Biology subjects

Mann, U.

Publications and source records attributed to Mann, U..

5 recordsLinked to original sources

bioRxiv2026

JAK1/2 Inhibition Restores Tissue Integrity by Rewiring Type 1/2 Immunity Toward Targetable IL-17 Responses

Effective immune responses require coordinated communication between immune and epithelial cells to eliminate pathogens while limiting tissue damage. Disruption of this balance drives chronic inflammation and progressive tissue destruction. The Janus kinase (JAK) pathway coordinates cytokine signaling across these compartments and has emerged as a therapeutic target in inflammatory diseases. However, the consequences of JAK inhibition within a complex inflammatory environment remain incompletely understood. Here, we dissect the molecular, cellular, immunological and phenotypical effects of topical JAK1/2 inhibition in a chronic model of tissue-destructive skin inflammation driven by barrier dysfunction and bacterial superinfection. Single-cell transcriptomics and functional profiling revealed that JAK1/2 blockade selectively suppressed pathogenic CD8 T cells and their IFN-{gamma} production while shifting Th2-polarized CD4 T cells toward a Th17 phenotype, preserving type 3 immunity consisting of IL-17A-producing {gamma}{delta}-T cells and neutrophil responses. This immune rebalancing occurs rapidly and concomitantly with the restoration of epithelial barrier integrity through tight junction reinforcement, followed by recovery of antimicrobial defenses and reduced bacterial burden. Combination of JAK1/2 and IL-17A blockade further improved tissue homeostasis by targeting residual type 3-driven pathology. Thus, JAK1/2 inhibition acts as selective immunomodulator rather than a broad immunosuppressant, targeting pathogenic type 1/2 responses while preserving type-3-associated antimicrobial defense programs. These findings reveal how JAK1/2 inhibition coordinates immune rebalancing with epithelial repair and support its therapeutic potential in chronic type 1/2-driven inflammatory disease, while identifying residual IL-17A-mediated pathology as a target for combination therapy.

immunology↗

bioRxiv2026

A Conserved Chromatin-Driven Checkpoint Defines Late Macrophage Maturation Independent of Tissue Specialization

Macrophage identity is widely viewed as a product of ontogeny and tissue-specific imprinting. Here, we identify a conserved, chromatin-driven maturation checkpoint that operates independently of initial lineage commitment and broadly across tissue contexts. Using long-term bone marrow-derived macrophage cultures, we uncover a late-stage transition characterized by coordinated transcriptional and epigenomic remodeling. Integration with in vivo developmental, tissue-resident, and monocyte-repopulation datasets demonstrates that this program is conserved across ontogenies, tissues, species, and experimental systems, revealing a previously unrecognized stage of macrophage maturation. Functionally, late maturation preserves core macrophage activities while promoting lysosomal expansion and fundamentally rewiring innate immune responsiveness. Mature macrophages display enhanced stimulus-specific responses to interferons and microbial danger signals, coupled to increased metabolic and inflammatory competence while restricting interferon-induced transcriptional memory. Together, our findings identify late macrophage maturation as a conserved regulatory checkpoint that reprograms the logic of innate immune responsiveness through chromatin remodeling shaping innate immune function.

immunology↗

bioRxiv2026

A human lung organoid co-culture model of early bone sarcoma metastasis reveals contact-dependent epithelial remodeling at the metastatic interface

Lung metastasis drives mortality across cancer types, yet how infiltrating tumor cells remodel the lung epithelium to establish metastatic niches remains poorly understood. Here we establish MESCUL (MEtastatic Sarcoma Co-CULture), a co-culture platform combining human lung organoids with patient-derived bone sarcoma cells to model early tumor-lung epithelial interactions in a physiologically relevant 3D system. MESCUL reveals that direct tumor-epithelial contact induces rapid, reproducible lung epithelial remodeling across Ewing sarcoma (ES) and osteosarcoma (OS) models and multiple organoid donor backgrounds, which is contact-dependent and not recapitulated by paracrine signaling. Single-cell RNA sequencing identifies LIMES (Lung Interface Metastasis Signature), a shared transcriptional program encompassing focal adhesion assembly, matrix metalloprotease (MMP) upregulation, and emergence of a damage-associated transitional cell state, in both ES and OS. Mechanistically, tumor-derived fibronectin (FN1) engages epithelial integrin receptors to activate focal adhesion kinase (FAK), driving amphiregulin (AREG) induction and MMP-mediated remodeling; FN1 alone phenocopies this response, and FAK inhibition attenuates it, nominating the FN1-integrin-FAK-AREG axis as a candidate therapeutic vulnerability. The LIMES program, identified through the MESCUL co-culture model, is spatially confined to the tumor-lung interface in patient metastases of both ES and OS, as demonstrated by spatial transcriptomics across nine patients. Massons trichrome staining of matched patient sections reveals pronounced collagen deposition in the peri-tumoral lung parenchyma, consistent with LIMES acting upstream of a wound-healing cascade that proceeds to structural fibrotic remodeling in patient tissue. Together, these findings establish the lung epithelium as an active participant in metastatic colonization, characterize a pharmacologically targetable, spatially restricted epithelial remodeling response at the bone sarcoma-lung interface across OS and ES, and introduce MESCUL as a tractable 3D platform for investigating lung metastasis, with possible implications for tumor types beyond bone sarcomas.

cancer biology↗

bioRxiv2025

Development and validation of an ultra-low-cost, open source normothermic ex vivo organ perfusion platform

BackgroundNormothermic ex vivo organ perfusion (NEVOP) promises to catalyze organ preservation, therapeutic discovery, and organ-specific disease modeling. Existing technology platforms remain inaccessible for research due to restricted access to commercial organ perfusion devices, high costs of both devices and proprietary consumables, and steep technical learning curves. Additionally, the available technology is not optimized to perfuse smaller organs such as the kidney. MethodsTo overcome these barriers, a custom NEVOP circuit was developed using recycled, repurposed, and low-cost components. Porcine kidneys and autologous blood were used to iteratively optimize circuit design. A porcine kidney autotransplantation protocol was adapted to evaluate in vivo kidney function after ex vivo perfusion. To pilot the flexibility of this system as a multi-organ platform for ex vivo human biology, non-transplantable human donor kidney, spleen, and pancreas specimens were stably perfused using human blood products and analyzed. ResultsAn ultra low-cost NEVOP system engineered to perfuse porcine kidneys and diverse human organs (kidney, pancreas, and spleen) sustained viable organs for up to 24 hours with evidence of both function and viability. Key innovations included a parallel flow resistor to facilitate low-flow perfusion in non-heparinized organs and a containment bag with adjustable magnets to provide vascular stability and recycling of venous overflow. The circuit costs less than 1,500USD to construct, and porcine kidneys perfused for 24 hours on this platform demonstrated healthy in vivo function upon autotransplantation. ConclusionsCustom NEVOP platforms constitute novel and potentially transformative research platforms which use low-cost and readily available materials. Paired with access to non-transplantable research organs from altruistic donors, this model provides a road map for investigators to advance biomedical discovery and human ex vivo biology.

bioengineering↗

bioRxiv2022

Single-cell RNA sequencing analyses of primary cutaneous B-cell disorders reveal distinct molecular patterns consistent with clinical behavior

Primary cutaneous B-cell lymphomas comprise a heterogeneous group of extranodal non-Hodgkin lymphomas. While primary cutaneous diffuse large B-cell lymphoma leg type (pcDLBCL-LT) is highly aggressive, the two other subtypes, primary cutaneous follicle centre lymphoma (pcFCL) and primary cutaneous marginal zone lymphoma (pcMZL), usually follow an indolent course. To better understand the molecular landscape of these entities, we performed single-cell RNA sequencing of pcFCL, pcMZL, and pcDLBCL-LT skin lesions and compared them to B-cell rich lymphoid proliferation (rB-LP) lesions, gastric MALT lymphoma, nodal FCL, and nodal DLBCL. Our data show that these lymphomas can be clearly distinguished from each other on a transcriptomic level based on scRNA-seq. pcMZL, pcFCL, and rB-LP all exhibited a persistent germinal centre reaction as evidenced by the presence of required support cells and continuous somatic hypermutation within the expanded clone. By contrast, malignant clones of pcDLBCL-LT and gastric MALT lymphoma lesions lacked these features. Further, pcMZL top expanded clones were developing within lesions from naive and not post-germinal centre B cells as currently presumed. Therefore, pcMZL may represent a non-malignant reaction against a yet to be determined antigen. Conversely, in pcFCL, B cells showed a larger amount of clonal expansion. The lack of further differentiation of these B cells may explain its indolent clinical course. In contrast to pcDLCBL-LT, our data thus indicate that pcMZL and pcFCL, similar to rB-LP are characterised by a functional germinal centre reaction likely driven by (a yet unknown) antigen recognition, which supports the classification of pcMZL as a lymphoproliferative disease. Key pointsO_LIIndolent B cell neoplasms are uniquely characterised by ongoing, antigen-driven germinal centre reactions. C_LIO_LIPrimary cutaneous B cell lymphomas are distinct entities compared to their systemic counterparts. C_LI

cancer biology↗