Biology subjects

Billia, F.

Publications and source records attributed to Billia, F..

5 recordsLinked to original sources

bioRxiv2026

Latent Transforming Growth Factor Binding Protein ? 2 promotes microfibrillar TGF-? bioavailability to drive pathologic fibrosis in remote regions of infarcted hearts

Myocardial infarction (MI) initiates ventricular remodeling that extends beyond the infarct into remote, viable myocardium, where diffuse extracellular matrix (ECM) remodeling and stiffening contribute to progressive dysfunction and heart failure. Latent transforming growth factor binding protein 2 (LTBP2) is an injury-induced, microfibril-associated ECM glycoprotein that, among the LTBP family, does not covalently bind latent TGF-{beta}. We asked whether LTBP2 regulates remote remodeling after MI, and how a protein lacking latent TGF-{beta}-binding capacity could influence TGF-{beta}-dependent fibrosis. Wild-type and Ltbp2-null mice underwent permanent coronary ligation or sham surgery and were followed for 28 days by echocardiography and speckle-tracking strain analysis. Remote myocardium was assessed by histology, atomic force microscopy, and quantitative proteomics. Mechanism was interrogated in primary cardiac fibroblasts using a TGF-{beta} reporter assay. Sufficiency was tested with a fibrillin-1?binding module of LTBP2 delivered as purified protein or by lentiviral expression. LTBP2 was induced in injury-activated cardiac fibroblasts and localized to infarct and remote myocardium by 7 days post-MI. Ltbp2 deletion improved 28-day survival (P=0.0272) where Ltbp2-null hearts showed preserved ejection fraction and faster diastolic strain rates, with protection concentrated in segments remote from the infarct. Remote myocardium contained less interstitial collagen and was significantly less stiff. Proteomic profiling showed enrichment of ECM organization and TGF-{beta}-responsive programs in wild-type hearts that was attenuated in knockouts. In fibroblasts, loss of LTBP2 increased LTBP1 matrix incorporation and shifted TGF-{beta} from the soluble to the matrix-bound compartment; conversely, the minimal LTBP2 module bound fibrillin-1 directly and mobilized latent TGF-{beta} from established matrix within 20 minutes. LTBP2 drives maladaptive remodeling of remote myocardium after MI by limiting matrix sequestration of latent TGF-{beta} and expanding the activatable pool, resolving how an LTBP that does not bind latent TGF-{beta} amplifies TGF-{beta}- dependent fibrosis. LTBP2 and its fibrillin-1 interaction surface may be tractable targets.

physiology↗

bioRxiv2026

Transcriptomic analysis of human induced pluripotent stem cell cardiomyocytes and myocardial tissue reveals novel role for miR-9-5p in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is an inherited disease characterized by the thickening of the heart muscle. Mutations in genes encoding contractile proteins, such MYBPC3 and MYH7 account for over half of patients with familial HCM. MicroRNAs (miRNAs) are pivotal regulators of gene expression that may influence disease progression. Despite their potential significance, there is a scarcity of published data on miRNAs in HCM. Induced pluripotent stem cells (iPSCs) have emerged as valuable tools for modeling various cardiovascular diseases, including HCM. However, the miRNA expression profiles associated with HCM remain largely unexplored within iPSC models. Investigating the differential expression of miRNAs in HCM patients offers a promising avenue to identify potential therapeutic targets for individuals affected by this condition. In this study, we performed an unbiased screen using a microarray (NanoString Technologies) that contained 798 miRNAs to identify differentially expressed miRNAs in iPSC-cardiomyocytes (CM) and myocardial tissues derived from healthy donors and HCM patients with MYBPC3 and MYH7 mutations, identifying miR-9-5p as significantly downregulated in all HCM iPSC-CM and myectomy tissue compared to control. KEGG pathway analysis of gene targets using miRTarBase and g:Profiler revealed that miR-9-5p regulates genes in the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance pathway, which is involved in hypercontractility associated with HCM. Modulation of miR-9-5p expression in vitro using mimics significantly reduced cardiomyocyte size and contractility of MYBPC3 mutant iPSC-CMs whereas healthy control iPSC-CMs treated with antagomiRs exhibited hypertrophy. Our findings identify miR-9-5p as a regulator of cardiomyocyte hypertrophy and contractility, and suggest the miR-9-5p/EGFR tyrosine kinase inhibitor resistance axis as a potential therapeutic target to mitigate hypertrophy and hypercontractility exhibited in HCM.

molecular biology↗

bioRxiv2025

Blood-based Epigenetic Instability Linked to Human Aging and Disease

The abundance, dynamics, and context-dependent heterogeneity of DNA methylation--where a pattern considered abnormal in one cell type may be normal in another--poses challenges in identifying methylation abnormalities linked to disease risk. Through genome-wide analyses, we identified CpG sites with remarkably consistent methylation profiles in healthy whole blood, predominantly existing in an unmethylated state. We examined alterations at these epigenetically stable loci in diverse cohorts, including those with cardiovascular disease and hematological cancers. Our findings reveal methylation pattern disruption in myeloid and lymphoid malignancies, correlating with clonal burden fluctuations during leukemia treatment. In non-cancer cohorts, we observed that normally stable CpG sites exhibited progressive instability with advancing age, which was also associated with the onset of cardiovascular disease and decreased survival rates. This study links DNA methylation instability with the expansion of risk-prone blood cells and highlights its role as a biomarker for both cancer and cardiovascular disease.

genetics↗

bioRxiv2023

Myosin inhibitor reverses hypertrophic cardiomyopathy in pediatric iPSC-cardiomyocytes to mirror variant correction

Hypertrophic cardiomyopathy (HCM) is mainly caused by sarcomere gene variants in MYH7 and MYBPC3. Targeted drugs like myosin ATPase inhibitors have shown efficacy in adult HCM but have not been evaluated in children. We generated iPSC-cardiomyocytes (CMs) from four children with HCM harboring variants in MYH7 (V606M; R453C) or MYBPC3 (G148R; P955fs and TNNI3_A157P), variant-corrected controls, and a healthy individual. All CMs showed hypertrophy and sarcomere disorganization. All 3 single variant CMs showed higher contractility, slower relaxation, higher calcium transients and higher ATPase activity. Only MYH7 variant CMs showed stronger myosin-actinin binding. Targeted myosin ATPase inhibitor showed complete rescue of the phenotype in affected CMs and in cardiac Biowires to mirror isogenic controls. The response was stronger compared to verapamil or metoprolol, highlighting the need for clinical trials of myosin targeted therapy in pediatric HCM patients. The phenotype and response to drug therapy are influenced by the underlying genotype.

genetics↗

bioRxiv2022

Advanced physiological maturation of iPSC-derived human cardiomyocytes using an algorithm-directed optimization of defined media components

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold tremendous promise for in vitro modeling to assess native myocardial function and disease mechanisms as well as testing drug safety and efficacy. However, current iPSC- CMs are functionally immature, resembling in vivo CMs of fetal or neonatal developmental states. The use of targeted culture media and organoid formats have been identified as potential high-yield contributors to improve CM maturation. This study presents a novel iPSC-CM maturation medium formulation, designed using a differential evolutionary approach targeting metabolic functionality for iterative optimization. Relative to gold-standard reference formulations, our medium significantly matured morphology, Ca2+ handling, electrophysiology, and metabolism, which was further validated by multiomic screening, for cells in either pure or co-cultured microtissue formats. Together, these findings not only provide a reliable workflow for highly functional iPSC-CMs for downstream use, but also demonstrate the power of high-dimensional optimization processes in evoking advanced biological function in vitro.

bioengineering↗