Biology subjects

Sander, M.

Publications and source records attributed to Sander, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Distinct macrophage and T cell programs shape pancreatic inflammation during metabolic stress and aging

Type 2 diabetes is linked to systemic inflammation driven by metabolic stress and aging. Although pancreatic inflammation associated with these factors is well documented, the dynamics of immune cell populations and their molecular changes remain poorly understood. We characterized immune cell alterations in the pancreas and pancreatic islets during Western diet (WD) feeding and aging using imaging mass cytometry (IMC) and single-cell RNA sequencing (scRNA-seq). Spatial and transcriptional analyses were performed to define immune cell subtype composition, activation states, and inferred cell-cell communication programs under metabolic and age-related stress conditions. Our analyses identified expansion of an F4/80low macrophage subtype and activated effector-like CD8+ T cells throughout the pancreas during WD feeding and aging. Within pancreatic islets, single-cell RNA sequencing identified a type I interferon-responsive macrophage population with low F4/80 expression that expanded during overnutrition. Notably, the type I interferon responses elicited by these stressors diverged: aging was associated with a more canonical type I interferon response, whereas overnutrition induced a broader response that included STAT3-associated transcriptional programs. We further provide evidence for enhanced cytokine-mediated communication between macrophages and a CD8+ cytotoxic T-cell population under overnutrition and aging. These findings show that metabolic stress and aging remodel pancreatic inflammation through overlapping but distinct immune mechanisms, involving expansion of F4/80low macrophages, activation of divergent type I interferon programs, and enhanced macrophage-CD8+ T-cell communication. Together, these findings suggest that distinct therapeutic approaches may be required to preserve islet function in type 2 diabetes driven by metabolic stress versus aging. Article HighlightsO_LIMetabolic stress and aging remodel pancreatic inflammation through overlapping but distinct immune mechanisms. C_LIO_LISpatial and single-cell analyses identified conserved remodeling of pancreatic macrophage populations accompanied by activation of cytotoxic T-cell responses during metabolic stress and aging. C_LIO_LIIn pancreatic islets, macrophages exhibited distinct type I interferon-associated transcriptional programs, with aging showing a more canonical interferon response and metabolic stress eliciting a broader inflammatory program that included STAT3-associated transcriptional signatures. C_LIO_LIThese findings provide a framework for understanding how metabolic stress and aging differentially shape pancreatic inflammation. C_LI

cell biology↗

bioRxiv2026

Conserved multiheme cytochrome machinery for extracellular electron transfer is widespread and transcriptionally active across deep peat profiles

Northern peatlands store approximately one-third of global soil organic carbon, yet the anaerobic respiratory pathways governing carbon turnover remain unclear. In ombrotrophic bogs, the scarcity of inorganic terminal electron acceptors (TEAs) and high CO2:CH4 ratios indicate that methanogenesis alone cannot account for the observed CO2 production. Peat particulate organic matter (POM) has been proposed as an alternative TEA, but whether resident microorganisms encode and express extracellular electron transfer (EET) machinery required to use such extracellular TEAs remains unknown. Using depth-resolved metagenomics and metatranscriptomics across peat profiles from four ombrotrophic Swedish bogs, we identified conserved EET machinery in dominant yet uncultured Acidobacteriota and Verrucomicrobiota, comprising multiheme cytochromes and outer-membrane porins arranged in syntenic gene clusters. This machinery was transcriptionally active up to several meters depth, alongside broader anaerobic respiratory pathways, while methane-cycling processes were more prominent in the upper layers. These results provide systematic genomic and transcriptomic evidence for EET capacity in peatland microorganisms, establishing a molecular foundation for EET-based respiration and its potential role in suppressing methane formation and emissions.

microbiology↗

bioRxiv2026

Workload-induced changes to cell state contribute to β-cell failure in diabetes

Insufficient insulin secretion relative to insulin demand is a key feature of type 2 diabetes (T2D). While the defects of insulin-producing {beta}-cells in T2D are well defined, little is known about how {beta}-cells progress from the functionally normal state to the decompensated state during the natural history of this disease. Here, we provide evidence that workload-induced {beta}-cell overstimulation precipitates {beta}-cell failure in T2D. We employ scRNA-seq to define workload-induced changes to {beta}-cell transcriptional states, identifying a novel compensating state that is distinct from the stressed state of decompensated {beta}-cells. We demonstrate a key role for the chromatin-modifying enzyme Lysine-specific demethylase 1 (Lsd1) in restraining workload-induced {beta}-cell state transitions, indicating epigenomic control of {beta}-cell state. Experimental manipulations that promote the compensating state accelerate {beta}-cell failure in mouse models of diabetes. Altogether, these findings show that the compensatory response of the {beta}-cell to increased workload becomes maladaptive over time and contributes to the pathogenesis of T2D.

physiology↗

bioRxiv2026

Functional genomics reveals mediators of beta cell survival in ER stress and type 2 diabetes risk

Endoplasmic reticulum (ER) stress in pancreatic beta cells contributes to impaired function and type 2 diabetes (T2D). In this study we performed genome-wide perturbation screens and genomic profiling in beta cells to identify novel mediators of ER stress responses and diabetes risk. We defined gene regulatory networks in beta cells and identified specific beta cell networks enriched for T2D risk variants with altered expression in ER stress. We performed a loss-of-function CRISPR screen for survival under ER stress in EndoC-{beta}H1 cells, which identified 167 pro-survival and 47 pro-death genes involved in processes related to insulin secretion, mitochondrial transport and protein ubiquitination. Beta cell survival genes collectively had limited genomic change in stress yet showed significant, independent enrichment for T2D risk variants, including novel T2D candidate gene DTNB which we validated protects against beta cell death during stress. Overall, our results revealed mediators of ER stress responses in beta cells and identified new therapeutic targets to preserve beta cells in diabetes pathogenesis.

genomics↗

bioRxiv2025

Environmental DNA metabarcoding of invertebrate-incubated water supports WFD-compliant and animal-friendly bioassessment with added trait insights

Environmental (eDNA) metabarcoding is recently being considered for bioassessment under the Water Framework Directive (WFD). While tissue-based ("bulk") metabarcoding of macroinvertebrates produces comparable ecological status class values to morphology-based methods, eDNA-based metabarcoding often includes DNA signals from upstream sites, limiting its site-specificity. A promising alternative involves the incubation of locally collected invertebrates in water, followed by eDNA metabarcoding of the incubated water. In this study, we tested the suitability of two different approaches of the incubation strategy for ecological status assessment under the WFD. The first approach uses conventional multi-habitat sampling (MH) for the collection of the local macroinvertebrates and the second natural substrate exposures (NSEs) that are actively colonised. Using metabarcoding of the incubated water from both approaches (MH/NSE eDNA), we compared community composition, trait diversity and the derived ecological status classes (ESCs) to the local signal reference (MH/NSE bulk DNA) and the regional signal reference (stream water eDNA). For both approaches, community and trait composition were highly congruent between the incubated water and bulk samples. Trait composition did not differ between MH and NSE samples or among NSE types (wood-leaf vs. gravel). However, we detected small-scale spatial differences in the trait composition between NSEs placed at different flow regimes (pool vs. riffle). ESCs derived from all approaches (MH/NSE incubated water eDNA, MH/NSE bulk DNA and stream water eDNA) were highly similar and consistent with those from morpho-taxonomic assessments. Our findings support the incubation strategy using the conventional MH sampling as the most suitable approach for a minimally invasive, site-specific stream bioassessment within the context of the WFD.

ecology↗

bioRxiv2025

Single-cell multiome and spatial profiling reveals pancreas cell type-specific gene regulatory programs driving type 1 diabetes progression

Cell type-specific regulatory programs that drive type 1 diabetes (T1D) in the pancreas are poorly understood. Here we performed single nucleus multiomics and spatial transcriptomics in up to 32 non-diabetic (ND), autoantibody-positive (AAB+), and T1D pancreas donors. Genomic profiles from 853,005 cells mapped to 12 pancreatic cell types, including multiple exocrine sub- types. Beta, acinar, and other cell types, and related cellular niches, had altered abundance and gene activity in T1D progression, including distinct pathways altered in AAB+ compared to T1D. We identified epigenomic drivers of gene activity in T1D and AAB+ which, combined with genetic association, revealed causal pathways of T1D risk including antigen presentation in beta cells. Finally, single cell and spatial profiles together revealed widespread changes in cell-cell signaling in T1D including signals affecting beta cell regulation. Overall, these results revealed drivers of T1D progression in the pancreas, which form the basis for therapeutic targets for disease prevention.

genomics↗

bioRxiv2024

Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2

Selective and controlled expansion of endogenous {beta}-cells has been pursued as a potential therapy for diabetes. Ideally, such therapies would preserve feedback control of {beta}-cell proliferation to avoid excessive {beta}-cell expansion and an increased risk of hypoglycemia. Here, we identified a regulator of {beta}-cell proliferation whose inactivation results in controlled {beta}-cell expansion: the protein deacetylase Sirtuin 2 (SIRT2). Sirt2 deletion in {beta}-cells of mice increased {beta}-cell proliferation during hyperglycemia with little effect in homeostatic conditions, indicating preservation of feedback control of {beta}-cell mass. SIRT2 restrains proliferation of human islet {beta}-cells cultured in glucose concentrations above the glycemic set point, demonstrating conserved SIRT2 function. Analysis of acetylated proteins in islets treated with a SIRT2 inhibitor revealed that SIRT2 deacetylates enzymes involved in oxidative phosphorylation, dampening the adaptive increase in oxygen consumption during hyperglycemia. At the transcriptomic level, Sirt2 inactivation has context-dependent effects on {beta}-cells, with Sirt2 controlling how {beta}-cells interpret hyperglycemia as a stress. Finally, we provide proof-of-principle that systemic administration of a GLP1-coupled Sirt2-targeting antisense oligonucleotide achieves {beta}-cell selective Sirt2 inactivation and stimulates {beta}-cell proliferation under hyperglycemic conditions. Overall, these studies identify a therapeutic strategy for increasing {beta}-cell mass in diabetes without circumventing feedback control of {beta}-cell proliferation.

physiology↗

bioRxiv2023

Integration of single-cell multiomic measurements across disease states with genetics identifies mechanisms of beta cell dysfunction in type 2 diabetes

Altered function and gene regulation of pancreatic islet beta cells is a hallmark of type 2 diabetes (T2D), but a comprehensive understanding of mechanisms driving T2D is still missing. Here we integrate information from measurements of chromatin activity, gene expression and function in single beta cells with genetic association data to identify disease-causal gene regulatory changes in T2D. Using machine learning on chromatin accessibility data from 34 non-diabetic, pre-T2D and T2D donors, we robustly identify two transcriptionally and functionally distinct beta cell subtypes that undergo an abundance shift in T2D. Subtype-defining active chromatin is enriched for T2D risk variants, suggesting a causal contribution of subtype identity to T2D. Both subtypes exhibit activation of a stress-response transcriptional program and functional impairment in T2D, which is likely induced by the T2D-associated metabolic environment. Our findings demonstrate the power of multimodal single-cell measurements combined with machine learning for identifying mechanisms of complex diseases.

systems biology↗

bioRxiv2022

Engineered vasculature induces functional maturation of pluripotent stem cell-derived islet organoids

Blood vessels play a critical role in pancreatic islet health and function, yet current culture methods to generate islet organoids from human pluripotent stem cells (SC-islets) lack a vascular component. Here, we engineered 3D vascularized SC-islet organoids by assembling SC-islet cells, human primary endothelial cells (ECs) and fibroblasts both in a non-perfused model and a microfluidic device with perfused vessels. Vasculature improved stimulus-dependent Ca2+ influx into SC-{beta}-cells, a hallmark of {beta}-cell function that is blunted in non-vascularized SC-islets. We show that an islet-like basement membrane is formed by vasculature and contributes to the functional improvement of SC-{beta}-cells. Furthermore, cell-cell communication networks based on scRNA-seq data predicted BMP2/4-BMPR2 signaling from ECs to SC-{beta}-cells. Correspondingly, BMP4 augmented the SC-{beta}-cell Ca2+ response and insulin secretion. These vascularized SC-islet models will enable further studies of crosstalk between {beta}-cells and ECs and can serve as in vivo-mimicking platforms for disease modeling and therapeutic testing.

cell biology↗

bioRxiv2022

Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes

Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, CDX2+ pre-{beta}-cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro {beta}-cell maturation and identify sex hormones as drivers of {beta}-cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem cell-derived islets and a framework for manipulating cell identities and maturity.

cell biology↗

bioRxiv2021

A vascularized 3D model of the human pancreatic islet for ex vivo study of immune cell-islet interaction

Insulin is an essential regulator of blood glucose homeostasis that is produced exclusively by {beta} cells within the pancreatic islets of healthy individuals. In those affected by diabetes, immune inflammation, damage, and destruction of islet {beta} cells leads to insulin deficiency and hyperglycemia. Current efforts to understand the mechanisms underlying {beta} cell damage in diabetes rely on in vitro-cultured cadaveric islets. However, isolation of these islets involves removal of crucial matrix and vasculature that supports islets in the intact pancreas. Unsurprisingly, these islets demonstrate reduced functionality over time in standard culture conditions, thereby limiting their value for understanding native islet biology. Leveraging a novel, vascularized micro-organ (VMO) approach, we have recapitulated elements of the native pancreas by incorporating isolated human islets within a three-dimensional matrix nourished by living, perfusable blood vessels. Importantly, these islets show long-term viability and maintain robust glucose-stimulated insulin responses. Furthermore, vessel-mediated delivery of immune cells to these tissues provides a model to assess islet-immune cell interactions and subsequent islet killing -- key steps in type 1 diabetes pathogenesis. Together, these results establish the islet-VMO as a novel, ex vivo platform for studying human islet biology in both health and disease.

cell biology↗

bioRxiv2021

Systemic LSD1 inhibition prevents aberrant remodeling of metabolism in obesity

The transition from lean to obese states involves systemic metabolic remodeling that impacts insulin sensitivity, lipid partitioning, inflammation, and glycemic control. Here, we have taken a pharmacological approach to test the role of a nutrient-regulated chromatin modifier, lysine-specific demethylase (LSD1), in obesity-associated metabolic reprogramming. We show that systemic administration of an LSD1 inhibitor (GSK-LSD1) reduces food intake and body weight, ameliorates non-alcoholic fatty liver disease (NAFLD), and improves insulin sensitivity and glycemic control in mouse models of obesity. GSK-LSD1 has little effect on systemic metabolism of lean mice, suggesting LSD1 has a context-dependent role in promoting maladaptive changes in obesity. Analysis of insulin target tissues identified white adipose tissue as the major site of insulin sensitization by GSK-LSD1, where it reduces adipocyte inflammation and lipolysis. We demonstrate that GSK-LSD1 reverses NAFLD in a non-hepatocyte-autonomous manner, suggesting an indirect mechanism via inhibition of adipocyte lipolysis and subsequent effects on lipid partitioning. Pair-feeding experiments further revealed that effects of GSK-LSD1 on hyperglycemia and NAFLD are not a consequence of reduced food intake and weight loss. These findings suggest that targeting LSD1 could be a strategy for treatment of obesity and its associated complications including type 2 diabetes and NAFLD. O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/469928v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@17232dcorg.highwire.dtl.DTLVardef@6940a0org.highwire.dtl.DTLVardef@11d3deorg.highwire.dtl.DTLVardef@6cc0fd_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2021

Type 1 diabetes risk genes mediate pancreatic beta cell survival in response to proinflammatory cytokines

Beta cells intrinsically contribute to the pathogenesis of type 1 diabetes (T1D), but the genes and molecular processes that mediate beta cell survival in T1D remain largely unknown. We combined high throughput functional genomics and human genetics to identify T1D risk loci regulating genes affecting beta cell survival in response to the proinflammatory cytokines IL-1{beta}, IFN{gamma}, and TNF. We mapped 38,931 cytokine-responsive candidate cis-regulatory elements (cCREs) active in beta cells using ATAC-seq and single nuclear ATAC-seq (snATAC-seq), and linked cytokine-responsive beta cell cCREs to putative target genes using single cell co-accessibility and HiChIP. We performed a genome-wide pooled CRISPR loss-of-function screen in EndoC-{beta}H1 cells, which identified 867 genes affecting cytokine-induced beta cell loss. Genes that promoted beta cell survival and had up-regulated expression in cytokine exposure were specifically enriched at T1D loci, and these genes were preferentially involved in inhibiting inflammatory response, ubiquitin-mediated proteolysis, mitophagy and autophagy. We identified 2,229 variants in cytokine-responsive beta cell cCREs altering transcription factor (TF) binding using high-throughput SNP-SELEX, and variants altering binding of TF families regulating stress, inflammation and apoptosis were broadly enriched for T1D association. Finally, through integration with genetic fine mapping, we annotated T1D loci regulating beta cell survival in cytokine exposure. At the 16p13 locus, a T1D variant affected TF binding in a cytokine-induced beta cell cCRE that physically interacted with the SOCS1 promoter, and increased SOCS1 activity promoted beta cell survival in cytokine exposure. Together our findings reveal processes and genes acting in beta cells during cytokine exposure that intrinsically modulate risk of T1D.

genomics↗

bioRxiv2021

A missense KCNQ1 Mutation Impairs Insulin Secretion in Neonatal Diabetes

KCNQ1/Kv7 is a voltage-gated K+ channel that regulates heart rhythm, glucose and salt homeostasis. Mutations of KCNQ1 are primarily associated with long-QT syndrome and type 2 diabetes; however, thus far KCNQ1 mutations have not been associated with monogenetic diabetes. Here, we identified a homozygous KCNQ1 missense mutation (R397W) in an individual with permanent neonatal diabetes (PND). To identify the mechanisms that link the mutation to the disease, we introduced the mutation into human embryonic stem cells (hESCs), and used them to derived pancreatic {beta}-like cells (hESC-{beta} cell). In early {beta}-like cells, we observed atypical membrane electrical activity, increased levels of cytoplasmic Ca2+, and a hypersecretion of insulin. Upon extended culture, their insulin secretion decreased and the number of apoptotic cells increased, resulting in a reduction in the numbers of {beta}-like cells. Late-stage {beta}-like cells exhibited a decrease in the expression of metabolic genes, e.g. HNF4, PDX1 and GLUT1, providing a possible mechanism for {beta}-cell dysfunction. Our study identifies KCNQ1 as a novel candidate gene of monogenetic diabetes and shows that KCNQ1 regulates {beta}-cell function and survival.

cell biology↗

bioRxiv2021

Dispersed Sleep Microstates and Associated Structural Changes in GBA1 Mouse: Relevance to Rapid Eye Movement Behavior Disorder

Rapid eye movement (REM) sleep behaviour disorder (RBD) is a rare parasomnia that may predict the later occurrence of alpha-synucleinopathies. Variants in the gene encoding for the lysosomal enzyme glucocerebrosidase, GBA, strongly increase the risk of RBD. In a GBA1-mouse model recently shown to mimic prodromal stages of -synucleinopathy, we now demonstrate striking REM and NREM sleep abnormalities accompanied by distinct structural changes in the more widespread sleep neurocircuitry.

neuroscience↗

bioRxiv2021

Large-scale genetic association and single cell accessible chromatin mapping defines cell type-specific mechanisms of type 1 diabetes risk

Translating genome-wide association studies (GWAS) of complex disease into mechanistic insight requires a comprehensive understanding of risk variant effects on disease-relevant cell types. To uncover cell type-specific mechanisms of type 1 diabetes (T1D) risk, we combined genetic association mapping and single cell epigenomics. We performed the largest to-date GWAS of T1D in 489,679 samples imputed into 59.2M variants, which identified 74 novel association signals including several large-effect rare variants. Fine-mapping of 141 total signals substantially improved resolution of causal variant credible sets, which primarily mapped to non-coding sequence. To annotate cell type-specific regulatory mechanisms of T1D risk variants, we mapped 448,142 candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cell types using snATAC-seq of 131,554 nuclei. T1D risk variants were enriched in cCREs active in CD4+ T cells as well as several additional cell types including pancreatic exocrine acinar and ductal cells. High-probability T1D risk variants at multiple signals mapped to exocrine-specific cCREs including novel loci near CEL, GP2 and CFTR. At the CFTR locus, the likely causal variant rs7795896 mapped in a ductal-specific distal cCRE which regulated CFTR and the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in T1D pathogenesis and highlight the power of combining large-scale GWAS and single cell epigenomics to provide insight into the cellular origins of complex disease.

genetics↗

bioRxiv2020

A dual mechanism of enhancer activation by FOXA pioneer factors induces endodermal organ fates

FOXA pioneer transcription factors (TFs) displace nucleosomes and prime chromatin across enhancers of different endodermal organs in multipotent precursors before lineage induction. Here, we examined patterns and mechanisms of FOXA target site engagement using human pluripotent stem cell models of endodermal organ development. Unexpectedly, we find that only a subset of pancreatic, hepatic, and alveolar enhancers are FOXA-primed, whereas the majority are unprimed and engage FOXA only upon lineage induction. Analysis of sequence architecture revealed more abundant and stronger FOXA motifs at primed than unprimed enhancers and enrichment for lineage-specific TF motifs at unprimed enhancers. We show that FOXA recruitment to unprimed enhancers specifically depends on lineage-specific TFs, suggesting that regulatory DNA sequence logic governs temporal FOXA recruitment. Our findings suggest that FOXA-mediated enhancer priming broadly facilitates initiation of organ lineage programs, while secondary FOXA recruitment by lineage-specific TFs to the majority of enhancers confers organ specificity to gene expression.

genomics↗

bioRxiv2020

Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development

Genetic variants associated with type 2 diabetes (T2D) risk affect gene regulation in metabolically relevant tissues, such as pancreatic islets. Here, we investigated contributions of regulatory programs active during pancreatic development to T2D risk. Generation of chromatin maps from developmental precursors throughout pancreatic differentiation of human embryonic stem cells (hESCs) identifies enrichment of T2D variants in pancreatic progenitor-specific stretch enhancers that are not active in islets. Genes associated with progenitor-specific stretch enhancers are predicted to regulate developmental processes, most notably tissue morphogenesis. Through gene editing in hESCs, we demonstrate that progenitor-specific enhancers harboring T2D-associated variants regulate cell polarity genes LAMA1 and CRB2. Knockdown of lama1 or crb2 in zebrafish embryos causes a defect in pancreas morphogenesis and impairs islet cell development. Together, our findings reveal that a subset of T2D risk variants specifically affects pancreatic developmental programs, suggesting that dysregulation of developmental processes can predispose to T2D.

genomics↗