Biology subjects

Ackers-Johnson, M.

Publications and source records attributed to Ackers-Johnson, M..

3 recordsLinked to original sources

bioRxiv2025

Macrophage-like vascular smooth muscle cells dominate early atherosclerosis and are inhibited by targeting iron regulation

Vascular smooth muscle cells (VSMCs) contribute dynamically to atherosclerosis at all stages but the molecular drivers of their phenotypic switching, especially during early plaque development, and how they contribute to plaque progression remain unclear. We performed spatial transcriptomics on 12 human aortic tissues with and without atherosclerotic plaque. Macrophage-like SMCs were the predominant cell-type in the atheroma, displaying high iron storage and dysregulation, confirmed by spatial elemental mapping with nuclear microscopy. The combination of soluble iron and oxidized LDL promoted foamy macrophage-like VSMC cell state transition, while chelation inhibited this switching. In vivo, iron dysregulation induced neointimal thickening and macrophage-like switching in wire-injured Ldlr-/- mice, which was significantly reversed by ferrostatin-1, a ferroptosis inhibitor. These data show how targeting iron regulation modifies the macrophage-like VSMC cell state, and inhibits disease progression in atherogenesis.

genomics↗

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↗

bioRxiv2021

Long noncoding RNA VENTHEART is required for cardiomyocyte specification and function

RationaleLong noncoding RNAs (lncRNAs) control cardiac gene expression during heart development and disease. It is accordingly plausible for the same lncRNA to regulate both cardiac development, as well as play a role in adult heart disease progression. lncRNA regulators of early cardiomyocyte (CM) lineage commitment have been identified and characterised, however those controlling later CM specification remain unknown. ObjectivesIn this study we identified a novel lncRNA required for CM specification, maturation and function, and also discovered its suggested relevance to heart disease. Methods and ResultsWe performed single cell RNA-seq on human embryonic stem cell derived cardiomyocytes at 2, 6 and 12 weeks of differentiation. Weighted correlation network analysis (WGCNA) identified core gene modules, including lncRNAs highly abundant and uniquely expressed in the human heart. A lncRNA (we call VENTHEART, VHRT) co-expressed with cardiac maturation and ventricular-specific genes MYL2 and MYH7, as well as in adult human ventricular tissue. CRISPR-mediated excision of VHRT led to impaired CM sarcomere formation, and loss of the CM specification gene program. VHRT knockdown (KD) in hESC-CMs confirmed its regulatory role for key cardiac contraction, calcium hemostasis and heart development genes, including MYH6 and RYR2. Functional evaluation after VHRT KD using impedance-based technology and action potential recordings, proved reduced contraction amplitude and loss of the ventricular-like action potential in CM, respectively. Through an integrative analysis of genome-wide association studies (GWAS), expression quantitative trait locus (eQTL) and gene co-expression network, we found VHRT to be co-regulated with core cardiac contractile genes, and the likely source of a heart failure genetic association signal overlapping the VHRT gene locus. Finally, VHRT KD and human failing heart transcriptome comparison validates the consistent downregulation again of cardiac contractile and calcium regulatory genes (P<0.05). ConclusionWe conclude that VHRT lncRNA is required for proper CM specification and function. Furthermore, reduced VHRT may contribute to the development or progression of human heart disease.

cell biology↗