Biology subjects

Andersson, S.

Publications and source records attributed to Andersson, S..

15 recordsLinked to original sources

bioRxiv2026

mTORC1-dependent control of Hedgehog signaling mediates nutrient-responsive licensing of intestinal stem cell differentiation

How progenitor cells couple their metabolic state to the regulation of fate and differentiation remains a fundamental question in tissue development and regeneration. Here, we identify a nutrient-responsive circuit that links progenitor anabolism to differentiation in the Drosophila midgut. We show that the mTORC1 downstream effector PWP1 is necessary and sufficient for differentiation of intestinal stem cell progeny toward the absorptive lineage in fed animals. In progenitors with high mTORC1 activity, PWP1 controls gene expression to promote Hedgehog (Hh) signaling, which cell autonomously drives progenitor differentiation into enterocytes. This circuit is constrained by feedback regulation, as elevated Hh activity inhibits mTORC1 and consequently excludes PWP1 from the nucleus. Disruption of the mTORC1-PWP1-Hh axis causes a progressive failure of enterocyte turnover during aging and reduced lifespan. While the aged midguts retain their barrier function, defective renewal leads to aging-associated deregulation of intestinal metabolism. Collectively, these observations support the concept of growth-dependent licensing of differentiation, whereby the nutrient-responsive anabolic state of a progenitor cell controls its lineage progression, consequently enabling organ renewal.

physiology↗

bioRxiv2026

Nutrient-responsive midgut turnover is spatially controlled by serotonin signaling

Barrier epithelia undergo rapid turnover, yet how spatial tissue heterogeneity and environmental cues shape turnover rates remains poorly understood. Here, we show that serotonin signaling spatially regulates homeostatic turnover of the Drosophila midgut epithelium in a nutrient-responsive manner. Organ-wide analysis revealed regions of constitutively high and low turnover, as well as areas whose renewal depends on nutrient intake. In rapidly renewing posterior regions, serotonin accumulates in enterocytes undergoing programmed cell death (erebosis) in response to nutrient availability. Serotonin signals through the conserved 5HT7 receptor to promote enteroblast (EB) maturation and migration-associated morphological changes. 5HT7 signaling is both necessary and sufficient for renewal in high-turnover regions, and its sustained disruption leads to epithelial multilayering. Mechanistically, 5HT7 signaling regulates genes involved in metabolic pathways, such as the serine biosynthesis pathway, and in the actin cytoskeleton, which drive EB maturation and morphological change, respectively. Together, our findings establish a signaling mechanism that links nutritional cues to the spatial regulation of barrier epithelium turnover.

physiology↗

bioRxiv2025

Ancient amino acid sets enable stable protein folds

Early proteins likely arose from a chemically limited set of amino acids available through prebiotic chemistry, raising a central question in molecular evolution: could such primitive compositions yield stable, functional folds? Using de novo design, we constructed three ancient protein architectures using a reduced, evolution-inspired alphabet of ten amino acids, e.g. lacking all basic and aromatic residues. The resulting structures adopted their intended topologies and showed exceptional resistance to thermal and chemical denaturation. Computational simulations further revealed that proteins built from this restricted alphabet were as mutation-resilient as those using all twenty canonical residues. Besides their evolutionary implications, our results provide a foundation for minimalist protein design and generation of simplified, robust systems in minimal cell engineering.

biochemistry↗

bioRxiv2023

Cell Types or Cell States? An Investigation of Adrenergic and Mesenchymal Cell Phenotypes in Neuroblastoma

Neuroblastoma is a pediatric cancer that exhibits two cellular phenotypes: adrenergic (ADRN) and mesenchymal (MES). ADRN is differentiated and therapy-sensitive, while MES is less differentiated with elevated therapy resistance. To understand neuroblastoma and its treatment response, it is important to elucidate how these phenotypes impact the eco-evolutionary dynamics of cancer cell populations and whether they represent distinct cell types or dynamic cell states. Here, we show that neuroblastoma cells undergo an ADRN to a MES phenotypic switch under chemotherapy treatment. We use a strong inference approach to generate four hypotheses on how this switch may occur: cell types without resistance, cell types with resistance, cell states without resistance, and cell states with resistance. For each of these hypotheses, we create theoretical models to make qualitative predictions about their resulting eco-evolutionary dynamics. Our results provide a framework to further experimentally determine whether ADRN and MES phenotypes are distinct cell types or dynamic cell states.

cancer biology↗

bioRxiv2023

The α-dystroglycan N-terminus is a broad-spectrum antiviral agent against SARS-CoV-2 and enveloped viruses

The COVID-19 pandemic has shown the need to develop effective therapeutics in preparedness for further epidemics of virus infections that pose a significant threat to human health. As a natural compound antiviral candidate, we focused on -dystroglycan, a highly glycosylated basement membrane protein that links the extracellular matrix to the intracellular cytoskeleton. Here we show that the N-terminal fragment of -dystroglycan (-DGN), as produced in E. coli in the absence of post-translational modifications, blocks infection of SARS-CoV-2 in cell culture, human primary gut organoids and the lungs of transgenic mice expressing the human receptor angiotensin I-converting enzyme 2 (hACE2). Prophylactic and therapeutic administration of -DGN reduced SARS-CoV-2 lung titres and protected the mice from respiratory symptoms and death. Recombinant -DGN also blocked infection of a wide range of enveloped viruses including the four Dengue virus serotypes, influenza A virus, respiratory syncytial virus, tick-borne encephalitis virus, but not human adenovirus, a non-enveloped virus in vitro. This study establishes soluble recombinant -DGN as a broad-band, natural compound candidate therapeutic against enveloped viruses.

microbiology↗

bioRxiv2023

Trunk neural crest gene MOXD1 affects embryonic development

Ectoderm-derived neural crest is a transient structure arising during early embryogenesis in vertebrates. Neural crest consists of four derivatives based on their anterior- to posterior location along the body axis; cranial, vagal, trunk and sacral, respectively. We recently showed that trunk neural crest-specific gene MOXD1 functions as a tumor suppressor in trunk neural crest-derived childhood cancer form neuroblastoma and is essential for proper development of healthy adrenal glands. However, the role of MOXD1 during early embryogenesis is not known. Here, we conditionally knocked out MOXD1 in trunk neural crest cells before they become lineage-committed, using a CRISPR/Cas9 approach in chick embryos. Assessment of embryo growth showed that knockout of MOXD1 delayed development with knockout embryos being smaller. RNA sequencing of trunk-derived neural crest cells from control and knockout embryos showed enrichment of genes connected to gland development, copper ion metabolism and neuroblastoma progression. In conclusion, MOXD1 is important during early and prolonged embryonic development with effects on gland formation, possibly mediated via its role in copper metabolism.

developmental biology↗

bioRxiv2023

Golgi organization is a determinant of stem cell function in the small intestine

Cell-to-cell signalling between niche and stem cells regulates tissue regeneration. While the identity of many mediating factors is known, it is largely unknown whether stem cells optimize their receptiveness to niche signals according to the niche organization. Here, we show that Lgr5+ small intestinal stem cells (ISCs) regulate the morphology and orientation of their secretory apparatus to match the niche architecture, and to increase transport efficiency of niche signal receptors. Unlike the progenitor cells lacking lateral niche contacts, ISCs orient Golgi apparatus laterally towards Paneth cells of the epithelial niche, and divide Golgi into multiple stacks reflecting the number of Paneth cell contacts. Stem cells with a higher number of lateral Golgi transported Epidermal growth factor receptor (Egfr) with a higher efficiency than cells with one Golgi. The lateral Golgi orientation and enhanced Egfr transport required A-kinase anchor protein 9 (Akap9), and was necessary for normal regenerative capacity in vitro. Moreover, reduced Akap9 in aged ISCs renders ISCs insensitive to niche-dependent modulation of Golgi stack number and transport efficiency. Our results reveal stem cell-specific Golgi complex configuration that facilitates efficient niche signal reception and tissue regeneration, which is compromised in the aged epithelium.

cell biology↗

bioRxiv2023

MOXD1 is a gate-keeper of organ homeostasis and functions as a tumor-suppressor in neuroblastoma

Neuroblastoma is a childhood cancer believed to result from dysfunctional development. Its origin during embryogenesis remains poorly understood. The lack of appropriate models has hindered in-depth mapping of tumor-driving events. Here, we identify a novel tumor-suppressor gene that predicts poor survival in high-risk disease, by applying bulk and single cell RNA sequencing data of neuroblastoma and human fetal adrenal glands. Trunk neural crest-specific MOXD1 discriminates cell populations during normal and tumor development, with implications for deciphering neuroblastoma cell origin. We created an embryonic conditional knockout model and show that cell type-specific loss of MOXD1 leads to disrupted organ homeostasis and failed adrenal gland formation, home for neuroblastoma. We show that MOXD1 is a tumor suppressor gene in zebrafish, chick, and mice in vivo models. One-Sentence SummaryNeural crest-specific MOXD1 is a de novo tumor-suppressor gene in childhood cancers arising during embryogenesis.

cancer biology↗

bioRxiv2022

Object-centered population coding in CA1 of the hippocampus

Objects and landmarks are crucial for guiding navigation and must be integrated into the cognitive map of space. Studies of object coding in the hippocampus have primarily focused on activity of single cells. Here we record simultaneously from large numbers of hippocampal CA1 neurons to determine how the presence of a salient object in the environment alters single-neuron and neural-population dynamics of the area. Only a small number of cells fired consistently at the object location, or at a fixed distance and direction from it; yet the majority of the cells showed some change in their spatial firing patterns when the object was introduced. At the neural population level, these changes were systematically organized according to the animals distance from the object. This organization was widely distributed across the cell sample, suggesting that some features of cognitive maps - including object representation - are best understood as emergent properties of neural populations.

neuroscience↗

bioRxiv2021

PCSK9 affects expression of key surface proteins in human pancreatic beta cells through intra- and extracellular regulatory circuits

Aims/hypothesisProprotein convertase subtilisin/kexin 9 (PCSK9) is involved in the degradation of LDLR. However, PCSK9 can target other proteins in a cell-type specific manner. While PCSK9 has been detected in pancreatic islets, its expression in insulin-producing pancreatic beta cells is debated. Herein, we studied PCSK9 expression, regulation and function in the human pancreatic beta cell line EndoC-{beta}H1. MethodsWe assessed PCSK9 expression in mouse and human pancreatic islets, and in the pancreatic beta cell line EndoC-{beta}H1. We also studied PCSK9 regulation by cholesterol, lipoproteins, Mevastatin, and by SREBPs transcription factors. To evaluate PCSK9 function in pancreatic beta cells, we performed PCSK9 gain-and loss-of-function experiments in EndoC-{beta}H1 using siPCSK9 or recombinant PCSK9 treatments, respectively. ResultsWe demonstrate that PCSK9 is expressed and secreted by pancreatic beta cells. In EndoC-{beta}H1 cells, PCSK9 expression is regulated by cholesterol and by SREBPs transcription factors. Importantly, PCSK9 knockdown results in multiple transcriptome, proteome and secretome deregulations and impaired insulin secretion. By gain- and loss-of-function experiments, we observed that PCSK9 regulates the expression levels of LDLR and VLDLR through an extracellular mechanism while CD36, PD-L1 and HLA-ABC are regulated through an intracellular mechanism. Conclusions/interpretationCollectively, these results highlight PCSK9 as an important regulator of CD36, PD-L1 and HLA-ABC cell surface expression in pancreatic beta cells. Data availabilityRNA-seq data have been deposited to GEO database with accession number GSE182016. Mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the following identifiers: PXD027921, PXD027911 and PXD027913.

cell biology↗

bioRxiv2021

Characterization of the secretome, transcriptome and proteome of human β cell line EndoC-βH1

Early diabetes research is hampered by limited availability, variable quality and instability of human pancreatic islets in culture. Little is known about the human {beta} cell secretome, and recent studies question translatability of rodent {beta} cell secretory profiles. Here, we verify representativeness of EndoC-{beta}H1, one of the most widely used human {beta} cell lines, as a translational human {beta} cell model based on omics and characterize the EndoC-{beta}H1 secretome. We profiled EndoC-{beta}H1 cells using RNA-seq, Data Independent Acquisition (DIA) and Tandem Mass Tag proteomics of cell lysate. Omics profiles of EndoC-{beta}H1 cells were compared to human {beta} cells and insulinomas. Secretome composition was assessed by DIA proteomics. Agreement between EndoC-{beta}H1 cells and primary adult human {beta} cells was ~90% for global omics profiles as well as for {beta} cell markers, transcription factors and enzymes. Discrepancies in expression were due to elevated proliferation rate of EndoC-{beta}H1 cells compared to adult {beta} cells. Consistently, similarity was slightly higher with benign non-metastatic insulinomas. EndoC-{beta}H1 secreted 671 proteins in untreated baseline state and 3,278 proteins when stressed with non-targeting control siRNA, including known {beta} cell hormones INS, IAPP, and IGF2. Further, EndoC-{beta}H1 secreted proteins known to generate bioactive peptides such as granins and enzymes required for production of bioactive peptides. Unexpectedly, exosomes appeared to be a major mode of secretion in EndoC-{beta}H1 cells. We believe that secretion of exosomes and bioactive peptides warrant further investigation with specialized proteomics workflows in future studies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/459582v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1976bc0org.highwire.dtl.DTLVardef@233c4eorg.highwire.dtl.DTLVardef@14c3350org.highwire.dtl.DTLVardef@1bcf0d5_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIWe validate EndoC-{beta}H1 as a translational human {beta} cell model using omics. C_LIO_LIWe present the first unbiased proteomics composition of human {beta} cell line secretome. C_LIO_LIThe secretome of human {beta} cells is more extensive than previously thought. C_LIO_LIUntreated cells secreted 671 proteins and stressed cells secreted 3,278 proteins. C_LIO_LISecretion of exosomes and bioactive peptides constitute directions of future research. C_LI

bioinformatics↗

bioRxiv2021

Quantitative intracellular retention of delivered RNAs through optimized cell fixation and immuno-staining

Detection of nucleic acids within sub-cellular compartments is key to understanding their function. Determining the intracellular distribution of nucleic acids requires quantitative retention and estimation of their association with different organelles by immunofluorescence microscopy. This is important also for the delivery of nucleic acid therapeutics which depends on endocytic uptake and endosomal escape. However, the current methods fail to preserve the majority of exogenously delivered nucleic acids in the cytoplasm. To solve this problem, by monitoring Cy5-labeled mRNA delivered to primary human adipocytes via lipid nanoparticles (LNP), we optimized cell fixation, permeabilization and immuno-staining of a number of organelle markers, achieving quantitative retention of mRNA and allowing visualization of levels which escape detection using conventional procedures. Additionally, we demonstrated the protocol to be effective on exogenously delivered siRNA, miRNA, as well as endogenous miRNA. Our protocol is compatible with RNA probes of single molecule fluorescence in-situ hybridization (smFISH) and molecular beacon, thus demonstrating that it is broadly applicable to study a variety of nucleic acids.

cell biology↗

bioRxiv2021

Fetal-like reversion in the regenerating intestine is regulated by mesenchymal Asporin

Epithelial tissues undergo fetal-like cellular reprogramming to regenerate after damage1,2. Although the mesenchyme and the extracellular matrix (ECM) play critical roles in tissue homeostasis and regeneration2-5, their role in repurposing developmental programs in epithelium is unknown. To model epithelial regeneration, we culture intestinal epithelium on decellularized small intestinal scaffold (iECM), and identify Asporin (Aspn), an ECM bound proteoglycan, as a critical mediator of cellular reprogramming. Aspn is produced by the mesenchyme, and we show that its effect on epithelial Tgf{beta}-signalling via CD44 is critical for fetal-like conversion. Furthermore, we demonstrate that Aspn is transiently increased upon chemotherapy-induced damage and pivotal for a timely induction of the fetal-like state and tissue regeneration. In summary, we establish a platform for modelling epithelial injury responses ex vivo, and show that the mesenchymal Aspn-producing niche controls tissue repair by regulating epithelial fetal-like reprogramming.

developmental biology↗

bioRxiv2020

Endosomal escape of delivered mRNA from endosomal recycling tubules visualized at the nanoscale

Delivery of exogenous mRNA using lipid nanoparticles (LNP) is a promising strategy for therapeutics. However, a bottleneck remains the poor understanding of the parameters that correlate with endosomal escape vs. cytotoxicity. To address this problem, we compared the endosomal distribution of six LNP-mRNA formulations of diverse chemical composition and efficacy, similar to those employed in mRNA-based vaccines, in primary human adipocytes, fibroblasts and HeLa cells. Surprisingly, we found that total uptake is not a sufficient predictor of delivery and different LNP vary considerably in endosomal distributions. Prolonged uptake impaired endosomal acidification, a sign of cytotoxicity, and caused mRNA to accumulate in compartments defective in cargo transport and unproductive for delivery. In contrast, early endocytic/recycling compartments have the highest probability for mRNA escape. By super-resolution microscopy we could resolve single LNP-mRNA within sub-endosomal compartments and capture events of mRNA escape from endosomal recycling tubules. Our results change the view of the mechanisms of endosomal escape and define quantitative parameters to guide the development of mRNA formulations towards higher efficacy and lower cytotoxicity.

bioengineering↗

bioRxiv2020

Genome-wide imaging screen uncovers molecular determinants of arsenite-induced protein aggregation and toxicity and an important role for transcriptional and translational control

Exposure to toxic metals and metalloids such as cadmium and arsenic results in widespread misfolding and aggregation of cellular proteins. How these protein aggregates are formed in vivo, the mechanisms by which they affect cells, and how cells prevent their accumulation during environmental stress is not fully understood. To find components involved in these processes, we performed a genome-wide imaging screen and identified yeast deletion mutants with either enhanced or reduced protein aggregation levels during arsenite exposure. Mutants with reduced aggregation levels were enriched for functions related to protein biosynthesis and transcription, whilst functions related to cellular signalling, metabolism, and protein folding and degradation were overrepresented among mutants with enhanced aggregation levels. On a genome-wide scale, protein aggregation correlated with arsenite resistance and sensitivity, indicating that many of the identified factors are crucial to safeguard protein homeostasis (proteostasis) and to protect against arsenite toxicity. Dedicated follow-up experiments indicated that intracellular arsenic is a direct cause of protein aggregation and that accurate transcriptional and translational control are crucial for proteostasis during arsenite stress. Specifically, we provide evidence that global transcription affects protein aggregation levels, that loss of transcriptional control impacts proteostasis through distinct mechanisms, and that translational repression is central to control protein aggregation and cell viability. Some of the identified factors are associated with pathological conditions suggesting that arsenite-induced protein aggregation may impact disease processes. The broad network of cellular systems that impinge on proteostasis during arsenic stress provides a valuable resource and a framework for further elucidation of the mechanistic details of metalloid toxicity and pathogenesis. AUTHOR SUMMARYHuman exposure to poisonous metals is increasing in many parts of the world and chronic exposure is associated with certain protein folding-associated disorders such as Alzheimers disease and Parkinsons disease. While the toxicity of many metals is undisputed, their molecular modes of action have remained unclear. Recent studies revealed that toxic metals such as arsenic and cadmium profoundly affect the correct folding of proteins, resulting in the accumulation of toxic protein aggregates. In this study, we used high-content microscopy to identify a broad network of cellular systems that impinge on protein homeostasis and cell viability during arsenite stress. Follow-up experiments highlight the importance of accurate transcriptional and translational control for mitigating arsenite-induced protein aggregation and toxicity. Some of the identified factors are associated with pathological conditions suggesting that arsenite-induced protein aggregation may impact disease processes. The broad network of cellular systems that impinge on proteostasis during arsenic stress provides a valuable resource and a framework for further elucidation of the mechanistic details of metal toxicity and pathogenesis.

cell biology↗