Biology subjects

Larcher, V.

Publications and source records attributed to Larcher, V..

5 recordsLinked to original sources

bioRxiv2025

Adventitial leptin receptor-expressing fibroblasts are preferential contributors to fibrotic remodeling of the heart post infarction

BackgroundCardiac fibrosis, a hallmark of heart failure and an unmet clinical need, arises from pathological activation of pre-existing cardiac fibroblasts (CFs), but the contribution of CF heterogeneity to this process remains unclear. MethodsMurine models were used to lineage trace or deplete a specific sub-population of CFs at baseline and after myocardial infarction (MI). Transcriptional and epigenetic differences between fibroblast subsets were assessed using next-generation sequencing. Conservation in humans was evaluated through single-cell RNA-seq datasets and histological examination. ResultsIn mice, fibroblasts were the sole cardiac cell type expressing the signaling-capable isoform of the leptin receptor (LepR). LepR+ CFs emerged neonatally, occupied a defined niche in the coronary adventitia, exhibited enhanced hedgehog signaling, and responded to leptin. After MI, LepR-Cre+ CFs proliferated more than interstitial CFs, became a predominant fibroblast lineage in the scar, and their genetic ablation reduced fibrosis while improving function. LepR+ CFs were also detected in the human heart, where they were embedded in an adipocyte-rich niche. ConclusionsThese findings identify adventitial fibroblasts as key drivers of pathological remodeling and demonstrate that fibroblasts, rather than cardiomyocytes, are the principal responders to leptin in the heart, redefining how this major endocrine pathway influences cardiac remodeling and disease.

cell biology↗

bioRxiv2025

Endothelial expression of ZBTB16 protects against cardiac aging

Background and aimAging significantly increases the risk of cardiovascular diseases, characterized by progressive cardiac dysfunction. The vascular niche is crucial for maintaining cardiac homeostasis, yet endothelial cell (EC) impairment during aging remains poorly understood. This study investigates epigenetically regulated mechanisms mediating EC-dependent cardiac aging and identifies a critical role of Zinc finger and BTB domain-containing protein 16 (ZBTB16). MethodsChromatin accessibility (snATAC-seq) and transcriptomic (snRNA-seq) analyses were performed on aged hearts to identify age-related regulatory changes. Functional studies using genetic models, assessed cardiac aging phenotypes. In vitro assays examined EC senescence and secretory profiles, while co-culture experiments analyzed the impact of ZBTB16-deficient EC supernatants on fibroblasts, cardiomyocytes, and neurons. Overexpression experiments in vitro and in vivo tested the potential for ZBTB16 to mitigate aging-associated dysfunction. ResultsAged hearts exhibited decreased chromatin accessibility and expression of the transcription factor ZBTB16 in both human and mice. Loss of ZBTB16 in young mice, including Zbtb16 haploinsufficient and endothelial-specific knockout mice, led to premature aging, diastolic dysfunction, and increased secretion of pro-fibrotic and inflammatory factors. Supernatants from ZBTB16-deficient ECs activated fibroblasts, induced cardiomyocyte hypertrophy, and impaired neuronal sprouting. Overexpression of ZBTB16 reversed these effects in senescent ECs and aged mice and reduced diastolic dysfunction. Mechanistic studies identified key downstream targets of ZBTB16, including nuclear receptor-interacting protein 1 (NRIP1). ZBTB16 suppressed NRIP1 expression, limiting fibroblast activation and pro-fibrotic signaling. ConclusionsZBTB16 is a key regulator of endothelial function, maintaining vascular niche homeostasis and mitigating aging-associated cardiac dysfunction. Its loss promotes EC senescence and pro-fibrotic signaling, contributing to diastolic dysfunction. Overexpression of ZBTB16 presents a potential therapeutic strategy for preserving cardiac function during aging. These findings establish a novel role for ZBTB16 in endothelial aging and cardiovascular disease prevention. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/681100v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1a56e2org.highwire.dtl.DTLVardef@13e23fforg.highwire.dtl.DTLVardef@ad681eorg.highwire.dtl.DTLVardef@8eca8b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Vascular niches are the primary hotspots for aging within the multicellular architecture of cardiac tissue

BackgroundAging is a major, yet unmodifiable risk factor for cardiovascular diseases, leading to vascular alterations, increased cardiac fibrosis, and inflammation, all of which contribute to impaired cardiac function. However, the microenvironment inciting age-related alterations withing the multicellular architecture of the cardiac tissue is unknown. MethodsWe investigated local microenvironments in aged mice hearts applying an integrative approach combining single-nucleus RNA sequencing and spatial transcriptomics in 12-week-old and 18-month-old mice. We defined distinct cardiac niches and studied changes in their cellular composition and functional characteristics. ResultsIntegration of spatial transcriptomics data across young and aged hearts allowed us to identify 11 cardiac niches, which were characterized by distinct cellular composition and functional signatures. Aging did not alter the overall proportions of cardiac niches but leads to distinct regional changes, particularly in the left ventricle. Whereas cardiomyocyte-enriched niches show disrupted circadian clock gene expression, vascular niches showed major changes in pro-inflammatory and pro-fibrotic signatures and altered cellular composition. We particularly identified larger vessel-associated cellular niches as key hotspots for activated fibroblasts and macrophages in aged hearts, with interactions of both cell types through the C3:C3ar1 axis. These niches were also enriched in senescence cells exhibiting high expression of immune evasion mechanisms that may impair senescent cell clearance. ConclusionOur findings indicate that the microenvironment around the vasculature is particularly susceptible to age-related changes and serves as a primary site for inflammation-driven aging, so called "inflammaging". This study provides new insights into how aging reshapes cardiac cellular architecture, highlighting vessel-associated niches as potential therapeutic targets for age-related cardiac dysfunction.

physiology↗

bioRxiv2025

Food supplementation with molybdenum complexes improves honey bee health

In this study, we evaluated the impact of supplementing honey bee feed with molybdenum-based compounds. Among a dozen of dinuclear Mo(V) complexes, we first selected the most stable and non-toxic complexes, which were tested as food supplements in an extensive eight-year campaign involving more than 700 beehives across various environmental conditions in Moldova, France, Greece and USA. This unprecedented field campaign revealed that a few milligrams of compounds Na-Mo2O4-EDTA or Li-Mo2O4-EDTA provided in spring or autumn, increased queen fecundity, hygienic behavior, and honey production, while infestation rates of worker bees and brood by the mite Varroa destructor, and mortality rates in winter were dramatically reduced. Hive monitoring showed that the Mo-containing syrup can be consumed over 1.5 months and is well assimilated by larvae and workers within the hive. In particular, Mo levels increased significantly in the head of the bees. X-ray fluorescence measurements demonstrated that Na-Mo2O4-EDTA increases Mo levels in brain, neurolemma and hypopharyngeal glands. The metabolism of Mo complexes was addressed using X-Ray photoelectron spectroscopy (XPS) on bee faeces, which revealed that the complexes are oxidized into Mo(VI) species and thus suggesting that Mo complexes may function as antioxidant agents in bees. These findings offer promising solutions for the beekeeping industry, which is struggling with weakening honey bee colonies. Significance StatementHoney bees play a crucial role as pollinators. Unfortunately, colony losses have increased significantly over the past decades through the action of multiple environmental stressors. Currently, solutions are sought to strengthen bees health and resilience. This study shows that feeding bees with small amounts of trace elements like molybdenum can improve honey bee condition and increase the production of hive products. Through an unprecedented series of field and lab tests it notably demonstrates that molybdenum complexes are i) non-toxic, ii) consumed by bees over several generations, iii) assimilated particularly in the brain and hypopharyngeal glands, iv) acting as antioxidant. These results open new avenues for using trace elements to improve pollinator health.

zoology↗

bioRxiv2022

The epigenetic modifier DOT1L regulates gene regulatory networks necessary for cardiac patterning and cardiomyocyte cell cycle withdrawal

Mechanisms by which specific histone modifications regulate distinct gene regulatory networks remain little understood. We investigated how H3K79me2, a modification catalyzed by DOT1L and previously considered a general transcriptional activation mark, regulates gene expression in mammalian cardiogenesis. Early embryonic cardiomyocyte ablation of Dot1l revealed that H3K79me2 does not act as a general transcriptional activator, but rather regulates highly specific gene regulatory networks at two critical cardiogenic junctures: left ventricle patterning and postnatal cardiomyocyte cell cycle withdrawal. Mechanistic analyses revealed that H3K79me2 in two distinct domains, gene bodies and regulatory elements, synergized to promote expression of genes activated by DOT1L. Surprisingly, these analyses also revealed that H3K79me2 in specific regulatory elements contributed to silencing genes usually not expressed in cardiomyocytes. As DOT1L mutants had increased numbers of postnatal mononuclear cardiomyocytes and prolonged cardiomyocyte cell cycle activity, controlled inhibition of DOT1L might be a strategy to promote cardiac regeneration post-injury.

developmental biology↗