bioRxiv : the preprint server for biology最新文献

{"title":"Glucose-stimulated KIF5B-driven microtubule sliding organizes microtubule networks in pancreatic β cells.","authors":"Kai M Bracey, Margret Fye, Alisa Cario, Kung-Hsien Ho, Pi'illani Noguchi, Guoqiang Gu, Irina Kaverina","doi":"10.1101/2023.06.25.546468","DOIUrl":"10.1101/2023.06.25.546468","url":null,"abstract":"<p><p>In pancreatic islet β cells, molecular motors use cytoskeletal polymers microtubules as tracks for intracellular transport of insulin secretory granules. The β-cell microtubule network has a complex architecture and is non-directional, which provides insulin granules at the cell periphery for rapid secretion response, yet to avoid over-secretion and subsequent hypoglycemia. We have previously characterized a peripheral sub-membrane microtubule array, which is critical for the withdrawal of excessive insulin granules from the secretion sites. Microtubules in β cells originate at the Golgi in the cell interior, and how the peripheral array is formed is unknown. Using real-time imaging and photo-kinetics approaches in clonal mouse pancreatic β cells MIN6, we now demonstrate that kinesin KIF5B, a motor protein with a capacity to transport microtubules as cargos, slides existing microtubules to the cell periphery and aligns them to each other along the plasma membrane. Moreover, like many physiological β-cell features, microtubule sliding is facilitated by a high glucose stimulus. These new data, together with our previous report that in high glucose sub-membrane MT array is destabilized to allow for robust secretion, indicate that MT sliding is another integral part of glucose-triggered microtubule remodeling, likely replacing destabilized peripheral microtubules to prevent their loss over time and β-cell malfunction.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ae/fa/nihpp-2023.06.25.546468v1.PMC10327020.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10168225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular signature and functional properties of human pluripotent stem cell-derived brain pericytes.","authors":"Ruslan Rust, Abhay P Sagare, Kassandra Kisler, Youbin Kim, Mingzi Zhang, Casey Griffin, Yaoming Wang, Veronica Clementel, Carina Torres-Sepulveda, Julia Tcw, Berislav V Zlokovic, Marcelo P Coba","doi":"10.1101/2023.06.26.546577","DOIUrl":"10.1101/2023.06.26.546577","url":null,"abstract":"<p><p>Brain pericytes maintain the blood-brain barrier (BBB), secrete neurotrophic factors and clear toxic proteins. Their loss in neurological disorders leads to BBB breakdown, neuronal dysfunction, and cognitive decline. Therefore, cell therapy to replace lost pericytes holds potential to restore impaired cerebrovascular and brain functions. However, the molecular composition and function of human iPSC-derived brain pericytes (iPSC-PC) remains poorly characterized. Here, we show by a quantitative analysis of 8,344 proteins and 20,572 phosphopeptides that iPSC-PC share 96% of total proteins and 98% of protein phosphorylation sites with primary human brain pericytes. This includes cell adhesion and tight junction proteins, transcription factors, and different protein kinase families of the human kinome. In pericyte-deficient mice, iPSC-PC home to host brain capillaries to form hybrid human-mouse microvessels with ligand-receptor associations. They repair BBB leaks and protect against neuron loss, which we show requires PDGRFB and pleiotrophin. They also clear Alzheimer's amyloid-β and tau neurotoxins via lipoprotein receptor. Thus, iPSC-PC may have potential as a replacement therapy for pericyte-deficient neurological disorders.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12026417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82085031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNAi-based screen for pigmentation in <i>Drosophila melanogaster</i> reveals regulators of brain dopamine and sleep.","authors":"Samantha L Deal, Danqing Bei, Shelley B Gibson, Harim Delgado-Seo, Yoko Fujita, Kyla Wilwayco, Elaine S Seto, Shinya Yamamoto","doi":"10.1101/2023.07.20.549932","DOIUrl":"10.1101/2023.07.20.549932","url":null,"abstract":"<p><p>The dopaminergic system has been extensively studied for its role in behavior in animals as well as human neuropsychiatric and neurological diseases. However, we still know little about how dopamine levels are tightly regulated <i>in vivo</i> . To identify novel regulators of dopamine, we utilized <i>Drosophila melanogaster</i> cuticle pigmentation as a readout, where dopamine is a precursor to melanin. We measured dopamine from genes known to be critical for cuticle pigmentation and performed an RNAi-based screen to identify new regulators of pigmentation. We found 153 potential pigmentation genes, which were enriched for conserved homologs and disease- associated genes as well as developmental signaling pathways and mitochondria-associated proteins. From 35 prioritized candidates, we found 10 caused significant reduction in head dopamine levels and one caused an increase. Two genes, <i>clueless</i> and <i>mask (multiple ankyrin repeats single KH domain),</i> upon knockdown, reduced dopamine levels in the brain. Further examination suggests that Mask regulates the transcription of the rate-limiting dopamine synthesis enzyme, <i>tyrosine hydroxylase</i> , and its knockdown causes dopamine-dependent sleep phenotypes. In summary, by studying genes that affect cuticle pigmentation, a phenotype seemingly unrelated to the nervous system, we were able to identify several genes that affect dopamine metabolism as well as a novel regulator of behavior.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"51 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89188842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Growth directions and stiffness across cell layers determine whether tissues stay smooth or buckle.","authors":"Avilash Singh Yadav, Lilan Hong, Patrick M Klees, Annamaria Kiss, Manuel Petit, Xi He, Iselle M Barrios, Michelle Heeney, Anabella Maria D Galang, Richard S Smith, Arezki Boudaoud, Adrienne H K Roeder","doi":"10.1101/2023.07.22.549953","DOIUrl":"10.1101/2023.07.22.549953","url":null,"abstract":"<p><p>From smooth shapes to buckles, nature exhibits organs of various shapes and forms. How cells grow to produce smooth shaped leaves and sepals remain unclear. Here, we show that growth along the longitudinal axis during early developmental stages and comparable stiffness across both epidermal layers of Arabidopsis sepals are essential for smoothness, as seen in the wild type. We identified a mutant (<i>as2-7D</i>) with ectopic expression of <i>ASYMMETRIC LEAVES 2</i> (<i>AS2</i>) on the outer epidermis. Our analysis reveals that ectopic <i>AS2</i> expression causes the outer epidermis of <i>as2-7D</i> sepals to buckle during early stages of sepal development. We show that buckling of the outer epidermis occurs due to conflicting cell growth directions and unequal tissue stiffness across the epidermal layers. Overexpression of cyclin-dependent kinase (CDK) inhibitor Kip-related protein 1 (KRP1) in <i>as2-7D</i> restores sepal smoothness by aligning the growth directions of the outer epidermal cells along the longitudinal axis, while also increasing the overall stiffness of the outer epidermis. Furthermore, buckling is associated with the convergence of auxin efflux transporter protein PIN-FORMED 1 (PIN1) to generate outgrowth in the sepals at later stages, suggesting that buckling can initiate outgrowths. Our findings suggest that in addition to molecular cues influencing tissue mechanics, tissue mechanics can also modulate molecular signals, giving rise to well-defined shapes.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e7/dd/nihpp-2023.07.22.549953v2.PMC10401922.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9998901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recurrent Composite Markers of Cell Types and States.","authors":"Xubin Li, Justin Nguyen, Anil Korkut","doi":"10.1101/2023.07.17.549344","DOIUrl":"10.1101/2023.07.17.549344","url":null,"abstract":"<p><p>Biological function is mediated by the hierarchical organization of cell types and states within tissue ecosystems. Identifying interpretable composite marker sets that both define and distinguish hierarchical cell identities is essential for decoding biological complexity, yet remains a major challenge. Here, we present RECOMBINE, an algorithm that identifies recurrent composite marker sets to define hierarchical cell identities. Validation using both simulated and biological datasets demonstrates that RECOMBINE achieves higher accuracy in identifying discriminative markers compared to existing approaches, including differential gene expression analysis. When applied to single-cell data and validated with spatial transcriptomics data from the mouse visual cortex, RECOMBINE identified key cell type markers and generated a robust gene panel for targeted spatial profiling. It also uncovered markers of CD8+; T cell states, including GZMK+;HAVCR2-; effector memory cells associated with anti-PD-1 therapy response, and revealed a rare intestinal subpopulation with composite markers in mice. Finally, using data from the Tabula Sapiens project, RECOMBINE identified composite marker sets across a broad range of human tissues. Together, these results highlight RECOMBINE as a robust, data-driven framework for optimized marker selection, enabling the discovery and validation of hierarchical cell identities across diverse tissue contexts.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10370072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9886161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An adult clock regulator links circadian rhythms to pancreatic β-cell maturation.","authors":"Ana P Montalvo Landivar, Zihan Gao, Mai Liu, Zoe L Gruskin, Andrew Leduc, Sam Preza, Yu Xie, Andrea V Rozo, June H Ahn, Juerg R Straubhaar, Nicolai Doliba, Doris A Stoffers, Nikolai Slavov, Juan R Alvarez-Dominguez","doi":"10.1101/2023.08.11.552890","DOIUrl":"10.1101/2023.08.11.552890","url":null,"abstract":"<p><p>The circadian clock attunes metabolism to daily energy cycles, but how it regulates maturation of metabolic tissues is poorly understood. Here we show that DEC1, a clock transcription factor induced in adult islet β cells, coordinates their glucose responsiveness by synchronizing energetic and secretory rhythms. DEC1 binds and regulates maturity-linked genes to integrate insulin exocytosis with energy metabolism, and β-cell <i>Dec1</i> ablation disrupts their transcription synchrony. <i>Dec1</i>-disrupted mice develop lifelong glucose intolerance and insulin deficiency, despite normal islet formation and intact <i>Clock/Bmal1</i> genes. Metabolic dysfunction upon β-cell <i>Dec1</i> loss stems from poor coupling of insulin secretion to glucose metabolism, reminiscent of fetal/neonatal immaturity. We link stunted maturation to a deficit in circadian bioenergetics, prompted by compromised glucose utilization, mitochondrial dynamics, and respiratory metabolism, which is rescued by increased metabolic flux. Thus, DEC1 links circadian clockwork to β-cell metabolic maturation, revealing a hierarchy for how the clock programs metabolic tissue specialization.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/26/be/nihpp-2023.08.11.552890v1.PMC10441398.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10103162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cortical structure in relation to empathy and psychopathy in 800 incarcerated men.","authors":"Marcin A Radecki, J Michael Maurer, Keith A Harenski, David D Stephenson, Erika Sampaolo, Giada Lettieri, Giacomo Handjaras, Emiliano Ricciardi, Samantha N Rodriguez, Craig S Neumann, Carla L Harenski, Sara Palumbo, Silvia Pellegrini, Jean Decety, Pietro Pietrini, Kent A Kiehl, Luca Cecchetti","doi":"10.1101/2023.06.14.543399","DOIUrl":"10.1101/2023.06.14.543399","url":null,"abstract":"<p><strong>Background: </strong>Reduced affective empathy is a hallmark of psychopathy, which incurs major interpersonal and societal costs. Advancing our neuroscientific understanding of this reduction and other psychopathic traits is crucial for improving their treatment.</p><p><strong>Methods: </strong>In 804 incarcerated adult men, we administered the Perspective Taking (IRI-PT) and Empathic Concern (IRI-EC) subscales of the Interpersonal Reactivity Index, Hare Psychopathy Checklist-Revised (PCL-R; two factors), and T1-weighted MRI to quantify cortical thickness (CT) and surface area (SA). We also included the male sample of the Human Connectome Project (HCP; N = 501) to replicate patterns of macroscale structural organization.</p><p><strong>Results: </strong>Factor 1 (Interpersonal/Affective) uniquely negatively related to IRI-EC, while Factor 2 (Lifestyle/Antisocial) uniquely negatively related to IRI-PT. Cortical structure did not relate to either IRI subscale, although there was effect-size differentiation by microstructural class and/or functional network. CT related to Factor 1 (mostly positively), SA related to both factors (only positively), and both cortical indices demonstrated out-of-sample predictive utility for Factor 1. The high-psychopathy group (N = 178) scored uniquely lower on IRI-EC while having increased SA (but not CT). Regionally, these SA increases localized primarily in the paralimbic class and somatomotor network, with meta-analytic task-based activations corroborating affective-sensory importance. High psychopathy also showed \"compressed\" global and/or network-level organization of both cortical indices, and this organization in the total sample replicated in HCP. All findings accounted for age, IQ, and/or total intracranial volume.</p><p><strong>Conclusions: </strong>Psychopathy had negative relationships with affective empathy and positive relationships with paralimbic/somatomotor SA, highlighting the role of affect and sensation.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"11 suppl_1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88667717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-1 receptor antagonist is a conserved early factor for exacerbating tuberculosis susceptibility.","authors":"Ophelia V Lee, Daisy X Ji, Bruce A Rosa, David L Jaye, Sara Suliman, Makedonka Mitreva, Cem Gabay, Russell E Vance, Dmitri I Kotov","doi":"10.1101/2023.10.27.564420","DOIUrl":"10.1101/2023.10.27.564420","url":null,"abstract":"<p><p><i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) causes 1.25 million deaths a year. However, tuberculosis (TB) pathogenesis remains poorly understood and is not fully recapitulated in standard mouse models. Here we find that gene signatures from three different <i>Mtb</i>-susceptible mouse models predict active TB disease in humans significantly better than a signature from resistant C57BL/6 (B6) mice. Conserved among susceptible mice, non-human primates, and humans, but largely absent from B6 mice, was <i>Mtb</i>-induced differentiation of macrophages into an <i>Spp1</i> ⁺ differentiation state. <i>Spp1</i> ⁺ macrophages expressed high levels of immunosuppressive molecules including IL-1 receptor antagonist (IL-1Ra). IL-1Ra was previously reported to cause <i>Mtb</i> susceptibility in one mouse model, but whether IL-1Ra is broadly important remains uncertain. Here we report that enhancement of IL-1 signaling via deletion of IL-Ra promoted bacterial control across three susceptible mouse models. We found IL-1 signaling amplified production of multiple cytokines by lymphoid and stromal cells, providing a multifactorial mechanism for how IL-1 promotes <i>Mtb</i> control. Our results indicate that myeloid cell expression of immunosuppressive molecules, in particular IL-1 receptor antagonist, is a conserved early mechanism limiting <i>Mtb</i> control in mice, non-human primates, and humans.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92157699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemically induced partial unfolding of the multifunctional Apurinic/apyrimidinic endonuclease 1.","authors":"Ratan Rai, Olabode I Dawodu, Jingwei Meng, Steven M Johnson, Jonah Z Vilseck, Mark R Kelley, Joshua J Ziarek, Millie M Georgiadis","doi":"10.1101/2023.06.29.547112","DOIUrl":"10.1101/2023.06.29.547112","url":null,"abstract":"<p><p>Apurinic/apyrimidinic endonuclease I (APE1) acts as both an endonuclease and a redox factor to ensure cell survival. The two activities require different conformations of APE1. As an endonuclease, APE1 is fully folded. As a redox factor, APE1 must be partially unfolded to expose the buried residue Cys65, which reduces transcription factors including AP-1, NF-κB, and HIF-1α and thereby enables them to bind DNA. To determine a molecular basis for partial unfolding associated with APE1's redox activity, we characterized specific interactions of a known redox inhibitor APX3330 with APE1 through waterLOGSY and ¹ H- ¹⁵ N HSQC NMR approaches using ethanol and acetonitrile as co-solvents. We find that APX3330 binds to the endonuclease active site in both co-solvents and to a distant small pocket in acetonitrile. Prolonged exposure of APE1 with APX3330 in acetonitrile resulted in a time-dependent loss of ¹ H- ¹⁵ N HSQC chemical shifts (∼35%), consistent with partial unfolding. Regions that are partially unfolded include adjacent N- and C-terminal beta strands within one of the two sheets comprising the core, which converge within the small binding pocket defined by the CSPs. Removal of APX3330 via dialysis resulted in a slow reappearance of the ¹ H- ¹⁵ N HSQC chemical shifts suggesting that the effect of APX3330 is reversible. APX3330 significantly decreases the melting temperature of APE1 but has no effect on endonuclease activity using a standard assay in either co-solvent. Our results provide insights on reversible partial unfolding of APE1 relevant for its redox function as well as the mechanism of redox inhibition by APX3330.</p><p><strong>Toc graphic: </strong></p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10327033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9865745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Bone Marrow Adipose Tissue is a Hematopoietic Niche for Leptin-Driven Monopoiesis.","authors":"Zinger Yang Loureiro, Amruta Samant, Anand Desai, Tiffany DeSouza, Haley Cirka, Mai Ceesay, David Kostyra, Shannon Joyce, Lyne Khair, Javier Solivan-Rivera, Rachel Ziegler, Nathalia Ketelut Carneiro, Linus T Tsai, Michael Brehm, Louis M Messina, Katherine A Fitzgerald, Evan D Rosen, Silvia Corvera, Tammy T Nguyen","doi":"10.1101/2023.08.29.555167","DOIUrl":"10.1101/2023.08.29.555167","url":null,"abstract":"<p><p>During aging, adipose tissue within the bone marrow expands while the trabecular red marrow contracts. The impact of these changes on blood cell formation remains unclear. To address this question, we performed single-cell and single-nuclei transcriptomic analysis on adipose-rich yellow bone marrow (BMY) and adipose-poor trabecular red marrow (BMR) from human subjects undergoing lower limb amputations. Surprisingly, we discovered two distinct hematopoietic niches, in which BMY contains a higher number of monocytes and progenitor cells expressing genes associated with inflammation. To further investigate these niches, we developed an in-vitro organoid system that maintains features of the human bone marrow. We find cells from BMY are distinct in their expression of the leptin receptor, and respond to leptin stimulation with enhanced proliferation, leading to increased monocyte production. These findings suggest that the age-associated expansion of bone marrow adipose tissue drives a pro-inflammatory state by stimulating monocyte production from a spatially distinct, leptin-responsive hematopoietic stem/progenitor cell population.</p><p><strong>Significance: </strong>This study reveals that adipose tissue within the human bone marrow is a niche for hematopoietic stem and progenitor cells that can give rise to pro-inflammatory monocytes through leptin signaling. Expansion of bone marrow adipose tissue with age and stress may thus underlie inflammageing.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10491256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10570815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}