Biology subjects

Ruland, J.

Publications and source records attributed to Ruland, J..

7 recordsLinked to original sources

bioRxiv2026

The Human Pancreas Cell Atlas defines a healthy reference framework for disease contextualization and translational benchmarking

A central challenge in single-cell biology is distinguishing disease-associated remodeling from normal cellular heterogeneity. Addressing this challenge requires healthy reference frameworks that capture cellular diversity across individuals, technologies, and biological contexts. Here we present the Human Pancreas Cell Atlas (HPCA), a reference atlas of the healthy human pancreas integrating 815,126 single-cell and single-nucleus transcriptomes from 109 donors across 12 studies, diverse technologies, and demographics. Using benchmarked integration and community-driven annotations, HPCA defines 94 cell types and transcriptional states spanning endocrine, exocrine, immune, and stromal compartments. The atlas identifies rare endocrine populations, including a putative, spatially supported polyhormonal alpha-beta-delta state, and provides a unified framework for interpreting pancreatic cellular variation across diverse biological and demographic covariates. Projection of disease and model-system datasets onto HPCA contextualized endocrine and epithelial remodeling relative to healthy pancreatic states. Diabetes-associated endocrine cells remained embedded within the healthy endocrine state space while exhibiting disease-specific changes, as supported by spatial and eQTL concordance analyses. Integration with a pancreatic ductal adenocarcinoma atlas resolved injury-associated and malignant epithelial ecosystem regions across donors. Finally, the HPCA enables quantitative benchmarking of murine diabetes models and stem-cell-derived islets against human pancreatic reference states. Together, the HPCA establishes a healthy transcriptional coordinate system for interpreting disease-associated pathophysiology, experimental perturbation, and regenerative fidelity, illustrating how reference atlases can function as analytical frameworks rather than static cell catalogs.

bioinformatics↗

bioRxiv2025

OVEREXPRESSION OF TUMORPROTECTIVE CLUSTERIN PREVENTS EXHAUSTION OF TRANSGENIC T CELLS

1T cell therapies, such as chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) transgenic (tg) T cells, are a promising approach in the treatment of solid malignancies but are limited by T cell exhaustion caused by chronic antigen stimulation. Clusterin (CLU) is a chaperone protein known to protect both normal and malignant cells, from metabolic stress and reactive oxygen species (ROS). In this study, we investigated whether overexpression (OE) of CLU in TCRtg T cells and CAR-T cells respectively can reduce exhaustion induced by chronic antigen stimulation and enhance T cell functionality against Ewing sarcoma (EwS). Among other cytoprotective genes, we found that CLU was significantly downregulated in dysfunctional tumor infiltrating lymphocytes. Therefore, we engineered EwS-directed TCRtg T cells targeting a Chondromodulin-1 (Chm1)-derived peptide and GD2 CAR-T cells to overexpress CLU. We show here that CLU is downregulated in T cells following activation by tumor cells. CLU-overexpressing T cells exhibit decreased expression of exhaustion markers (PD1, LAG3) and reduced apoptosis after repetitive stimulation. These cells demonstrated improved infiltration into tumor spheroids and maintained functionality under hypoxic conditions. In vivo, CLU-overexpressing T cells showed enhanced persistence and a trend towards reduced tumor growth. Mechanistically, proteomic analysis suggested that reduced ribosomal activity might delay T cell exhaustion, implicating metabolic reprogramming. In conclusion, CLU OE in tg T cells enhances their persistence and functionality by mitigating exhaustion, possibly through modulation of ribosomal activity and metabolic pathways. This strategy holds potential for improving adoptive T cell therapies against solid tumors.

immunology↗

bioRxiv2025

B cell/adipocyte crosstalk drives pro-fibrotic macrophage migration and polarisation in Crohn`s disease-associated, inflamed adipose tissue

During Crohns disease (CD), hyperplasia of the mesenteric white adipose tissue (WAT), called creeping fat (CrF), is associated with the accumulation of immune cells. We here investigated whether B cell infiltration and their interaction with adipocytes influence inflammation and fibrosis of CD-associated adipose tissue. Analysing CrF of CD patients as well as WAT from a mouse model of intestinal inflammation, we found an accumulation of B cells and pro-fibrotic, M2-like macrophages. Depleting B cells through anti-CD20 antibody treatment diminished M2-like macrophage accumulation in inflamed mouse WAT. Mechanistically, we found that the B cell/adipocyte co-cultures led to elevated secretion of monocyte chemoattractant protein-1 (MCP-1) by primary adipocytes, in part due to TNF-a secretion by activated B cells. Adipocyte-derived MCP-1 resulted in enhanced macrophage migration. Furthermore, the supernatants of the B cell/adipocyte co-culture promoted pro-fibrotic, M2-like macrophage polarization in vitro, correlating with elevated levels of lactate. Single-cell RNA sequencing of human CrF and mouse WAT supported our in vitro findings suggesting that the B cell/adipocyte crosstalk supports a lactate-rich, inflammatory adipose tissue niche. Taken together, our results provide evidence for a crucial role of the B cell/adipocyte crosstalk to CD-associated adipose tissue inflammation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/664132v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@15de8f9org.highwire.dtl.DTLVardef@6a6873org.highwire.dtl.DTLVardef@1ef7a22org.highwire.dtl.DTLVardef@13b89a4_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryO_LIB cells and pro-fibrotic macrophages accumulate in IBD-associated, inflamed adipose tissue C_LIO_LIB cell depletion in a mouse model reduces pro-fibrotic macrophage accumulation in IBD-associated, inflamed adipose tissue C_LIO_LIB cell/adipocyte crosstalk promotes B cell activation and MCP-1 secretion by adipocytes C_LIO_LIAdipocyte-derived MCP-1 promotes migration of macrophages C_LIO_LIB cell/adipocyte crosstalk provides a lactate-rich, inflammatory environment which likely drives pro-fibrotic macrophage polarisation C_LI

immunology↗

bioRxiv2025

A microbial metabolite protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration

Changes in the intestinal microbiome and microbiota-derived metabolites predict clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that desaminotyrosine (DAT), a product of bacterial flavonoid metabolism, correlates with improved overall survival and reduced relapse rates in allo-HSCT patients. In preclinical mouse models, treatment with synthetic DAT prevents graft-versus-host disease by protecting the intestinal barrier and promoting intestinal regeneration and contributes to graft-vs.-leukemia responses. DATs beneficial effects on intestinal regeneration remain effective despite broad-spectrum antibiotics-induced dysbiosis, also when administered by fecal microbiota transfer with flavonoid-degrading F. plautii. Mechanistically, DAT promotes mTORC1-dependent activation and proliferation of intestinal stem cells, with concomitant engagement of the innate immune receptor STING required to mitigate metabolic stress and maintain an undifferentiated stem cell state independently of type-I interferon responses. Additionally, DAT can skew T cells towards an effector phenotype to modulate graft-versus-leukemia responses. Our data uncover DATs dual, tissue- and immune-modulating properties and underscore its potential in precision microbiome-based therapies to improve tissue regeneration and minimize immune-mediated side effects.

immunology↗

bioRxiv2022

Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary β-glucan-induced inflammatory adaptation

The lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms which lead to the functional and developmental adaptation of lung-associated macrophages remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal {beta}-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonal macrophage adaptation. Employing single-cell transcriptomics, high dimensional imaging and flow cytometric characterization paired to in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of Dectin-1 - Card9 signaling-dependent monocyte-derived macrophages (MoAM). MoAMs expressed high levels of CD11b, ApoE, Gpnmb and Ccl6, were glycolytic and produced large amounts of interleukin 6 upon restimulation. Myeloid cell specific ApoE ablation inhibited monocyte to MoAM differentiation dependent on M-CSF secretion, promoting MoAM cell death thus impeding MoAM maintenance. In vivo, {beta}-glucan-elicited MoAMs limited the bacterial burden of Legionella pneumophilia post infection and ameliorated fibrosis severity in a murine fibrosis model. Collectively these data identify MoAMs that are generated upon environmental cues and ApoE as an important determinant for lung immune resilience.

immunology↗

bioRxiv2022

B/T cell crosstalk and aberrant inflammatory IgG exacerbate autoimmune intestinal inflammation

Dysregulated B cell responses have been described in inflammatory-bowel disease (IBD) patients; however, the role of B cells in IBD pathology remained incompletely understood. We here described Wiskott-Aldrich Syndrome interacting protein deficient (Wipf1-/-) mice as novel mouse model of spontaneous, chronic colitis modelling human IBD. Concomitant with aberrant IgG production in colonic tissue of Wipf1-/- mice, we identified systemic, hypo-sialylated IgG as drivers of IL-1{beta} production in monocytes. Pathological antibody production was promoted by the hyper-reactivity of Wipf1-/- B cells in response to LPS stimulation, resulting in efficient activation of the MAPK/Erk and mTOR/Akt/4E-BP1 pathways and heightened metabolic activity. In addition to abundant inflammatory IgG, we found that B cells directly promoted the production of pro-inflammatory cytokines by intestinal CD4+ T cells. B/T co-culture assays defined the co-stimulatory molecule CD86 as driver of IFN-{gamma} and GM-CSF production by CD4+ T cells. CD86 expression was further enhanced by the presence of sCD40L, which was elevated in sera of Wipf1-/- mice. Similarly, colonic B cells of IBD patients expressed increased mRNA levels of CD86 correlating with enhanced levels of systemic sCD40L. Together, B cell-mediated pro-inflammatory cytokine secretion and B cell-derived inflammatory antibody production contributed to exacerbated pathogenesis during intestinal inflammation. O_FIG O_LINKSMALLFIG WIDTH=168 HEIGHT=200 SRC="FIGDIR/small/507066v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1449ae8org.highwire.dtl.DTLVardef@116045borg.highwire.dtl.DTLVardef@77f3f2org.highwire.dtl.DTLVardef@130a271_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryB cells fuel intestinal inflammation

immunology↗

bioRxiv2020

MondoA Drives Malignancy in cALL through Enhanced Adaptation to Metabolic Stress

Cancer cells are in most instances characterized by rapid proliferation and uncontrolled cell division. Hence, they must adapt to proliferation-induced metabolic stress through intrinsic or acquired anti-metabolic stress responses to maintain homeostasis and survival. One mechanism to achieve this is to reprogram gene expression in a metabolism-dependent manner. MondoA (also known as MLXIP), a member of the MYC interactome, has been described as an example of such a metabolic sensor. However, the role of MondoA in malignancy is not fully understood and the underlying mechanism in metabolic responses remains elusive. By assessing patient data sets we found that MondoA overexpression is associated with a worse survival in pediatric common acute lymphoblastic leukemia (cALL). Using CRISPR/Cas9 and RNA interference approaches, we observed that MondoA depletion reduces transformational capacity of cALL cells in vitro and dramatically inhibits malignant potential in an in vivo mouse model. Interestingly, reduced expression of MondoA in patient data sets correlated with enrichment in metabolic pathways. The loss of MondoA correlated with increased tricarboxylic acid (TCA) cycle activity. Mechanistically, MondoA senses metabolic stress in cALL cells by restricting oxidative phosphorylation through reduced PDH activity. Glutamine starvation conditions greatly enhance this effect and highlight the inability to mitigate metabolic stress upon loss of MondoA in cALL. Our findings give a novel insight into the function of MondoA in pediatric cALL and support the notion that MondoA inhibition in this entity offers a therapeutic opportunity and should be further explored. Key PointsMondoA maintains aggressiveness and leukemic burden in common ALL, modulating metabolic stress response.

cancer biology↗