Person: Vinegoni, Claudio
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Vinegoni
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Claudio
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Vinegoni, Claudio
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Publication Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease(Springer Science and Business Media LLC, 2021-07-14) McAlpine, Cameron; Park, Joseph; Griciuc, Ana; Kim, Eunhee; Choi, Se Hoon; Iwamoto, Yoshiko; Kiss, Máté G.; Christie, Kathleen; Vinegoni, Claudio; Poller, Wolfram; Mindur, John; Chan, Christopher; He, Shun; Janssen, Henrike; Wong, Lai Ping; Downey, Jeffrey; Singh, Sumnima; Anzai, Atsushi; Kahles, Florian; Jorfi, Mehdi; Feruglio, Paulo; Sadreyev, Ruslan; Weissleder, Ralph; Kleinstiver, Benjamin; Nahrendorf, Matthias; Tanzi, Rudolph; Swirski, FilipCommunication within the glial cell ecosystem is essential to neuronal and brain health1–3. The influence of glial cells on β-amyloid (Aβ) and neurofibrillary tau accumulation and clearance in Alzheimer’s disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) reprograms microglia to ameliorate AD pathology. Upon recognition of Aβ deposits, microglia augment IL-3Rɑ, IL-3’s specific receptor, rendering them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional reprograming of microglia endowing them with an acute immune response program, enhanced motility, and the capacity to cluster and clear Aβ and tau aggregates. These changes restrict AD pathology and cognitive decline. This study identifies IL-3 as a critical mediator of astrocyte-microglia crosstalk and a node for therapeutic intervention in AD.Publication Rapid, high efficiency isolation of pancreatic ß-cells(Nature Publishing Group, 2015) Clardy, Susan M.; Mohan, James F.; Vinegoni, Claudio; Keliher, Edmund J.; Iwamoto, Yoshiko; Benoist, Christophe; Mathis, Diane; Weissleder, RalphThe ability to isolate pure pancreatic ß-cells would greatly aid multiple areas of diabetes research. We developed a fluorescent exendin-4-like neopeptide conjugate for the rapid purification and isolation of functional mouse pancreatic β-cells. By targeting the glucagon-like peptide-1 receptor with the fluorescent conjugate, β-cells could be quickly isolated by flow cytometry and were >99% insulin positive. These studies were confirmed by immunostaining, microscopy and gene expression profiling on isolated cells. Gene expression profiling studies of cytofluorometrically sorted β-cells from 4 and 12 week old NOD mice provided new insights into the genetic programs at play of different stages of type-1 diabetes development. The described isolation method should have broad applicability to the β-cell field.Publication Automated motion artifact removal for intravital microscopy, without a priori information(Nature Publishing Group, 2014) Lee, Sungon; Vinegoni, Claudio; Sebas, Matthew; Weissleder, RalphIntravital fluorescence microscopy, through extended penetration depth and imaging resolution, provides the ability to image at cellular and subcellular resolution in live animals, presenting an opportunity for new insights into in vivo biology. Unfortunately, physiological induced motion components due to respiration and cardiac activity are major sources of image artifacts and impose severe limitations on the effective imaging resolution that can be ultimately achieved in vivo. Here we present a novel imaging methodology capable of automatically removing motion artifacts during intravital microscopy imaging of organs and orthotopic tumors. The method is universally applicable to different laser scanning modalities including confocal and multiphoton microscopy, and offers artifact free reconstructions independent of the physiological motion source and imaged organ. The methodology, which is based on raw data acquisition followed by image processing, is here demonstrated for both cardiac and respiratory motion compensation in mice heart, kidney, liver, pancreas and dorsal window chamber.Publication Chronic variable stress activates hematopoietic stem cells(2014) Heidt, Timo; Sager, Hendrik B; Courties, Gabriel; Dutta, Partha; Iwamoto, Yoshiko; Zaltsman, Alex; von zur Muhlen, Constantin; Bode, Christoph; Fricchione, Gregory; Denninger, John; Lin, Charles; Vinegoni, Claudio; Libby, Peter; Swirski, Filip; Weissleder, Ralph; Nahrendorf, MatthiasExposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis1,2. While incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known crosstalk between the brain and immune system includes the hypothalamic–pituitary–adrenal axis, which centrally drives glucocorticoid production in the adrenal cortex, and the sympathetic–adrenal–medullary axis, which controls stress–induced catecholamine release in support of the fight–or–flight reflex3,4. It remains unknown however if chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive progenitors, giving rise to higher levels of disease–promoting inflammatory leukocytes. We found that chronic stress induced monocytosis and neutrophilia in humans. While investigating the source of leukocytosis in mice, we discovered that stress activates upstream hematopoietic stem cells. Sympathetic nerve fibers release surplus noradrenaline, which uses the β3 adrenergic receptor to signal bone marrow niche cells to decrease CXCL12 levels. Consequently, elevated hematopoietic stem cell proliferation increases output of neutrophils and inflammatory monocytes. When atherosclerosis–prone ApoE−/− mice encounter chronic stress, accelerated hematopoiesis promotes plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans.Publication Design and Development of Fluorescent Vemurafenib Analogs for In Vivo Imaging(Ivyspring International Publisher, 2017) Mikula, Hannes; Stapleton, Shawn; Kohler, Rainer; Vinegoni, Claudio; Weissleder, RalphHerein we describe fluorescent derivatives of vemurafenib to probe therapeutic BRAF inhibition in live cells and in vivo. The compounds were evaluated and compared by determining target binding, inhibition of mutant BRAF melanoma cell lines and live cell imaging. We show that vemurafenib-BODIPY is a superior imaging drug to visualize the targets of vemurafenib in live cells and in vivo in non-resistant and resistant melanoma tumors.Publication New techniques for motion-artifact-free in vivo cardiac microscopy(Frontiers Media S.A., 2015) Vinegoni, Claudio; Lee, Sungon; Aguirre, Aaron; Weissleder, RalphIntravital imaging microscopy (i.e., imaging in live animals at microscopic resolution) has become an indispensable tool for studying the cellular micro-dynamics in cancer, immunology and neurobiology. High spatial and temporal resolution, combined with large penetration depth and multi-reporter visualization capability make fluorescence intravital microscopy compelling for heart imaging. However, tissue motion caused by cardiac contraction and respiration critically limits its use. As a result, in vitro cell preparations or non-contracting explanted heart models are more commonly employed. Unfortunately, these approaches fall short of understanding the more complex host physiology that may be dynamic and occur over longer periods of time. In this review, we report on novel technologies, which have been recently developed by our group and others, aimed at overcoming motion-induced artifacts and capable of providing in vivo subcellular resolution imaging in the beating mouse heart. The methods are based on mechanical stabilization, image processing algorithms, gated/triggered acquisition schemes or a combination of both. We expect that in the immediate future all these methodologies will have considerable applications in expanding our understanding of the cardiac biology, elucidating cardiomyocyte function and interactions within the organism in vivo, and ultimately improving the treatment of cardiac diseases.Publication Myocardial Infarction Activates CCR2+ Hematopoietic Stem and Progenitor Cells(Elsevier BV, 2015) Dutta, Partha; Sager, Hendrik B; Stengel, Kristy R.; Nahrendorf, Kamila; Courties, Gabriel; Saez, Borja; Silberstein, Lev; Heidt, Timo; Sebas, Matthew; Sun, Yuan; Wojtkiewicz, Gregory; Feruglio, Paolo Fumene; King, Kevin Robert; Baker, Joshua N.; van der Laan, Anja M.; Borodovsky, Anna; Fitzgerald, Kevin; Hulsmans, Maarten; Hoyer, Friedrich; Iwamoto, Yoshiko; Vinegoni, Claudio; Brown, Dennis; Di Carli, Marcelo; Libby, Peter; Hiebert, Scott W.; Scadden, David; Swirski, Filip; Weissleder, Ralph; Nahrendorf, MatthiasFollowing myocardial infarction (MI), myeloid cells derived from the hematopoietic system drive a sharp increase in systemic leukocyte levels that correlates closely with mortality. The origin of these myeloid cells, and the response of hematopoietic stem and progenitor cells (HSPCs) to MI, however, is unclear. Here, we identify a CCR2+CD150+CD48− LSK hematopoietic subset as the most upstream contributor to emergency myelopoiesis after ischemic organ injury. This subset has 4-fold higher proliferation rates than CCR2−CD150+CD48− LSK cells, displays a myeloid differentiation bias, and dominates the migratory HSPC population. We further demonstrate that the myeloid translocation gene 16 (Mtg16) regulates CCR2+ HSPC emergence. Mtg16−/− mice have decreased levels of systemic monocytes and infarct-associated macrophages and display compromised tissue healing and post-MI heart failure. Together, these data provide insights into regulation of emergency hematopoiesis after ischemic injury and identify potential therapeutic targets to modulate leukocyte output after MI.Publication Tyrosine kinase-mediated axial motility of basal cells revealed by intravital imaging(Nature Publishing Group, 2016) Roy, Jeremy; Kim, Bongki; Hill, Eric; Visconti, Pablo; Krapf, Dario; Vinegoni, Claudio; Weissleder, Ralph; Brown, Dennis; Breton, SylvieEpithelial cells are generally considered to be static relative to their neighbours. Basal cells in pseudostratified epithelia display a single long cytoplasmic process that can cross the tight junction barrier to reach the lumen. Using in vivo microscopy to visualize the epididymis, a model system for the study of pseudostratified epithelia, we report here the surprising discovery that these basal cell projections—which we call axiopodia—periodically extend and retract over time. We found that axiopodia extensions and retractions follow an oscillatory pattern. This movement, which we refer to as periodic axial motility (PAM), is controlled by c-Src and MEK1/2–ERK1/2. Therapeutic inhibition of tyrosine kinase activity induces a retraction of these projections. Such unexpected cell motility may reflect a novel mechanism by which specialized epithelial cells sample the luminal environment.Publication Computational imaging reveals mitochondrial morphology as a biomarker of cancer phenotype and drug response(Nature Publishing Group, 2016) Giedt, Randy; Fumene Feruglio, Paolo; Pathania, Divya; Yang, Katherine; Kilcoyne, Aoife; Vinegoni, Claudio; Mitchison, Timothy; Weissleder, RalphMitochondria, which are essential organelles in resting and replicating cells, can vary in number, mass and shape. Past research has primarily focused on short-term molecular mechanisms underlying fission/fusion. Less is known about longer-term mitochondrial behavior such as the overall makeup of cell populations’ morphological patterns and whether these patterns can be used as biomarkers of drug response in human cells. We developed an image-based analytical technique to phenotype mitochondrial morphology in different cancers, including cancer cell lines and patient-derived cancer cells. We demonstrate that (i) cancer cells of different origins, including patient-derived xenografts, express highly diverse mitochondrial phenotypes; (ii) a given phenotype is characteristic of a cell population and fairly constant over time; (iii) mitochondrial patterns correlate with cell metabolic measurements and (iv) therapeutic interventions can alter mitochondrial phenotypes in drug-sensitive cancers as measured in pre- versus post-treatment fine needle aspirates in mice. These observations shed light on the role of mitochondrial dynamics in the biology and drug response of cancer cells. On the basis of these findings, we propose that image-based mitochondrial phenotyping can provide biomarkers for assessing cancer phenotype and drug response.Publication Myocardial Infarction Accelerates Atherosclerosis(Nature Publishing Group, 2012) Leuschner, Florian; Robbins, Clinton; Iwamoto, Yoshiko; Thompson, Brian; Carlson, Alicia L.; Heidt, Timo; Lasitschka, Felix; Etzrodt, Martin; Waterman, Peter; Waring, Michael T.; Chicoine, Adam T.; van der Laan, Anja M.; Niessen, Hans W.M.; Piek, Jan J.; Rubin, Barry B.; Butany, Jagdish; Katus, Hugo A.; Murphy, Sabina A.; Pittet, Mikael; Lin, Charles; Dutta, Partha; Courties, Gabriel; Wei, Ying; Gorbatov, Rostic; Majmudar, Maulik; Stone, James; Morrow, David; Sabatine, Marc; Vinegoni, Claudio; Moskowitz, Michael; Libby, Peter; Swirski, Filip; Weissleder, Ralph; Nahrendorf, MatthiasDuring progression of atherosclerosis, myeloid cells destabilize lipid-rich plaque in the arterial wall and cause its rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, apoE\(^{−/−}\) mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. When seeking the source of surplus monocytes in plaque, we found that myocardial infarction liberated hematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signaling. The progenitors then seeded the spleen yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.