Biology subjects

Heiles, S.

Publications and source records attributed to Heiles, S..

5 recordsLinked to original sources

bioRxiv2026

SIMO - Single Section Integrative Multi-Omics - spatial mapping of metabolites and lipids combined with region-specific proteomics in a single tissue slice

Technological advances in biomedical sciences have accelerated multi-omics research, enabling high-resolution spatial mapping of diverse molecular compound classes. However, integrating spatial omics often requires serial tissue sections, limiting the alignment correlation across modalities. We present a single-section integrative multi-omics (SIMO) workflow that combines metabolite and lipid imaging with histopathology and region-specific proteomics. Using MALDI-MSI, tissue staining, and laser microdissection (LMD), SIMO delivers comprehensive metabolic, lipidomic, and proteomic insight from the same sample. Using mouse cardiac tissue we develop, control, and validate the methodology resulting in [~]60 imaged lipids and [~]60 imaged metabolites at 20 {micro}m pixel size and subsequently spatial proteomics by LMD, detecting over 5,000 proteins from the same tissue. To demonstrate the capabilities of the workflow in preclinical context, we apply SIMO to a metastasizing melanoma PDX model, identifying over 100 spatially localized lipids and metabolites, and over 5,000 proteins across metastases and non-tumor tissues in liver. SIMO enables precise ROI selection, statistical comparison of protein regulation, and alignment of metabolic and lipidomics pathways across spatial omics and region-specific proteomics, demonstrating its value as a spatial multi-omics platform.

biochemistry↗

bioRxiv2026

Isotopic tracing of scyllo-inositol uncovers its incorporation into phosphatidylinositols in mammalian cells

Inositols are a family of cyclic sugar alcohols comprising nine stereoisomers. Myo-inositol is the most abundant isomer found in humans and has been studied most extensively. It plays an important role in osmoregulation and is incorporated into membrane-anchored phosphatidylinositols. Scyllo-inositol is the second most abundant inositol isomer in the human brain and aberrant concentrations are associated with various diseases; however, its biological functions remain poorly understood. Here, the development and application of [13C6]scyllo-inositol as an isotopic tracer to study its metabolism is reported. A concise and robust synthetic route was established to obtain [13C6]scyllo-inositol from [13C6]myo-inositol in good yield. The uptake of [13C6]scyllo-inositol and responses of endogenous inositol isomers were measured in multiple cell lines by HILIC-MS/MS, showcasing the advantages of isotopic tracing. [13C6]scyllo-inositol proved to be a versatile isotopic tracer, when coupled with MS-based lipidomics and 2D NMR experiments. These experiments provide evidence that scyllo-inositol is incorporated into phosphatidylinositols in different cell lines. The results suggest a previously underappreciated role of scyllo-inositol in mammalian cells. The utilization of [13C6]scyllo-inositol will help to elucidate the role of scyllo-inositol metabolism in healthy and diseased states. SignificanceScyllo-inositol is a cyclic sugar alcohol found predominantly in the human brain. Changes in its concentration are associated with different diseases, and scyllo-inositol has been investigated as a potential drug against Alzheimers disease in clinical trials. However, its metabolic fate in mammalian cells is not well understood. We report here a synthetic strategy to obtain [13C6]scyllo-inositol and demonstrate, through isotopic tracing, its incorporation into phosphatidylinositols in different human-derived cell lines. This new stable isotopic tracer enables the investigation of the biological role of scyllo-inositol in mammals and beyond. HighlightsO_LIConcise synthesis of [13C6]scyllo-inositol C_LIO_LI[13C6]scyllo-inositol uptake and response of endogenous inositol isomers studied in multiple cell lines C_LIO_LIUse of [13C6]scyllo-inositol as an isotopic tracer in metabolomics and lipidomics experiments C_LIO_LIEvidence for scyllo-inositol incorporation into phosphatidylinositol in mammalian cells C_LI

biochemistry↗

bioRxiv2025

Automatic colocalization of high resolution MALDI MSI and Raman imaging applied to cardiac tissue of Fabry disease mouse models

Understanding early molecular changes in biological tissues is crucial for diagnosing pathological and genetic diseases and for elucidating their underlying mechanisms. However, localized molecular alterations of low molecular-weight compounds are not inferred from conventional staining or genetic methods. Here, we established a multimodal imaging approach that integrates Raman spectroscopy and atmospheric pressure matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-MALDI MSI): two complementary, label-free techniques enabling molecular profiling of a broad spectrum of biomolecules from one single tissue section. This method was applied to detect Gb3 accumulation in heart tissue of murine models of Fabry disease, including mice deficient in -galactosidase A (GLA) activity (GLA knock-out) and transgenic mice with a GLA knock-out and an upregulation of globotriaosylceramides (Gb3) synthase. With AP-MALDI MSI we were able to discern the heterogenous expression of Gb3 lipoforms with down to 5 {micro}m pixel size and reveal the significantly increased Gb3 content in mice containing a GLA knock-out combined with human Gb3 synthase overexpression compared to GLA knock-out and wild type samples. By employing Raman microscopy with a pixel size of 2 {micro}m, we were able to contextualize the physiological alterations in cardiac tissue by identifying components associated with nuclei, tissue, collagen, and lipids for the same three genotypes. An automated co-localization algorithm aligned Raman and AP-MALDI-MSI data from the same tissue section with (5.1 {+/-} 1.6) {micro}m precision, enabling overlay at 5 {micro}m and 2 {micro}m resolution. The method resolved heterogeneous Gb3 distributions and distinct lipid species in cardiac mouse tissue.

molecular biology↗

bioRxiv2024

Enhanced cardiac mitochondrial biogenesis by nitro-oleic acid remedies diastolic dysfunction in a mouse model of heart failure with preserved ejection fraction

Prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, while treatment options are inadequate. Hypertension and obesity-related metabolic dysfunctions contribute to HFpEF progression. Nitro-oleic acid (NO2-OA) impacts metabolic processes by improving glucose tolerance and adipocyte function. In this study, 4 week treatment with NO2-OA ameliorated diastolic dysfunction in a HFpEF mouse model induced by high-fat diet and inhibition of the endothelial nitric oxide synthase. A proteomic analysis of left ventricular tissue revealed, that one third of the identified proteins, mostly mitochondrial proteins, were upregulated in hearts of NO2-OA-treated HFpEF mice compared to controls and vehicle-treated HFpEF mice, which was confirmed by immunoblot. Activation of the 5-adenosine-monophosphate-activated-protein-kinase (AMPK) signaling pathway mediated an enhancement of mitochondrial biogenesis in hearts of NO2-OA-treated HFpEF mice. In cardiomyocytes under metabolic stress, NO2-OA increased mitochondrial protein level accompanied by enhanced oxidative phosphorylation. In conclusion, targeting mitochondrial integrity in HFpEF leads to improved diastolic function.

pathology↗

bioRxiv2023

Lipid signatures and inter-cellular heterogeneity of naive and lipopolysaccharide-stimulated human microglia-like cells

Microglia are non-neuronal cells, which are residing in the central nervous system and are known to play an important role in health and disease. We investigated lipidomic phenotypes of human naive and stimulated microglia-like cells by atmospheric-pressure scanning microprobe matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-SMALDI MSI). With lateral resolutions between 5 m and 1.5 m, we were able to chart lipid compositions of individual cells, enabling to differentiate cell lines and stimulation conditions. This allowed us to reveal local lipid heterogeneities in naive and lipopolysaccharide (LPS)-stimulated cells. We were able to identify individual cells with elevated triglyceride (TG) levels and could show that the number of these TG-enriched cells increased with LPS stimulation as a hallmark for a proinflammatory phenotype. Additionally, observed local abundance alterations of specific phosphatidylinositols (PIs) indicate a cell specific regulation of the PI metabolism.

biochemistry↗