Biology subjects

Haase, M.

Publications and source records attributed to Haase, M..

12 recordsLinked to original sources

bioRxiv2026

Expression trajectories in the aging male mouse colon transcriptome

Characterizing temporal dynamics during aging is crucial to understanding the course of aging-related events. The transcriptome is extensively remodeled with age, but the temporal trajectories of these changes, particularly through midlife, remain poorly defined in many tissues. Here, we address this gap in the male mouse colon. Using a dataset of 83 RNA-Seq samples from five time points during adult mouse lifespan, we show that colon aging is characterized by multiple gene-expression trajectories unfolding in parallel, with a major shift occurring during a mid- to late-life transition marked by a collapse of the unfolded protein response (UPR). Moreover, we report widespread non-monotonic trajectories, including genes that peak or dip in midlife and would be missed by comparisons limited to young versus old ages. We further describe age-dependent dynamics of transposable element-containing transcripts and a nonlinear course of transcriptomic entropy across the lifespan. Importantly, we identify a small set of genes that track chronological age and use only three of them to construct a compact transcriptomic clock, which we validate using an independent RNA-seq dataset and qPCR data. Together, our results indicate that nonlinear patterns dominate the aging colon transcriptome and underscore the value of high temporal resolution for identifying key transitions during aging.

bioinformatics↗

bioRxiv2025

Social isolation of aged mice drives dramatic release of inflammatory lipoxygenase-derived oxylipins

Oxylipins, signalling molecules derived from polyunsaturated fatty acids, act as key mediators controlling inflammatory processes. Ageing fuels the disruption of this network, promoting inflammageing. Social isolation, a common feature of ageing, may contribute to the emergence of pro-inflammatory responses, further aggravating conditions like cognitive decline and frailty. Here, we studied how repeated social isolation impacts inflammation-related oxylipin profiles in seven different organs and serum of aged mice. Additionally, we explored physical exercise as a tool to ameliorate age- and isolation-associated inflammation. Our results show that social isolation induces significant increases in interleukin-1{beta} levels and stimulates a dramatic production of lipoxygenase (LOX)-derived oxylipins in an organ-dependent manner, particularly pronounced in liver, lung, and spleen. Physical exercise failed to mitigate the pro-inflammatory effects induced by social isolation. These effects did not occur in the circulatory system as serum oxylipin levels remained relatively unchanged by isolation. The unexpected and striking elevation of oxylipins across the organs highlights the detrimental effect of social isolation and proposes key roles of oxylipins in stress-related inflammageing.

immunology↗

bioRxiv2025

NKCC1 a Regulator of Glioblastoma Progression

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with poor prognosis despite multimodal therapy. Chloride cotransporters NKCC1 and KCC2 are key regulators of intracellular chloride levels and thereby determine whether GABA acts inhibitory or excitatory. In GBM, disrupted chloride homeostasis promotes proliferation, migration, and stem-like properties, but its clinical relevance is not fully understood. We analysed NKCC1 and KCC2 expression in glioblastoma samples, considering clinical parameters such as age, gender, and MGMT promoter methylation. Statistical analyses included ROC-based cutoff determination, Kaplan-Meier survival analysis and subgroup. Immunohistochemistry was performed to identify cell types expressing NKCC1. NKCC1 expression was significantly higher in older patients and emerged as a prognostic marker for recurrence-free survival, with lower levels correlating with delayed recurrence, although overall survival was unaffected. NKCC1 was expressed in stem-like, astrocytic, and progenitor cells, but not in mature neurons. These findings identify NKCC1 as a regulator of GBM progression and recurrence, linking chloride transporter imbalance to GABAergic signalling. Targeting NKCC1 and restoring chloride homeostasis may provide promising new treatment strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/677289v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@a964f1org.highwire.dtl.DTLVardef@1224400org.highwire.dtl.DTLVardef@9e5c94org.highwire.dtl.DTLVardef@d0324f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Multi-omics analysis highlights the link of aging-related cognitive decline with systemic inflammation and alterations of tissue-maintenance

Aging-related cognitive decline is associated with changes across different tissues and the gut microbiome, including dysfunction of the gut-brain axis. However, only few studies have linked multi-organ alterations to cognitive decline during aging. Here we report a multi-omics analysis integrating metabolomics, transcriptomics, DNA methylation, and metagenomics data from hippocampus, liver, colon, and fecal samples of mice, correlated with cognitive performance in the Barnes Maze spatial learning task across different age groups. We identified 734 molecular features associated with cognitive rank within individual data layers, of which 227 features remain when integrating all data layers with each other. Among the single-layer predictors, several host and microbial features were highlighted, with host-associated markers being predominant. Host features associated with cognitive function mainly belong to innate and adaptive inflammatory activity (inflammaging) and developmental processes. Our findings suggest that cognitive decline in aging is tightly coupled to systemic, age-associated inflammation, potentially initiated by microbiome-driven gastrointestinal inflammatory activity, emphasizing a link between peripheral tissue alterations and brain function.

systems biology↗

bioRxiv2025

The chloride cotransporter NKCC1 regulates self-renewal of hippocampal neural stem cells via the transcription factor Sox11

The GABAergic-mediated depolarization plays a key role in controlling stem cell fate and neurogenesis within the dentate gyrus of the hippocampal formation. This depolarization effect is highly dependent on the balance between the chloride co-transporters NKCC1 and KCC2. It is not known how changes in NKCC1 modulate the fate of Nestin-positive stem cells (NSCs) in the hippocampus during adult neurogenesis. In our study, we demonstrate that a knockout of Nkcc1 in NSCs increase their proliferation by symmetric self-renewal and expand the stem cell pool. Using single-cell RNA sequencing, we identified Sox11 as a key transcription factor that is significantly downregulated following Nkcc1 knockout. In agreement with this finding, we found that Sox11 knockout enhances proliferation and self-renewal of NSCs, which is also marked by an increase in symmetric stem cell division. Based on these findings, we propose that altering Nkcc1 expression in NSCs shifts their fate from neurogenesis towards self-renewal via Sox11 regulation. Furthermore, we observed that NKCC1 levels decline in NSCs during aging, which correlates with a further increase in self-renewal. Our data strongly suggest that the age-related decline in NKCC1 levels promote symmetric division and self-renewal contributing to the age-dependent decrease in neurogenesis. NKCC1 via Sox11 is a key regulator of NSCs fate decision, critically balancing self-renewal and neuronal differentiation in the adult hippocampus. HighlightsNKCC1 is a key factor in regulating the Nestin-positive neural stem cell symmetric self-renewal. Sox11 is a downstream effector of NKCC1 in Nestin-positive stem cells and is involved in expansion of the stem cell pool. Aging reduces NKCC1 expression in Nestin-positive stem cells and increases their self-renewal. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/662334v1_ufig1.gif" ALT="Figure 1000"> View larger version (38K): org.highwire.dtl.DTLVardef@1babdcforg.highwire.dtl.DTLVardef@1038bfborg.highwire.dtl.DTLVardef@1db105corg.highwire.dtl.DTLVardef@10f2cde_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Pathological meprin α expression associated with degradation of dermokine drives a psoriasis-like skin phenotype in a genetic mouse model

Keratinocyte proliferation and differentiation is regulated via proteolytic networks. Dysregulation of proteases within these networks can cause hyperproliferative and inflammatory skin disorders. In healthy skin the metalloprotease meprin is localized in the stratum basale. In contrast, in wound healing tissue and psoriatic lesions increased meprin levels are found in the upper epidermal layers. We developed a transgenic mouse model for inducible expression of pathological meprin levels (K5M) to investigate its epidermal degradome and identify molecular links to keratinocyte proliferation and skin inflammation. K5M mice developed a severe skin phenotype characterized by hyperkeratosis, acanthosis and parakeratosis accompanied by increased transepidermal water loss and a strong inflammatory response within six days after induction of meprin overexpression. Histological and molecular analyses showed that increasing meprin expression correlates with meprin activity and keratinocyte hyperproliferation. Proteomics analyses revealed massive changes in proteins associated with keratinocyte differentiation and epidermal barrier integrity already three days after induction. N-terminomics data indicated a dominant chymotryptic activity with elevated proteolytic turnover of proteins associated with the cytoskeleton, cellular stress responses and cell adhesion. By filtering for cleavage sites that match with the specificity of meprin , we identified highly elevated dermokine-derived peptides. Subsequent mass spectrometric analyses validated dermokine as a novel substrate of meprin and identified the cleavage site, which is highly conserved in mammals. Based on the striking similarities with the phenotype reported for dermokine {beta}{gamma}-/- mice, we propose meprin as a central regulator of keratinocyte proliferation and leukocyte recruitment by proteolytic inactivation of dermokine. Hence, pathological meprin activity could be a driver of hyperproliferative, inflammatory skin disorders like psoriasis vulgaris.

molecular biology↗

bioRxiv2025

Characterization of nuclear genome size and variation in a freshwater snail model system featuring a recent whole-genome duplication

Species are defined by unique nuclear genome characteristics like nucleotide composition, genomic structure, and genome size. These fundamental aspects of the nuclear genome can themselves be the object of natural selection. We here provide the first high-quality direct measurements of nuclear genome DNA content in a representative diverse sample of Potamopyrgus antipodarum, an Aotearoa New Zealand freshwater snail that is a textbook example of the maintenance of sexual reproduction in nature and is invasive worldwide. We used propidium-iodide-based flow cytometry to characterize nuclear DNA content, and its variation, in nearly 100 P. antipodarum from multiple populations representing both sexual and asexual individuals. We also estimated nuclear DNA content in multiple P. estuarinus, a closely related obligately sexual species. These data confirmed and extended earlier lines of evidence for polyploidy and variable genome size within asexual P. antipodarum and provided the first direct evidence for distinctly higher nuclear genome content in diploid (sexual) P. antipodarum relative to diploid sexual P. estuarinus. These data are consistent with genomic evidence for a recent whole-genome duplication (WGD) and subsequent and in-process rediploidization in P. antipodarum, setting the stage for use of Potamopyrgus as a model for WGD and its consequences.

evolutionary biology↗

bioRxiv2024

Injury-Specific Muscle Regeneration: A Computational Blueprint for Cellular and Cytokine Drivers

Skeletal muscle regeneration is crucial for maintaining muscle health and mobility, making it a key research focus. Common experimental models of muscle injury used to study this process in vivo include cardiotoxin injury (CTX), freeze-induced (FI) injury, and eccentric contraction (EC) injury. While the response to injury varies across these models, these variations are often overlooked in experimental designs. The cellular dynamics throughout the time course of muscle regeneration differ significantly between these injury types, presenting challenges for both experimental investigation and literature analysis. To enhance understanding of how regeneration responses differ across injury types, we extend our previously validated computational model of skeletal muscle regeneration to simulate muscle fiber remodeling during regeneration following CTX, FI, and EC injuries. We further validate our model against multiple literature-derived metrics of regeneration for each injury type. Analysis of model outcomes reveals that recovery from each injury type is sensitive to unique combinations of cells and cytokines acting at different critical time points, exerting the greatest influence on regeneration at 28 days post-injury. Notably, the cytokines responsible for satellite cell (SSC) recruitment, proliferation, and differentiation required for regeneration vary across injury types, driven by biological redundancy and feedback mechanisms. Specifically, for EC injuries, cross-sectional area (CSA) recovery was predominantly associated with hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGF-A) during the early stages of regeneration, with SSC dynamics playing a critical role throughout. FI injuries demonstrated a consistent reliance on HGF across all phases, with additional influences from transforming growth factor beta (TGF-{beta}), tumor necrosis factor-alpha (TNF-), monocyte chemoattractant protein-1 (MCP-1), and SSC dynamics in later stages. CTX injuries showed early dependence on TGF-{beta}, with significant contributions from SSC, TNF-, VEGF-A, and fibroblast dynamics over time. Our findings emphasize the importance of considering the molecular and cellular mechanisms relevant to each injury type used in pre-clinical in vivo studies, and motivates the development of therapeutic strategies that are designed for specific injury types to optimize recovery outcomes.

systems biology↗

bioRxiv2024

Metabolic modeling reveals the aging-associated decline of host-microbiome metabolic interactions in mice

Aging is the predominant cause of morbidity and mortality in industrialized countries. The specific molecular mechanisms that drive aging are poorly understood, especially the contribution of the microbiota in these processes. Here, we combined multi-omics with metabolic modeling in mice to comprehensively characterize host-microbiome interactions and how they are affected by aging. Our findings reveal a complex dependency of host metabolism on microbial functions, including previously known as well as novel interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome, which we attribute to reduced beneficial interactions in the microbial community and a reduction in its metabolic output. These microbial changes coincided with a corresponding downregulation of key host pathways predicted by our model to be dependent on the microbiome that are crucial for maintaining intestinal barrier function, cellular replication, and homeostasis. Our results elucidate microbiome-host interactions that potentially influence host aging processes, focusing on microbial nucleotide metabolism as a pivotal factor in aging dynamics. These pathways could serve as future targets for the development of microbiome-based therapies against aging. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/587009v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@a8e7faorg.highwire.dtl.DTLVardef@115f35aorg.highwire.dtl.DTLVardef@1bbf32org.highwire.dtl.DTLVardef@1a58c7f_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2023

Agent-based model demonstrates the impact of nonlinear, complex interactions between cytokines on muscle regeneration

Muscle regeneration is a complex process due to dynamic and multiscale biochemical and cellular interactions, making it difficult to identify microenvironmental conditions that are beneficial to muscle recovery from injury using experimental approaches alone. To understand the degree to which individual cellular behaviors impact endogenous mechanisms of muscle recovery, we developed an agent-based model (ABM) using the Cellular Potts framework to simulate the dynamic microenvironment of a cross-section of murine skeletal muscle tissue. We referenced more than 100 published studies to define over 100 parameters and rules that dictate the behavior of muscle fibers, satellite stem cells (SSC), fibroblasts, neutrophils, macrophages, microvessels, and lymphatic vessels, as well as their interactions with each other and the microenvironment. We utilized parameter density estimation to calibrate the model to temporal biological datasets describing cross-sectional area (CSA) recovery, SSC, and fibroblast cell counts at multiple time points following injury. The calibrated model was validated by comparison of other model outputs (macrophage, neutrophil, and capillaries counts) to experimental observations. Predictions for eight model perturbations that varied cell or cytokine input conditions were compared to published experimental studies to validate model predictive capabilities. We used Latin hypercube sampling and partial rank correlation coefficient to identify in silico perturbations of cytokine diffusion coefficients and decay rates to enhance CSA recovery. This analysis suggests that combined alterations of specific cytokine decay and diffusion parameters result in greater fibroblast and SSC proliferation compared to individual perturbations with a 13% increase in CSA recovery compared to unaltered regeneration at 28 days. These results enable guided development of therapeutic strategies that similarly alter muscle physiology (i.e. converting ECM-bound cytokines into freely diffusible forms as studied in cancer therapeutics or delivery of exogenous cytokines) during regeneration to enhance muscle recovery after injury.

systems biology↗

bioRxiv2022

cGAS/STING-DEPENDENT SENSING OF ENDOGENOUS RNA

Defects in nucleic acid metabolizing enzymes lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing a pathogenic type I interferon response and inflammatory diseases. In these pathophysiological conditions, cGAS-driven IFN production is linked to spontaneous DNA damage. Physiological, or tonic, IFN signaling on the other hand is essential to functionally prime nucleic acid sensing pathways. Here we show that low-level chronic DNA damage in mice lacking the Aicardi-Goutieres syndrome gene SAMHD1 reduced tumor-free survival when crossed to a p53-deficient, but not to DNA mismatch repair-deficient background. Increased DNA damage did not result in higher levels of type I interferon. Instead, we found that the chronic interferon response in SAMHD1-deficient mice was driven by the MDA5/MAVS pathway but required functional priming through the cGAS/STING pathway. Our work positions cGAS/STING upstream of tonic IFN signaling and highlights an important role of the pathway in physiological and pathophysiological innate immune priming. SummaryLoss of the dNTPase and DNA repair enzyme SAMHD1 is associated with cancer and causes systemic autoimmunity. We show transformation-promoting spontaneous DNA damage and MDA5-driven but cGAS/STING-dependent chronic type I interferon production in SAMHD1-deficient mice.

immunology↗

bioRxiv2018

Pathogenic Budding Yeasts Isolated outside of Clinical Settings

Budding yeasts are distributed across a wide range of habitats, including as human commensals. However, under some conditions, these commensals can cause superficial, invasive, and even lethal infections. Despite their importance to human health, little is known about the ecology of these opportunistic pathogens, aside from their associations with mammals and clinical environments. During a survey of approximately 1000 non-clinical samples across the United States of America, we isolated 54 strains of budding yeast species considered opportunistic pathogens, including Candida albicans and Candida (Nakaseomyces) glabrata. We found that, as a group, pathogenic yeasts were positively associated with fruits and soil environments, while the species Pichia kudriavzevii (syn. Candida krusei syn. Issatchenkia orientalis) had a significant association with plants. These results suggest that pathogenic yeast ecology is more complex and diverse than is currently appreciated and raises the possibility that these additional environments could be a point of contact for human infections.\n\nImportanceWe isolated several opportunistic pathogenic species of yeasts from the subphylum Saccharomycotina from multiple non-clinical environments across the United States of America. Among those strains isolated, over 50% represent the most common opportunistic pathogens. These species, C. albicans, Candida tropicalis, Candida parapsilosis, and C. glabrata, have been rarely isolated from non-clinical settings and have been usually interpreted as contamination. Our extensive isolations from natural settings challenge this assumption, suggesting that opportunistic pathogens can persist in alternative niches and that their ecology may be more complicated than is currently assumed. Non-clinical environments could be a short-term habitat as these yeasts are passed between their predominant hosts, endothermic animals.

microbiology↗