Biology subjects

Ninh, V. K.

Publications and source records attributed to Ninh, V. K..

4 recordsLinked to original sources

bioRxiv2025

An infusible decellularized extracellular matrix material binds to vasculature in infarcted myocardium and induces pro-reparative gene expression following acute myocardial infarction through inherent avidity and bioactive signaling

To treat acute myocardial infarction immediately after reperfusion, we previously engineered an intravascularly infusible decellularized extracellular matrix (iECM) biomaterial that exerts immunomodulatory and pro-reparative effects. However, the impact of the heterogeneous contents of iECM on infarct localization and downstream biological function is unknown. Using liquid chromatography, iECM is separated into a high molecular weight (MW) and low MW component. Mass spectrometry confirms compositional similarity, while biochemical assays and transmission electron microscopy highlight differences in biochemical features and structure, revealing a nanofibrillar high MW component and a globular peptide low MW. Quartz crystal microbalance studies show binding of each component to basal lamina ECM proteins and endothelial cell surface receptors under flow, demonstrating the specificity of ECM biomaterials to permeable vasculature. In vivo, the low MW component reduces vascular permeability, while neither component alone achieves the retention levels of complete iECM. Using single-nucleus RNA sequencing to probe bioactivity, both components elicited comparable angiogenic, immunomodulatory, and pro-reparative transcriptional programs. These findings illustrate that highly coupled materials and biological characterization uncover fundamental behaviors and properties of iECM biomaterials. Additionally, we show the unique binding behavior of iECM to the gaps of permeable vasculature, which could be exploited for future nanomaterial design.

bioengineering↗

bioRxiv2025

Infusible Extracellular Matrix Biomaterial Enhances Cell-Specific Pro-Repair Responses Following Acute Myocardial Infarction

To mitigate the pathological effects of myocardial infarction, we developed and investigated pro-reparative decellularized extracellular matrix (ECM) biomaterials: an intravascularly infusible ECM (iECM). However, the cellular and molecular mechanisms by which iECM mediates repair are unknown because investigations have relied on bulk techniques. Here, we leverage single nucleus RNA sequencing (snRNAseq) to measure pro-repair in various cell types across acute timepoints (1, 3 and 7 days post infusion). In iECM, we found pro-reparative macrophage activation, fibroblast remodeling, increased vasculaure development, lymphangiogenesis, cardioprotection, and neurogenesis. These findings were validated through spatial transcriptomics. Thus, we define the pro-reparative nature of decellularized ECM biomaterials on cardiac cell types and elucidate previously undiscovered therapeutic pathways, further demonstrating the potential of iECM as an MI therapy as well as display the wealth of data generated from next-generation sequencing.

bioengineering↗

bioRxiv2025

Spatial transcriptomic profiling of the human aortic valve reveals cellular sex differences near sites of calcification

Sex differences in aortic valve stenosis (AVS) progression have been documented clinically, but the underlying cellular mechanisms that drive sex-dependent calcification in aortic valve tissue remain poorly understood. Here, we harnessed single cell and spatial transcriptomics to investigate mechanisms that drive sex dependent spatial organization of valvular interstitial cell (VIC) and macrophage gene expression near calcification sites in human male and female aortic valve tissue. Histological analyses of aortic valve tissues stratified into healthy and diseased cohorts based on degree of calcification reveal increased valve calcification area in diseased male aortic valves relative to female, and increased valve thickening in diseased female aortic valves. Single cell sequencing analysis of heterogeneous valvular interstitial cell (VIC) populations reveals male-dependent gene expression of the Activator Protein 1 (AP-1) transcription factor complex. Spatial transcriptomics and RNA-FISH analyses of VIC populations near sites of calcification revealed male-dependent gene expression localization of Cartilage Oligomeric Matrix Protein (COMP), as opposed to diffuse COMP expression in female VICs. Cell-cell communication analyses were used to determine female-specific macrophage-VIC interactions. Secreted phosphoprotein 1 (also known as osteopontin) expressed from macrophages interacts with the cell surface receptor CD44 expressed by VICs to drive a pro-fibrotic phenotype in female aortic valves. Together, our results reveal sex differences in VIC and macrophage heterogeneity and functions near sites of calcification in aortic valve tissue. Our results highlight the importance of sex-based transcriptomics analyses to understand the cellular phenotypes responsible for causing sex differences in aortic valve fibrosis calcification.

genomics↗

bioRxiv2025

Uncovering the Regional and Cell Specific Bioactivity of Injectable Extracellular Matrix Biomaterials in Myocardial Infarction through Spatial and Single Nucleus Transcriptomics

Myocardial infarction (MI) remains a global health concern. To mitigate MI pathophysiology, we previously investigated a pro-reparative decellularized extracellular matrix (ECM) hydrogel for treating subacute and chronic MI. Despite increasing interest in biomaterial scaffolds, single cell and spatially resolved transcriptomics have not been used to probe their therapeutic activity in the heart. Here, we utilize spatial transcriptomics and single nucleus RNA sequencing to delineate the regional and cell-specific bioactivity of ECM biomaterials. ECM hydrogel subacute treatment induced cardiac resident macrophage preservation, fibroblast activation, and increased lymphatic, vasculature, smooth muscle and cardiomyocyte development as well as neurogenesis. Chronic treatment elicited macrophage polarization, cardiomyocyte and vasculature development, alongside fibroblast development. When comparing treatment timepoints, subacute administration had stronger immune modulation, while the chronic timepoint demonstrated higher cardiac development markers. Both subacute and chronic administration were associated with fibroblast activation and vasculature development. Thus, we elucidate undiscovered therapeutic targets of the ECM hydrogel, further demonstrating the potential of ECM biomaterials as an MI therapy.

bioengineering↗