Biology subjects

Foo, R. S.

Publications and source records attributed to Foo, R. S..

4 recordsLinked to original sources

bioRxiv2026

Enzymatic extracellular matrix remodeling in ex vivo slices of aged myocardium

Cardiac aging is accompanied by extracellular matrix (ECM) remodeling and increased myocardial stiffness, which may contribute to age-associated functional decline. However, whether direct remodeling of the aged cardiac ECM can modify myocardial mechanics and function remains poorly understood. Here, we established an ex vivo living myocardial slice platform to investigate whether enzymatic remodeling of the aged ECM can alter myocardial structure, mechanics, and function. Left ventricular myocardial slices (LMS) from young and aged mice were maintained under static stretch for 48 hours using a custom 3D-printed culture setup. Aged slices were treated with collagenase and subsequently characterized using quantitative imaging, tensile testing, contractility measurements, and transcriptomic analysis. Aged myocardium exhibited increased collagen and fibronectin abundance, altered collagen network architecture, and increased stiffness compared with young tissue. Collagenase treatment reduced collagen and network complexity and reduced myocardial stiffness toward young tissue values without compromising ultimate tensile stress. Despite these structural and biomechanical changes, age-associated differences in myocardial contractility remained comparable across groups. Transcriptomic analysis indicated that treated aged tissue largely retained its age-associated molecular phenotype, despite pathway-level shifts involving metabolism, cardiac function, and inflammatory responses. These findings demonstrate that enzymatic ECM remodeling can modify the aged myocardial mechanical environment while selected functional and transcriptional features of aging persist over 48 hours. The LMS platform provides a controllable ex vivo tissue-level approach for investigating ECM contributions during cardiac aging and evaluating strategies for ECM engineering.

bioengineering↗

bioRxiv2025

Coronary Artery Disease Risk Variant rs6903956 Links to Endothelial Dysfunction via PHACTR1 Regulation

Ischemic heart disease, particularly coronary artery disease (CAD), remain leading causes of mortality worldwide. The single nucleotide polymorphism rs6903956 on chromosome 6p24.1 has been identified as a susceptibility locus for CAD in East Asian populations through genome-wide association studies. However, its functional role has not been fully elucidated. This study investigates the mechanistic basis of rs6903956 and its contribution to CAD pathogenesis, focusing on endothelial cell dysfunction. We first conducted cohort studies, revealing an association between the rs6903956 A risk allele and blood pressure phenotypes, along with impaired endothelial responsiveness indicated by reduced flow-mediated dilation. Single-base editing of induced pluripotent stem cell-derived endothelial cells obtained from patients with CAD and expression quantitative trait loci analysis highlighted a cisacting impact of the A allele on PHACTR1 and EDN1 expression, suggesting allelespecific regulatory effects. Using in silico modeling by AlphaFold 3 platform, the A allele exhibited enhanced binding affinity for HOXA4 and MEIS1 transcription factors, forming a stable ternary complex that promoted transcriptional activation of PHACTR1. Functional assays demonstrated the enhancer role of rs6903956 A in PHACTR1 promoter activity, supporting its locus-specific regulatory function in endothelial cells. Under pathological flow conditions, endothelial cells harboring the A allele display elevated ICAM-1 expression and increased monocyte adhesion compared to the G allele, indicating allele-specific endothelial inflammatory activation. These findings propose a model in which rs6903956 influences PHACTR1 expression via HOX-MEIS cooperative binding, thereby modulating endothelial function and contributing to CAD susceptibility. This study provides mechanistic insights into the role of rs6903956 in endothelial dysfunction and CAD, informing potential therapeutic targets arising from genetic determinants in cardiovascular pathogenesis.

molecular biology↗

bioRxiv2023

Hybrid hydrogel-extracellular matrix scaffolds identify distinct ligand and mechanical signatures in cardiac aging

Extracellular matrix (ECM) remodeling of cardiac tissue is a key contributor to age-related cardiovascular disease and dysfunction. Aberrant secretion, structural perturbations, and degradation of specific ECM components lead to significant alterations in ECM properties that disrupt healthy cell and tissue homeostasis. These changes in ECM are multifaceted, as alterations in ligand presentation, including both biochemical and architectural aspects, are often accompanied by stiffness changes, clouding our understanding of how and which ECM properties contribute to a dysfunctional state. To identify the specific roles of these interconnected ECM cues and elucidate their mechanistic regulation in cellular function, we developed a material system that can independently present these two distinct matrix properties, i.e., ligand presentation and stiffness, to cultured cells in vitro. We describe a decellularized ECM-synthetic hydrogel hybrid scaffold that maintains native matrix composition and organization of young or aged murine cardiac tissue with independently tunable scaffold mechanics that mimic young or aged tissue stiffness. Seeding these scaffolds with primary cardiac fibroblasts (CFs) from young or aged mice, we identify distinct age- and ECM-dependent mechanisms of CF activation. Importantly, we show that ligand presentation of young ECM can outweigh profibrotic stiffness cues typically present in aged ECM in maintaining or driving CF quiescence, thereby highlighting the unique roles of ECM in aging. Ultimately, these tunable scaffolds can enable the discovery of specific ECM targets to prevent aging dysfunction and promote rejuvenation. DECIPHER: DECellularized In Situ Polyacrylamide Hydrogel-ECM hybRid

bioengineering↗

bioRxiv2018

Large-scale whole-genome sequencing of three diverse Asian populations in Singapore

Asian populations are currently underrepresented in human genetics research. Here we present whole-genome sequencing data of 4,810 Singaporeans from three diverse ethnic groups: 2,780 Chinese, 903 Malays, and 1,127 Indians. Despite a medium depth of 13.7x, we achieved essentially perfect (>99.8%) sensitivity and accuracy for detecting common variants and good sensitivity (>89%) for detecting extremely rare variants with <0.1% allele frequency. We found 89.2 million single-nucleotide polymorphisms (SNPs) and 9.1 million small insertions and deletions (INDELs), more than half of which have not been cataloged in dbSNP. In particular, we found 126 common deleterious mutations (MAF>0.01) that were absent in the existing public databases, highlighting the importance of local population reference for genetic diagnosis. We describe fine-scale genetic structure of Singapore populations and their relationship to worldwide populations from the 1000 Genomes Project. In addition to revealing noticeable amounts of admixture among three Singapore populations and a Malay-related novel ancestry component that has not been captured by the 1000 Genomes Project, our analysis also identified some fine-scale features of genetic structure consistent with two waves of prehistoric migration from south China to Southeast Asia. Finally, we demonstrate that our data can substantially improve genotype imputation not only for Singapore populations, but also for populations across Asia and Oceania. These results highlight the genetic diversity in Singapore and the potential impacts of our data as a resource to empower human genetics discovery in a broad geographic region.

genetics↗