Biology subjects

Cheng, Y. S.

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

4 recordsLinked to original sources

bioRxiv2025

Anatomical integrity of the human cochlea estimated with optical coherence tomography for future clinical application

The human cochlea is encased within the otic capsule, the densest bone in the body, posing significant challenges for anatomical imaging of cochlear structures. Because of difficult access and fragility of cochlear structures, our understanding of intracochlear anatomy has historically relied on postmortem histology. We thus have a limited understanding of human cochlear anatomy in its native, unfixed state. Clinical diagnostics for hearing loss, such as audiometry and otoacoustic emissions, offer functional assessments but fail to elucidate the often diverse underlying structural pathologies with any degree of precision. To address the critical need for assessing the human cochlear anatomy and associated pathologies without the risk of traumatizing cochlear structures, we imaged fresh cochleae in situ soon after death through the intact round window membrane with Optical Coherence Tomography (OCT) without inserting instruments inside or opening the cochlea. Micron-resolution OCT cross-sectional images of the human intracochlear structures were acquired and compared with corresponding histology systematically to aid in the identification of fine structural features and possible pathologies. With OCT imaging, we observed varied anatomy of the organ of Corti, and developed a cochlear "integrity" rating system to differentiate healthy appearing cochleae from various pathological states. These results demonstrate the capability of OCT to non-traumatically visualize cochlear integrity, highlighting its potential as a diagnostic tool. This work shows promise in translating the ability to determine the likelihood of existing or lack of hair cells and supporting cells in live patients, which would enable appropriate targeted treatments.

physiology↗

bioRxiv2025

Modeling 3D Mesoscaled Neuronal Complexity through Learning-based Dynamic Morphometric Convolution

Accurate reconstruction of neuronal morphology from three-dimensional (3D) light microscopy is fundamental to neuroscience. Nevertheless, neuronal arbors intrinsically exhibit slender, tortuous geometries with high orientation variability, posing significant challenges for standard 3D convolutions whose static, axis-aligned receptive fields lack adaptability to such complex morphology. To address this, we propose the Dynamic Morph-Aware Convolution (DMAC) framework, which incorporates inherent geometric priors into convolution by jointly adapting both the shape and orientation of the kernel. This enables morphology-aware feature extraction tailored to arborized and variably oriented neuronal trajectories. Specifically, we first apply dynamic tubular convolutions to bridge the structural mismatch between isotropic convolution kernels and the slender morphology of neurons. To sufficiently accommodate the 3D orientation variability of neuronal branches, we further introduce a rotation mechanism that dynamically reorients the tubular kernel via two learnable angles (elevation and azimuth), enabling precise alignment with local neuronal directions. We validate our method through extensive experiments on four mesoscaled neuronal imaging datasets, including two from the BigNeuron project (Drosophila and Mouse) and two additional benchmarks (NeuroFly and CWMBS). Our approach consistently outperforms state-of-the-art methods, achieving average improvements of 5.4% in Entire Structure Average (ESA), 6.9% in Different Structure Average (DSA), and 7.5% in Percentage of Different Structure (PDS). These results demonstrate the effectiveness of our proposed DMAC in capturing complex morphological variations and enhancing structural fidelity across diverse mesoscaled neuronal morphologies.

neuroscience↗

bioRxiv2025

MAPK Signaling and Angiopoietin-2 Contribute to Endothelial Permeability in Capillary Malformations

Capillary malformations (CM) are slow-flow vascular abnormalities present at birth and predominantly manifest as cutaneous lesions. In the rare neurocutaneous disorder known as Sturge Weber Syndrome (SWS), individuals exhibit CM not only on the skin but also within the leptomeninges of the brain and the choroid of the eye. >90% of CM are caused by a somatic R183Q mutation in GNAQ, the gene encoding Gq - a heterotrimeric G-protein subunit. The somatic GNAQ mutation is notably enriched in endothelial cells (ECs) isolated from CM-affected regions. Here we show blood vessels in cutaneous and leptomeningeal SWS lesions exhibit extravascular fibrin indicating a compromised endothelial barrier. Longitudinal MRI of the brain in one SWS patient further suggests vascular permeability. To explore this pathological phenotype, we employed the trans-endothelial electrical resistance (TEER) assay to measure permeability of the EC-EC barrier in vitro. Human EC CRISPR edited to create a GNAQ R183Q allele (EC-R183Q) exhibited a reduced barrier compared to mock edited EC (EC-WT). We sought to identify signaling molecules needed for EC barrier formation. Knockdown of angiopoietin-2 (ANGPT2), known to be significantly increased in EC-R183Q and in CM, partially yet significantly restored the barrier, while an anti-ANGPT2 function blocking antibody did not. We next tested the MEK1,2 inhibitor (Trametinib) because MAPK signaling is increased by GNAQ mutation. MEK1,2 inhibitors partially restored the EC barrier, implicating involvement of MAPK/ERK signaling. The combination of ANGPT2 knockdown and Trametinib significantly restored the EC barrier to near EC-WT levels. The additive impacts of ANGPT knockdown and MEK1,2 inhibition indicate the two operate in separate pathways. In summary, we discovered that GNAQ p.R183Q ECs exhibit compromised endothelial barrier formation, reflecting the compromised EC barrier in CM lesions, and that ANGPT2 knockdown combined with Trametinib effectively restores the EC-EC barrier. NONSTANDARD ABBREVIATIONS AND ACRONYMS O_TBL View this table: org.highwire.dtl.DTLVardef@e1081eorg.highwire.dtl.DTLVardef@1dc05b7org.highwire.dtl.DTLVardef@1fb6ac0org.highwire.dtl.DTLVardef@11d8f59org.highwire.dtl.DTLVardef@1ae5406_HPS_FORMAT_FIGEXP M_TBL C_TBL NOVELTY AND SIGNIFICANCEO_ST_ABSWhat is known?C_ST_ABSO_LIThe mutant Gq-R183Q in endothelial cells activates phospholipase {beta}3, contributing to increased angiopoietin-2, a pro-angiogenic, proinflammatory molecule that contributes to vascular permeability. C_LIO_LIEndothelial Gq-R183Q is sufficient to drive formation of enlarged blood vessels akin to what is observed in CM. ANGPT2 shRNA knockdown prevented the enlarged vessel phenotype in a xenograft model. C_LIO_LIAn EC-specific GNAQ p.R183Q mouse model showed permeability in brain vessels, detected by perfusion of Evans Blue dye, indicating reduced vascular integrity. C_LI What New Information Does This Article Contribute?O_LIReduced vascular integrity in CM is confirmed by Martius Scarlet Blue staining and longitudinal MRI imaging of SWS brain. C_LIO_LIGNAQ p.R183Q EC form a weaker endothelial barrier in vitro compared to control ECs. The weakened endothelial barrier in the mutant ECscan be rescued by Gq inhibitor, YM254890, confirming the compromised barrier is a consequence of the mutant Gq. C_LIO_LITitration experiments modeling the mosaic nature of the GNAQ p.R183Q in CMshow that 5- 10% GNAQ p.R183Q EC in the monolayer is sufficient to reduce endothelial barrier formation. C_LIO_LIKnockdown of ANGPT2 or MEK1,2 inhibition partially restored the endothelial barrier in GNAQ p.R183Q EC. C_LIO_LICombining knockdown of ANGPT2 and addition of a MEK inhibitor, Trametinib, restored the endothelial barrier to near what is seen in wild type ECs. C_LI What is the translational message?Sturge Weber Syndrome (SWS) is a neurocutaneous disorder that involves atypical blood vessel overgrowth in the skin, brain and eye. It is associated with facial CM (aka port wine birthmark), leptomeningeal CM in the brain visible with MRI, and glaucoma. Theneurological sequalae involve seizures, cerebral atrophies and calcification, and intellectual disorders. Currently there are no molecularly targeted therapies for non-syndromic CM or SWS. Our study shows the involvement of MAPK pathway and the proinflammatory molecule ANGPT2 in endothelial permeability and suggests a path to target GNAQ p.R183Q driven CM.

pathology↗

bioRxiv2025

An endothelial specific mouse model for the capillary malformation mutation Gnaq p.R183Q

Capillary malformation (CM) is a congenital, non-hereditary lesion composed of enlarged and tortuous blood vessels. CM is associated with a somatic GNAQ p.R183Q activating mutation in endothelial cells (EC). Cutaneous CMs are present in 1/300 infants and in 55-70% of CM cases soft tissue overgrowth is observed. Pharmacotherapy for CM does not exist. Here we report a conditional mouse model allowing the simultaneous tissue specific expression of GNAQ p.R183Q and GFP from the R26 locus (R26GT-Gnaq-GFP). We show that expression of GNAQ p.R183Q in ECs results in vascular malformations with features similar to human CM lesions. GNAQ p.R183Q expression during embryonic development (Tg-Cdh5Cre) resulted in a severe vascular phenotype, lethal by embryonic (E) 16.5. Induction of mutant GNAQ expression in ECs at postnatal (P) day 1 (Tg-Cdh5CreER) led to tortuous and enlarged blood vessels, most noticeable in the intestines. GNAQ p.R183Q/GFP expressing ECs co-localized with lesions and displayed increased proliferation. Mutant ECs had abnormal mural cell coverage and abnormal pericellular extracellular matrix deposition, which was confirmed in human CM samples. Similar to human CM they displayed strong expression of the tip cell marker ESM1 and increased ANGPT2 expression. In conclusion, GNAQ p.R183Q expression in murine ECs causes vascular malformations supporting the causality of the mutation for CM. The lesions recapitulate multiple features of human CM, making the mouse model suitable for the preclinical testing of future CM pharmacotherapy.

cell biology↗