb15org.highwire.dtl.DTLVardef@179e6beorg.highwire.dtl.DTLVardef@1bcadborg.highwire.dtl.DTLVardef@a30fb8_HPS_FORMAT_FIGEXP M_FIG VWF deficiency in HUVECs results in increased Angpt-2 release and expression via the Tie2-Akt-FOXO1 pathway. A. Model pathway for the regulation of Angpt-2 levels by VWF. Loss of VWF results in increased Angpt-2 release from endothelial cells; Angpt-2 binds to and inhibits the Tie2 receptor, decreasing its phosphorylation as well as the downstream phosphorylation of Akt and FOXO1; this leads to FOXO1 activation and an increase expression of Angpt-2, generating a feedback loop. B. Model for the pathogenesis of angiodysplasia in VWD. In the absence of VWF, the increase in Angpt-2 disrupts vascular morphogenesis through multiple mechanisms: increased sprouting, impaired vascular remodelling and an imbalance between Angpt-1 and Angpt-2 in the gut. Figure generated with Biorender. C_FIG

cell biology↗

bioRxiv2025

Candida auris skin colonization is mediated by Als4112 and interactions with host extracellular matrix proteins

Candida auris is an often multidrug-resistant fungal pathogen notorious for persistent skin colonization and transmission in healthcare settings. However, the mechanisms driving its adherence to skin remain poorly understood. Here, we developed in vitro systems to allow for detailed analysis of early skin colonization events and identified critical host and pathogen mediators of attachment. Across multiple strains and clades of C. auris, we identified that Als4112, a conserved adhesin, is required for skin colonization via keratinocyte attachment and direct interactions with host extracellular matrix (ECM) proteins, especially basement membrane proteins such as laminin. In a murine epicutaneous infection and human skin explants, deletion of ALS4112 significantly reduced skin colonization, underscoring its essential role in establishing cutaneous persistence. Als4112 also contributes to systemic infection, highlighting the connection between adherence and pathogenicity in this organism. Finally, coating plastic and catheter surfaces with collagen I or III markedly inhibited C. auris attachment and biofilm formation, offering an approach to curb nosocomial transmission. Our study highlights the critical role of Als4112 in C. auris colonization and virulence in vivo, making it an attractive target for future vaccine development. This study also explores the potential of specific collagen coatings as a novel strategy to prevent C. auris adherence to abiotic surfaces, offering new therapeutic avenues to control the spread of C. auris in healthcare settings.

microbiology↗

bioRxiv2024

Hair follicles modulate skin barrier function

Our skin provides a protective barrier that shields us from our environment. Barrier function is typically associated with interfollicular epidermis; however, whether hair follicles influence this process remains unclear. Here, we utilize a potent genetic tool to probe barrier function by conditionally ablating a quintessential epidermal barrier gene, Abca12, which is mutated in the most severe skin barrier disease, harlequin ichthyosis. With this tool, we deduced 4 ways by which hair follicles modulate skin barrier function. First, the upper hair follicle (uHF) forms a functioning barrier. Second, barrier disruption in the uHF elicits non-cell autonomous responses in the epidermis. Third, deleting Abca12 in the uHF impairs desquamation and blocks sebum release. Finally, barrier perturbation causes uHF cells to move into the epidermis. Neutralizing Il17a, whose expression is enriched in the uHF, partially alleviated some disease phenotypes. Altogether, our findings implicate hair follicles as multi-faceted regulators of skin barrier function.

developmental biology↗

bioRxiv2023

Distinct mechanisms for sebaceous gland self-renewal and regeneration provide durability in response to injury

Sebaceous glands (SGs) release oils that protect our skin, but how these glands respond to injury has not been previously examined. Here, we report that SGs are largely self-renewed by dedicated stem cell pools during homeostasis. Using targeted single cell RNA-sequencing, we uncovered both direct and indirect paths by which these resident SG progenitors ordinarily differentiate into sebocytes, including transit through a PPAR{gamma}+Krt5+ transitional cell state. Upon skin injury, however, SG progenitors depart their niche, reepithelialize the wound, and are replaced by hair follicle-derived stem cells. Furthermore, following targeted genetic ablation of >99% of SGs from dorsal skin, these glands unexpectedly regenerate within weeks. This regenerative process is mediated by alternative stem cells originating from the hair follicle bulge, is dependent upon FGFR signaling, and can be accelerated by inducing hair growth. Altogether, our studies demonstrate that stem cell plasticity promotes SG durability following injury.

developmental biology↗

bioRxiv2022

The columnar structure of human telomeric chromatin suggests mechanisms for telomere maintenance

Telomeres, the ends of eukaryotic chromosomes, play pivotal roles in ageing and cancer and are targets of DNA damage and response. However, little is known about the structure and organization of telomeric chromatin at the molecular level. We used electron microscopy and single-molecule magnetic tweezers to characterize well-defined telomeric chromatin fibers of kilobasepair length. The cryo-EM structure of the compact telomeric tetranucleosome revealed a novel columnar folding, unusually short nucleosome repeat length of [~]132bp and the role of the histone N-terminal tails in stabilizing this structure. This is the first near-high resolution structure of chromatin with a native DNA sequence. The columnar structure exposes the DNA, making them susceptible to DNA damage. The telomeric tetranucleosome also exists in an alternative well-defined state, with one nucleosome open, accessible to protein factors. This suggests that protein factors, which plays a role in maintaining telomeres, can bind to telomeric chromatin in its compact heterochromatic form. The features of the telomeric chromatin structure reveals important insights of significant relevance for telomere function in vivo that provides information on mechanisms of nucleosome recognition by chromatin factors

molecular biology↗

bioRxiv2021

Tracing boundaries in Eastern Antarctica: Multi-scale drivers of soil microbial communities across the hyperarid Vestfold Hills

Microorganisms are key to sustaining core ecosystem processes across terrestrial Antarctica but they are rarely considered in conservation frameworks. Whilst greater advocacy has been made towards the inclusion of microbial data in this context, there is still a need for better tools to quantify multispecies responses to environmental change. Here, we extend the scope of Gradient Forest modelling beyond macroorganisms and small datasets to the comprehensive polar soil microbiome encompassing >17, 000 sequence variants for bacteria, micro-eukarya and archaea throughout the hyperarid Vestfold Hills of Eastern Antarctica. Quantification of microbial diversity against 79 physiochemical variables revealed that whilst rank-order importance differed, predictors were broadly consistent between domains, with greatest sharing occurring between bacteria and micro-eukarya. Moisture was identified as the most robust predictor for shaping the regional soil microbiome, with highest compositional turnover or "splits" occurring within the 10 - 12 % moisture content range. Often the most responsive taxa were rarer lineages of bacteria and micro-eukarya with phototrophic and nutrient-cycling capacities such as Cyanobacteria (up to 61.81 % predictive capacity), Chlorophyta (62.17 %) and Ochrophyta (57.81 %). These taxa groups are thus at greater risk of biodiversity loss or gain to projected climate trajectories, which will inevitably disturb current ecosystem dynamics. Better understanding of these threshold tipping points will positively aid conservation efforts across Eastern Antarctica. Furthermore, the successful implementation of an improved Gradient Forest model also presents an exciting opportunity to broaden its use on microbial systems globally.

microbiology↗

bioRxiv2020

Notch effector Hes1 marks an early perichondrial population of skeletal progenitor cells at the onset of endochondral bone development

The perichondrium, a fibrous tissue surrounding the fetal cartilage, is an essential component of developing endochondral bones that provides a source of skeletal progenitor cells. However, perichondrial cells remain poorly characterized due to lack of knowledge on their cellular diversity and subset-specific mouse genetics tools. Single cell RNA-seq analyses reveal a contiguous nature of the fetal chondrocyte-perichondrial cell lineage that shares an overlapping set of marker genes. Subsequent cell-lineage analyses using multiple creER lines active in fetal perichondrial cells - Hes1-creER, Dlx5-creER - and chondrocytes - Fgfr3-creER - illustrate their distinctive contribution to endochondral bone development; postnatally, these cells contribute to the functionally distinct bone marrow stromal compartments. Particularly, Notch effector Hes1-creER marks an early skeletal progenitor cell population in the primordium that robustly populates multiple skeletal compartments. These findings support the concept that perichondrial cells participate in endochondral bone development through a distinct route, by providing a complementary source of skeletal progenitor cells.

developmental biology↗

bioRxiv2019

Novel Quorum Sensing Activity in East Antarctic Soil Bacteria

Antarctica, being the coldest, driest and windiest continent on Earth, represents the most extreme environment a living organism can thrive in. Under constant exposure to harsh environmental threats, terrestrial Antarctica remains home to a great diversity of microorganisms, indicating that the soil bacteria must have adapted a range of survival strategies that require cell-to-cell communication. Survival strategies include secondary metabolite production, biofilm formation, bioluminescence, symbiosis, conjugation, sporulation and motility, all of which are often regulated by quorum sensing (QS), a type of bacterial communication. Up to now, such mechanisms have not been explored in terrestrial Antarctica. Here, for the first time, LuxI/LuxR-based quorum sensing (QS) activity was delineated in soil bacterial isolates recovered from Adams Flat, in the Vestfold Hills region of East Antarctica. Interestingly, we identified the production of potential homoserine lactones (HSLs) ranging from medium to long chain length in 19 bacterial species using three biosensors, namely Agrobacterium tumefaciens NTL4, Chromobacterium violaceum CV026 and Escherichia coli MT102, in conjunction with thin layer chromatography (TLC). The majority of detectable HSLs were from gram-positive microorganisms not previously known to produce HSLs. This discovery further expands our understand of the microbial community capable of this type of communication, as well as providing insights into physiological adaptations of microorganisms that allow them to survive in the harsh Antarctic environment.\n\nIMPORTANCEQuorum sensing, a type of bacterial communication, is widely known to regulate many processes including those that confer survival advantage. However, little is known about communication by bacteria thriving within Antarctic soils. Employing a combination of bacteria biosensors, analytical techniques, and genome mining, we found a variety of Antarctic soil bacteria speaking a common language, via the LuxI/LuxR-based quorum sensing, thus potentially supporting survival in a mixed microbial community. This is the first report of quorum sensing activity in Antarctic soils and has provided a platform for studying physiological adaptations of microorganisms that allow them to not just survive but thrive in the harsh Antarctic environment.

microbiology↗