Publications by authors named "Yoshiko Iwamoto"

102 Publications

Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis.

Cell 2021 Mar 25;184(5):1348-1361.e22. Epub 2021 Feb 25.

Center for Systems Biology, Department of Radiology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Clonal hematopoiesis, a condition in which individual hematopoietic stem cell clones generate a disproportionate fraction of blood leukocytes, correlates with higher risk for cardiovascular disease. The mechanisms behind this association are incompletely understood. Here, we show that hematopoietic stem cell division rates are increased in mice and humans with atherosclerosis. Mathematical analysis demonstrates that increased stem cell proliferation expedites somatic evolution and expansion of clones with driver mutations. The experimentally determined division rate elevation in atherosclerosis patients is sufficient to produce a 3.5-fold increased risk of clonal hematopoiesis by age 70. We confirm the accuracy of our theoretical framework in mouse models of atherosclerosis and sleep fragmentation by showing that expansion of competitively transplanted Tet2 cells is accelerated under conditions of chronically elevated hematopoietic activity. Hence, increased hematopoietic stem cell proliferation is an important factor contributing to the association between cardiovascular disease and clonal hematopoiesis.
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http://dx.doi.org/10.1016/j.cell.2021.01.049DOI Listing
March 2021

p53 dynamics vary between tissues and are linked with radiation sensitivity.

Nat Commun 2021 02 9;12(1):898. Epub 2021 Feb 9.

Department of Systems Biology and the Ludwig Center at Harvard, Blavatnik Institute at Harvard Medical School, Boston, MA, USA.

Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, the abundance of p53 protein does not correlate well with the extent of radiosensitivity across tissues. Given recent studies showing that the temporal dynamics of p53 influence the fate of cultured cells in response to irradiation, we set out to determine the dynamic behavior of p53 and its impact on radiation sensitivity in vivo. We find that radiosensitive tissues show prolonged p53 signaling after radiation, while more resistant tissues show transient p53 activation. Sustaining p53 using a small molecule (NMI801) that inhibits Mdm2, a negative regulator of p53, reduced viability in cell culture and suppressed tumor growth. Our work proposes a mechanism for the control of radiation sensitivity and suggests tools to alter the dynamics of p53 to enhance tumor clearance. Similar approaches can be used to enhance killing of cancer cells or reduce toxicity in normal tissues following genotoxic therapies.
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http://dx.doi.org/10.1038/s41467-021-21145-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873198PMC
February 2021

Multimodal imaging of bacterial-host interface in mice and piglets with endocarditis.

Sci Transl Med 2020 11;12(568)

Center for Systems Biology and Department of Radiology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.

Acute bacterial endocarditis is a rapid, difficult to manage, and frequently lethal disease. Potent antibiotics often cannot efficiently kill that colonizes the heart's valves. relies on virulence factors to evade therapeutics and the host's immune response, usurping the host's clotting system by activating circulating prothrombin with staphylocoagulase and von Willebrand factor-binding protein. An insoluble fibrin barrier then forms around the bacterial colony, shielding the pathogen from immune cell clearance. Targeting virulence factors may provide previously unidentified avenues to better diagnose and treat endocarditis. To tap into this unused therapeutic opportunity, we codeveloped therapeutics and multimodal molecular imaging to probe the host-pathogen interface. We introduced and validated a family of small-molecule optical and positron emission tomography (PET) reporters targeting active thrombin in the fibrin-rich environment of bacterial colonies. The imaging agents, based on the clinical thrombin inhibitor dabigatran, are bound to heart valve vegetations in mice. Using optical imaging, we monitored therapy with antibodies neutralizing staphylocoagulase and von Willebrand factor-binding protein in mice with endocarditis. This treatment deactivated bacterial defenses against innate immune cells, decreased in vivo imaging signal, and improved survival. Aortic or tricuspid endocarditis in piglets was also successfully imaged with clinical PET/magnetic resonance imaging. Our data map a route toward adjuvant immunotherapy for endocarditis and provide efficient tools to monitor this drug class for infectious diseases.
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http://dx.doi.org/10.1126/scitranslmed.aay2104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818516PMC
November 2020

Detecting Immune Response to Therapies Targeting PDL1 and BRAF by Using Ferumoxytol MRI and Macrin in Anaplastic Thyroid Cancer.

Radiology 2021 01 27;298(1):123-132. Epub 2020 Oct 27.

From the Center for Systems Biology, Massachusetts General Hospital Research Institute, 185 Cambridge St, Suite 5.210, Boston, MA 02114 (T.S.C.N., R.L., M.P., Y.I., R.H.K., R.W., M.A.M.); Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass (T.S.C.N.); Departments of Surgery (V.G., S.P.) and Radiology (R.L., R.W., M.A.M.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; and Department of Systems Biology, Harvard Medical School, Boston, Mass (R.W.).

Background Anaplastic thyroid cancer (ATC) is aggressive with a poor prognosis, partly because of the immunosuppressive microenvironment created by tumor-associated macrophages (TAMs). Purpose To understand the relationship between TAM infiltration, tumor vascularization, and corresponding drug delivery by using ferumoxytol-enhanced MRI and macrin in an ATC mouse model. Materials and Methods ATC tumors were generated in 6-8-week-old female B6129SF1/J mice through intrathyroid injection to model orthotopic tumors, or intravenously to model hematogenous metastasis, and prospectively enrolled randomly into treatment cohorts ( = 94 total; August 1, 2018, to January 15, 2020). Mice were treated with vehicle or combined serine/threonine-protein kinase B-Raf (BRAF) kinase inhibitor (BRAFi) and anti-PDL1 antibody (aPDL1). A subset was cotreated with therapies, including an approximately 70-nm model drug delivery nanoparticle (DDNP) to target TAM, and an antibody-neutralizing colony stimulating factor 1 receptor (CSF1R). Imaging was performed at the macroscopic level with ferumoxytol-MRI and microscopically with macrin. Genetically engineered -null allografts were used and complemented by a GFP-transgenic derivative and human xenografts. Tumor-bearing organs were processed by using tissue clearing and imaged with confocal microscopy and MRI. Two-tailed Wilcoxon tests were used for comparison (≥five per group). Results TAM levels were higher in orthotopic thyroid tumors compared with pulmonary metastatic lesions by 79% ± 23 (standard deviation; < .001). These findings were concordant with ferumoxytol MRI, which showed 136% ± 88 higher uptake in thyroid lesions ( = .02) compared with lung lesions. BRAFi and aPDL1 combination therapy resulted in higher tumor DDNP delivery by 39% ± 14 in pulmonary lesions ( = .004). Compared with the untreated group, tumors following BRAFi, aPDL1, and CSF1R-blocking antibody combination therapy did not show greater levels of TAM or DDNP ( = .82). Conclusion In a mouse model of anaplastic thyroid cancer, ferumoxytol MRI showed 136% ± 88 greater uptake in orthotopic thyroid tumors compared with pulmonary lesions, which reflected high vascularization and greater tumor-associated macrophage (TAM) levels. Serine/threonine-protein kinase B-Raf inhibitor and anti-programmed death ligand 1 antibody elicited higher local TAM levels and 43% ± 20 greater therapeutic nanoparticle delivery but not higher vascularization in pulmonary tumors. © RSNA, 2020 See also the editorial by Luker in this issue.
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http://dx.doi.org/10.1148/radiol.2020201791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771993PMC
January 2021

Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase.

Circulation 2020 Dec 23;142(25):2443-2455. Epub 2020 Oct 23.

Cardiovascular Research Center (L.X., S.C., A.H., A.B., J.T., M.N., P.T.E., D.J.M.), Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Background: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood.

Methods: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF.

Results: We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7; <0.0001).

Conclusions: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049210DOI Listing
December 2020

Imaging Cardiovascular and Lung Macrophages With the Positron Emission Tomography Sensor Cu-Macrin in Mice, Rabbits, and Pigs.

Circ Cardiovasc Imaging 2020 10 20;13(10):e010586. Epub 2020 Oct 20.

Biomedical Engineering and Imaging Institute (A.E.M., M.M.T.v.L., M.L.S., C.C., P.M.R., G.S., C.P.-M., A.J.P.T., Y.C.T., K.S., E.M.v.L., E.D.K., A.M.S., W.J.M.M.), Icahn School of Medicine at Mount Sinai, New York, NY.

Background: Macrophages, innate immune cells that reside in all organs, defend the host against infection and injury. In the heart and vasculature, inflammatory macrophages also enhance tissue damage and propel cardiovascular diseases.

Methods: We here use in vivo positron emission tomography (PET) imaging, flow cytometry, and confocal microscopy to evaluate quantitative noninvasive assessment of cardiac, arterial, and pulmonary macrophages using the nanotracer Cu-Macrin-a 20-nm spherical dextran nanoparticle assembled from nontoxic polyglucose.

Results: PET imaging using Cu-Macrin faithfully reported accumulation of macrophages in the heart and lung of mice with myocardial infarction, sepsis, or pneumonia. Flow cytometry and confocal microscopy detected the near-infrared fluorescent version of the nanoparticle (Macrin) primarily in tissue macrophages. In 5-day-old mice, Cu-Macrin PET imaging quantified physiologically more numerous cardiac macrophages. Upon intravenous administration of Cu-Macrin in rabbits and pigs, we detected heightened macrophage numbers in the infarcted myocardium, inflamed lung regions, and atherosclerotic plaques using a clinical PET/magnetic resonance imaging scanner. Toxicity studies in rats and human dosimetry estimates suggest that Cu-Macrin is safe for use in humans.

Conclusions: Taken together, these results indicate Cu-Macrin could serve as a facile PET nanotracer to survey spatiotemporal macrophage dynamics during various physiological and pathological conditions. Cu-Macrin PET imaging could stage inflammatory cardiovascular disease activity, assist disease management, and serve as an imaging biomarker for emerging macrophage-targeted therapeutics.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.010586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583675PMC
October 2020

Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche.

Nat Biomed Eng 2020 11 5;4(11):1076-1089. Epub 2020 Oct 5.

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Bone-marrow endothelial cells in the haematopoietic stem-cell niche form a network of blood vessels that regulates blood-cell traffic as well as the maintenance and function of haematopoietic stem and progenitor cells. Here, we report the design and in vivo performance of systemically injected lipid-polymer nanoparticles encapsulating small interfering RNA (siRNA), for the silencing of genes in bone-marrow endothelial cells. In mice, nanoparticles encapsulating siRNA sequences targeting the proteins stromal-derived factor 1 (Sdf1) or monocyte chemotactic protein 1 (Mcp1) enhanced (when silencing Sdf1) or inhibited (when silencing Mcp1) the release of stem and progenitor cells and of leukocytes from the bone marrow. In a mouse model of myocardial infarction, nanoparticle-mediated inhibition of cell release from the haematopoietic niche via Mcp1 silencing reduced leukocytes in the diseased heart, improved healing after infarction and attenuated heart failure. Nanoparticle-mediated RNA interference in the haematopoietic niche could be used to investigate haematopoietic processes for therapeutic applications in cancer, infection and cardiovascular disease.
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http://dx.doi.org/10.1038/s41551-020-00623-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655681PMC
November 2020

Liver X receptors are required for thymic resilience and T cell output.

J Exp Med 2020 10;217(10)

Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)-a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity-critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαβ's functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαβ for cholesterol efflux, thymic epithelial cells (TECs) use LXRαβ for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαβ protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαβ limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ governs T lymphocyte education and illuminate LXRαβ's indispensable roles in adaptive immunity.
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http://dx.doi.org/10.1084/jem.20200318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537384PMC
October 2020

Bone Marrow Endothelial Cells Regulate Myelopoiesis in Diabetes Mellitus.

Circulation 2020 Jul 22;142(3):244-258. Epub 2020 Apr 22.

Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, Boston (F.F.H., M.J.S., D.R., C.S.A., Y.I., K.N., F.K.S., M.N.).

Background: Diabetes mellitus is a prevalent public health problem that affects about one-third of the US population and leads to serious vascular complications with increased risk for coronary artery disease. How bone marrow hematopoiesis contributes to diabetes mellitus complications is incompletely understood. We investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production.

Methods: In 3 types of mouse diabetes mellitus, including streptozotocin, high-fat diet, and genetic induction using leptin-receptor-deficient db/db mice, we assayed leukocytes, hematopoietic stem and progenitor cells (HSPC). In addition, we investigated bone marrow endothelial cells with flow cytometry and expression profiling.

Results: In diabetes mellitus, we observed enhanced proliferation of HSPC leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less , a retention factor promoting HSPC quiescence. Transcriptome-wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor (Egfr) signaling in mice with diet-induced diabetes mellitus. To explore whether endothelial Egfr plays a functional role in myelopoiesis, we generated mice with endothelial-specific deletion of Egfr (). We found enhanced HSPC proliferation and increased myeloid cell production in mice compared with wild-type mice with diabetes mellitus. Disrupted Egfr signaling in endothelial cells decreased their expression of the HSPC retention factor angiopoietin-1. We tested the functional relevance of these findings for wound healing and atherosclerosis, both implicated in complications of diabetes mellitus. Inflammatory myeloid cells accumulated more in skin wounds of diabetic mice, significantly delaying wound closure. Atherosclerosis was accelerated in mice, leading to larger and more inflamed atherosclerotic lesions in the aorta.

Conclusions: In diabetes mellitus, bone marrow endothelial cells participate in the dysregulation of bone marrow hematopoiesis. Diabetes mellitus reduces endothelial production of Cxcl12, a quiescence-promoting niche factor that reduces stem cell proliferation. We describe a previously unknown counterregulatory pathway, in which protective endothelial Egfr signaling curbs HSPC proliferation and myeloid cell production.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375017PMC
July 2020

Tissue-Specific Macrophage Responses to Remote Injury Impact the Outcome of Subsequent Local Immune Challenge.

Immunity 2019 11 12;51(5):899-914.e7. Epub 2019 Nov 12.

Center for Systems Biology, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, USA; Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany. Electronic address:

Myocardial infarction, stroke, and sepsis trigger systemic inflammation and organism-wide complications that are difficult to manage. Here, we examined the contribution of macrophages residing in vital organs to the systemic response after these injuries. We generated a comprehensive catalog of changes in macrophage number, origin, and gene expression in the heart, brain, liver, kidney, and lung of mice with myocardial infarction, stroke, or sepsis. Predominantly fueled by heightened local proliferation, tissue macrophage numbers increased systemically. Macrophages in the same organ responded similarly to different injuries by altering expression of tissue-specific gene sets. Preceding myocardial infarction improved survival of subsequent pneumonia due to enhanced bacterial clearance, which was caused by IFNɣ priming of alveolar macrophages. Conversely, EGF receptor signaling in macrophages exacerbated inflammatory lung injury. Our data suggest that local injury activates macrophages in remote organs and that targeting macrophages could improve resilience against systemic complications following myocardial infarction, stroke, and sepsis.
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http://dx.doi.org/10.1016/j.immuni.2019.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892583PMC
November 2019

Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells.

Nat Med 2019 11 7;25(11):1761-1771. Epub 2019 Nov 7.

Center for Systems Biology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice. Mechanistically, exercise diminishes leptin production in adipose tissue, augmenting quiescence-promoting hematopoietic niche factors in leptin-receptor-positive stromal bone marrow cells. Induced deletion of the leptin receptor in Prrx1-creER; Lepr mice reveals that leptin's effect on bone marrow niche cells regulates hematopoietic stem and progenitor cell (HSPC) proliferation and leukocyte production, as well as cardiovascular inflammation and outcomes. Whereas running wheel withdrawal quickly reverses leptin levels, the impact of exercise on leukocyte production and on the HSPC epigenome and transcriptome persists for several weeks. Together, these data show that physical activity alters HSPCs via modulation of their niche, reducing hematopoietic output of inflammatory leukocytes.
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http://dx.doi.org/10.1038/s41591-019-0633-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858591PMC
November 2019

Myeloperoxidase Molecular MRI Reveals Synergistic Combination Therapy in Murine Experimental Autoimmune Neuroinflammation.

Radiology 2019 10 3;293(1):158-165. Epub 2019 Sep 3.

From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge St, Boston, Mass 02114 (A.L., Y.W., B.P., G.R.W., Y.I., C.W., J.L., M.A., J.W.C.); Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Mass (B.P., C.W., J.W.C.); Department of Radiology, Qilu Hospital of Shandong University, Jinan, China (A.L.); and Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China (A.L., Y.W., X.F., Z.Y.).

Background Despite advances in immunomodulatory agents, most current therapies for multiple sclerosis target lymphocytes or lymphocytic function. However, therapy response may be less than optimal due to demyelination and axonal damage caused by myeloid cells. Purpose To determine if myeloperoxidase (MPO) molecular MRI can evaluate whether combination therapy targeting both lymphoid and myeloid inflammation can improve autoimmune neuroinflammation compared with either drug alone, even at suboptimal doses. Materials and Methods Four groups of 94 female mice (8-10 weeks old) were induced with experimental autoimmune encephalomyelitis (EAE) from August 2, 2016, to March 30, 2018, and divided into saline control ( = 22), 4-aminobenzoic acid hydrazide (ABAH) therapy group ( = 19), glatiramer acetate (GA) therapy group ( = 22), and combination therapy group ( = 31). Mice were administered suboptimal doses of ABAH, an irreversible inhibitor of MPO; GA, a first-line multiple sclerosis drug; both ABAH and GA; or saline (control). Mice were imaged with -5-hydroxytryptamide-diethylenetriaminepentaacetate gadolinium (hereafter, MPO-Gd) MRI. One-way analysis of variance, two-way analysis of variance, Kurskal-Wallis, and log-rank tests were used. < .05 was considered to indicate statistical significance. Results The combination-treated group showed delayed disease onset (day 11.3 vs day 9.8 for ABAH, day 10.4 for GA, day 9.9 for control; < .05) and reduced disease severity (clinical score during the acute exacerbation period of 1.8 vs 3.8 for ABAH, 3.1 for GA, 3.9 for control; < .05). The combination-treated group demonstrated fewer MPO-positive lesions (30.2 vs 73.7 for ABAH, 64.8 for GA, 67.2 for control; < .05), smaller MPO-positive lesion volume (16.7 mm vs 65.2 mm for ABAH, 69.9 mm for GA, 66.0 mm for control; < .05), and lower intensity of MPO-Gd lesion activation ratio (0.7 vs 1.9 for ABAH, 3.2 for GA, 2.3 for control; < .05). Reduced disease severity in the combination group was confirmed at histopathologic analysis, where MPO expression (1779 vs 2673 for ABAH, 2898 for GA; < .05) and demyelination (5.3% vs 9.0% for ABAH, 10.6% for GA; < .05) were ameliorated. Conclusion Myeloperoxidase molecular MRI can track the treatment response from immunomodulatory drugs even if the drug does not directly target myeloperoxidase, and establishes that combination therapy targeting both myeloid and lymphocytic inflammation is effective for murine autoimmune neuroinflammation, even at suboptimal doses. © RSNA, 2019 See also the editorial by Walczak in this issue.
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http://dx.doi.org/10.1148/radiol.2019182492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776885PMC
October 2019

A human organoid system that self-organizes to recapitulate growth and differentiation of a benign mammary tumor.

Proc Natl Acad Sci U S A 2019 06 17;116(23):11444-11453. Epub 2019 May 17.

Department of Systems Biology, Harvard Medical School, Boston, MA 02115;

As 3D culture has become central to investigation of tissue biology, mammary epithelial organoids have emerged as powerful tools for investigation of epithelial cell polarization and carcinogenesis. However, most current protocols start from single cells suspended in Matrigel, which can also restrict cell differentiation and behavior. Here, we show that the noncancerous mammary cell line HMT-3522 S1, when allowed to spontaneously form cell aggregates ("spheroids") in medium without Matrigel, switches to a collective growth mode that recapitulates many attributes of "usual ductal hyperplasia" (UDH), a common benign mammary lesion. Interestingly, these spheroids undergo a complex maturation process reminiscent of embryonic development: solid-cell cords form their own basement membrane, grow on the surface of initially homogeneous cell aggregates, and form asymmetric lumina lined by two distinct cell types that express basal and luminal cytokeratins. This sequence of events provides a cellular mechanism that explains how the characteristic crescent-shaped, asymmetrical lumina form in UDH. Our results suggest that HMT-3522 S1 spheroids are useful as an in vitro model system to study UDH biology, glandular lumen formation, and stem cell biology of the mammary gland.
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http://dx.doi.org/10.1073/pnas.1702372116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561274PMC
June 2019

Sleep modulates haematopoiesis and protects against atherosclerosis.

Nature 2019 02 13;566(7744):383-387. Epub 2019 Feb 13.

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Sleep is integral to life. Although insufficient or disrupted sleep increases the risk of multiple pathological conditions, including cardiovascular disease, we know little about the cellular and molecular mechanisms by which sleep maintains cardiovascular health. Here we report that sleep regulates haematopoiesis and protects against atherosclerosis in mice. We show that mice subjected to sleep fragmentation produce more Ly-6C monocytes, develop larger atherosclerotic lesions and produce less hypocretin-a stimulatory and wake-promoting neuropeptide-in the lateral hypothalamus. Hypocretin controls myelopoiesis by restricting the production of CSF1 by hypocretin-receptor-expressing pre-neutrophils in the bone marrow. Whereas hypocretin-null and haematopoietic hypocretin-receptor-null mice develop monocytosis and accelerated atherosclerosis, sleep-fragmented mice with either haematopoietic CSF1 deficiency or hypocretin supplementation have reduced numbers of circulating monocytes and smaller atherosclerotic lesions. Together, these results identify a neuro-immune axis that links sleep to haematopoiesis and atherosclerosis.
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http://dx.doi.org/10.1038/s41586-019-0948-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442744PMC
February 2019

Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease.

Nature 2019 02 30;566(7742):115-119. Epub 2019 Jan 30.

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways, how our bodies handle nutrients depends on strategically positioned metabolic sensors that link the intrinsic nutritional value of a meal with intermediary metabolism. Here we describe a subset of immune cells-integrin β7 natural gut intraepithelial T lymphocytes (natural IELs)-that is dispersed throughout the enterocyte layer of the small intestine and that modulates systemic metabolism. Integrin β7 mice that lack natural IELs are metabolically hyperactive and, when fed a high-fat and high-sugar diet, are resistant to obesity, hypercholesterolaemia, hypertension, diabetes and atherosclerosis. Furthermore, we show that protection from cardiovascular disease in the absence of natural IELs depends on the enteroendocrine-derived incretin GLP-1, which is normally controlled by IELs through expression of the GLP-1 receptor. In this metabolic control system, IELs modulate enteroendocrine activity by acting as gatekeepers that limit the bioavailability of GLP-1. Although the function of IELs may prove advantageous when food is scarce, present-day overabundance of diets high in fat and sugar renders this metabolic checkpoint detrimental to health.
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http://dx.doi.org/10.1038/s41586-018-0849-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367023PMC
February 2019

Self-reactive CD4 IL-3 T cells amplify autoimmune inflammation in myocarditis by inciting monocyte chemotaxis.

J Exp Med 2019 02 22;216(2):369-383. Epub 2019 Jan 22.

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA

Acquisition of self-reactive effector CD4 T cells is a major component of the autoimmune response that can occur during myocarditis, an inflammatory form of cardiomyopathy. Although the processes by which self-reactive T cells gain effector function have received considerable attention, how these T cells contribute to effector organ inflammation and damage is less clear. Here, we identified an IL-3-dependent amplification loop that exacerbates autoimmune inflammation. In experimental myocarditis, we show that effector organ-accumulating autoreactive IL-3 CD4 T cells stimulate IL-3R tissue macrophages to produce monocyte-attracting chemokines. The newly recruited monocytes differentiate into antigen-presenting cells that stimulate local IL-3 CD4 T cell proliferation, thereby amplifying organ inflammation. Consequently, mice resist developing robust autoimmune inflammation and myocardial dysfunction, whereas therapeutic IL-3 targeting ameliorates disease. This study defines a mechanism that orchestrates inflammation in myocarditis, describes a previously unknown function for IL-3, and identifies IL-3 as a potential therapeutic target in patients with myocarditis.
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http://dx.doi.org/10.1084/jem.20180722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363430PMC
February 2019

A Miniaturized, Programmable Pacemaker for Long-Term Studies in the Mouse.

Circ Res 2018 11;123(11):1208-1219

From the Department of Radiology, Center for Systems Biology (M.H., A.D.A., S.C., Y.I., K.R.K., F.K.S., R.W., M.N.), Massachusetts General Hospital and Harvard Medical School, Boston.

Rationale: Cardiac pacing is a critical technology for the treatment of arrhythmia and heart failure. The impact of specific pacing strategies on myocardial function is an area of intense research and high clinical significance. Mouse models have proven extremely useful for probing mechanisms of heart disease, but there is currently no reliable technology for long-term pacing in the mouse.

Objective: We sought to develop a device for long-term pacing studies in mice. We evaluated the device for (1) treating third-degree atrioventricular block after macrophage depletion, (2) ventricular pacing-induced cardiomyopathy, and (3) high-rate atrial pacing.

Methods And Results: We developed a mouse pacemaker by refashioning a 26 mm×6.7 mm clinical device powered by a miniaturized, highly efficient battery. The electrode was fitted with a single flexible lead, and custom software extended the pacing rate to up to 1200 bpm. The wirelessly programmable device was implanted in the dorsal subcutaneous space of 39 mice. The tunneled lead was passed through a left thoracotomy incision and attached to the epicardial surface of the apex (for ventricular pacing) or the left atrium (for atrial pacing). Mice tolerated the implantation and both long-term atrial and ventricular pacing over weeks. We then validated the pacemaker's suitability for the treatment of atrioventricular block after macrophage depletion in Cd11b mice. Ventricular pacing increased the heart rate from 313±59 to 550 bpm ( P<0.05). In addition, we characterized tachypacing-induced cardiomyopathy in mice. Four weeks of ventricular pacing resulted in reduced left ventricular function, fibrosis, and an increased number of cardiac leukocytes and endothelial activation. Finally, we demonstrated the feasibility of chronic atrial pacing at 1200 bpm.

Conclusions: Long-term pacing with a fully implantable, programmable, and battery-powered device enables previously impossible investigations of arrhythmia and heart failure in the mouse.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.313429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309285PMC
November 2018

Multimodal Molecular Imaging Demonstrates Myeloperoxidase Regulation of Matrix Metalloproteinase Activity in Neuroinflammation.

Mol Neurobiol 2019 Feb 28;56(2):954-962. Epub 2018 May 28.

Center for Systems Biology and Institute for Innovation in Imaging, Department of Radiology, Harvard Medical School, Massachusetts General Hospital, 185 Cambridge Street, 5.210 Richard B. Simches Research Building, Boston, MA, 02114, USA.

Myeloperoxidase (MPO) has paradoxically been found to be able to both activate matrix metalloproteinases (MMPs) as well as inhibit MMPs. However, these regulatory effects have not yet been observed in vivo, and it is unclear which pathway is relevant in vivo. We aim to track MPO regulation of MMP activity in living animals in neuroinflammation. Mice induced with experimental autoimmune encephalomyelitis (EAE), a mouse model of neuroinflammation and multiple sclerosis, were treated with either the MPO-specific inhibitor 4-aminobenzoic acid hydrazide or saline as control. Mice underwent concurrent magnetic resonance imaging (MRI) with the MPO-specific molecular imaging agent MPO-Gd and fluorescence molecular tomography (FMT) with the MMP-targeting agent MMPsense on day 12 after induction. Biochemical and histopathological correlations were performed. Utilizing concurrent MRI and FMT imaging, we found reduced MMP activity in the brain with MPO inhibition, demonstrating MPO activity positively regulates MMP activity in vivo. In vivo MMPSense activation and MMP-9 activity correlated with MPO-Gd lesion volume and disease severity. This was corroborated by in vitro assays and histopathological analyses that showed MMP activity and MMP-9 cells correlated with MPO activity and MPO cells. In conclusion, multimodal molecular imaging demonstrates for the first time MPO regulation of MMP activity in living animals. This approach could serve as a model to study the interactions of other biologically interesting molecules in living organisms.
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http://dx.doi.org/10.1007/s12035-018-1137-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261713PMC
February 2019

Erratum to "Characterizations of oral microbiota in elderly nursing home residents with diabetes".

J Oral Sci 2018 ;60(1):163

Department of Prosthodontics, Gerodontology and Oral Rehabilitation, Osaka University Graduate School of Dentistry.

The publisher regrets that in the above-mentioned article, there was an error in the list of references. The reference numbers "29-32" should be "28-31".
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http://dx.doi.org/10.2334/josnusd.16-072201DOI Listing
October 2018

Cardiac macrophages promote diastolic dysfunction.

J Exp Med 2018 02 16;215(2):423-440. Epub 2018 Jan 16.

Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA

Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen. In humans, we observed a parallel constellation of hematopoietic activation: circulating myeloid cells are more frequent, and splenic F-FDG PET/CT imaging signal correlates with echocardiographic indices of diastolic dysfunction. While diastolic dysfunction develops, cardiac macrophages produce IL-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. Deletion of IL-10 in macrophages improves diastolic function. These data imply expansion and phenotypic changes of cardiac macrophages as therapeutic targets for cardiac fibrosis leading to diastolic dysfunction.
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http://dx.doi.org/10.1084/jem.20171274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789416PMC
February 2018

Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF neutrophils.

Science 2017 12;358(6367)

Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.

Bone marrow-derived myeloid cells can accumulate within tumors and foster cancer outgrowth. Local immune-neoplastic interactions have been intensively investigated, but the contribution of the systemic host environment to tumor growth remains poorly understood. Here, we show in mice and cancer patients ( = 70) that lung adenocarcinomas increase bone stromal activity in the absence of bone metastasis. Animal studies reveal that the cancer-induced bone phenotype involves bone-resident osteocalcin-expressing (Ocn) osteoblastic cells. These cells promote cancer by remotely supplying a distinct subset of tumor-infiltrating SiglecF neutrophils, which exhibit cancer-promoting properties. Experimentally reducing Ocn cell numbers suppresses the neutrophil response and lung tumor outgrowth. These observations posit osteoblasts as remote regulators of lung cancer and identify SiglecF neutrophils as myeloid cell effectors of the osteoblast-driven protumoral response.
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http://dx.doi.org/10.1126/science.aal5081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343476PMC
December 2017

IRF3 and type I interferons fuel a fatal response to myocardial infarction.

Nat Med 2017 Dec 6;23(12):1481-1487. Epub 2017 Nov 6.

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections and cancer, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi-Goutières syndrome and STING-associated vasculopathy of infancy (SAVI). Myocardial infarction (MI) elicits inflammation, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production. In mice, single-cell RNA-seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts showed that MI provokes activation of an IRF3-interferon axis in a distinct population of interferon-inducible cells (IFNICs) that were classified as cardiac macrophages. Mice genetically deficient in cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection.
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http://dx.doi.org/10.1038/nm.4428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477926PMC
December 2017

Losartan/hydrochlorothiazide combination is safe and effective for morning hypertension in Very-Elderly patients.

Clin Exp Hypertens 2018 30;40(3):267-273. Epub 2017 Oct 30.

a Department of Internal Medicine, Division of Cardio-Vascular Medicine , Kurume University School of Medicine , Kurume , Japan.

Morning hypertension is an independent risk for cerebrovascular and cardiovascular events. Although the prevalence of morning hypertension increases with age, treatment of morning hypertension has not been established, particularly in Very-Elderly patients. We compared the safety and efficacy of a losartan/hydrochlorothiazide (HCTZ) combination in controlling morning hypertension between Very-Elderly (≥75 years) and Young/Elderly patients (<75 years). This study was a subanalysis of the Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy study, in which patients with morning hypertension (≥135/85 mmHg) received a 50-mg losartan/12.5-mg HCTZ combination tablet (combination therapy) or 100-mg losartan (high-dose therapy) for 3 months. High adherence rates and few adverse effects were observed in Very-Elderly patients receiving combination (n = 32) and high-dose (n = 34) therapies and in Young/Elderly patients receiving combination (n = 69) and high-dose (n = 66) therapies. Baseline morning systolic BP (SBP) was similar in both age groups receiving either therapy. Morning SBP was reduced by 20.2 and 18.1 mmHg with combination therapy and by 7.1 and 9.1 mmHg with high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Morning BP target (<135/85 mmHg) was achieved in 40.6% and 55.1% by combination therapy and in 14.7% and 24.2% by high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Neither therapy changed renal function and serum potassium in Very-Elderly patients. In conclusion, the losartan/HCTZ combination was safe and effective in controlling morning hypertension in Very-Elderly as well as Young/Elderly patients. In addition, combination therapy was also superior to high-dose therapy for lowering morning SBP in Very-Elderly patients.
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http://dx.doi.org/10.1080/10641963.2017.1368536DOI Listing
August 2018

Characterizations of oral microbiota in elderly nursing home residents with diabetes.

J Oral Sci 2017 Dec 6;59(4):549-555. Epub 2017 Oct 6.

Department of Prosthodontics, Gerodontology and Oral Rehabilitation, Osaka University Graduate School of Dentistry.

Over 700 bacterial species have been detected in the oral cavity. Several studies have suggested that periodontitis is associated with systemic disorders such as diabetes mellitus, indicating a key role for oral microbiota in human health. However, the relationship between oral microbiota and diabetes has not been well clarified. Therefore, we conducted microbiome analysis of saliva samples obtained from 15 elderly residents (3 with type 2 diabetes mellitus [DM] and 12 without diabetes [non-DM]) at three different nursing homes, as well as 9 young healthy controls (HC). Genomic DNA was extracted from each sample, and then the V4 region of the 16S rRNA gene was amplified and sequenced. Alpha diversity, in terms of operational taxonomic unit richness, was significantly higher in samples from the non-DM group than in those from the HC group. Weighted UniFrac distance analysis showed that salivary microbial communities in the DM group were separately clustered. Furthermore, in the DM group, Actinomyces and Selenomonas showed significantly higher abundance, whereas Alloprevotella showed significantly lower abundance, relative to the non-DM group. Although our findings were limited by the small sample size, oral bacterial diversity in the DM group was clearly different from that in the non-DM group.
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http://dx.doi.org/10.2334/josnusd.16-0722DOI Listing
December 2017

The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes.

J Exp Med 2017 Nov 4;214(11):3293-3310. Epub 2017 Oct 4.

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA

Myocardial infarction (MI) elicits massive inflammatory leukocyte recruitment to the heart. Here, we hypothesized that excessive leukocyte invasion leads to heart failure and death during acute myocardial ischemia. We found that shortly and transiently after onset of ischemia, human and mouse cardiac fibroblasts produce granulocyte/macrophage colony-stimulating factor (GM-CSF) that acts locally and distally to generate and recruit inflammatory and proteolytic cells. In the heart, fibroblast-derived GM-CSF alerts its neighboring myeloid cells to attract neutrophils and monocytes. The growth factor also reaches the bone marrow, where it stimulates a distinct myeloid-biased progenitor subset. Consequently, hearts of mice deficient in either GM-CSF or its receptor recruit fewer leukocytes and function relatively well, whereas mice producing GM-CSF can succumb from left ventricular rupture, a complication mitigated by anti-GM-CSF therapy. These results identify GM-CSF as both a key contributor to the pathogenesis of MI and a potential therapeutic target, bolstering the idea that GM-CSF is a major orchestrator of the leukocyte supply chain during inflammation.
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http://dx.doi.org/10.1084/jem.20170689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679174PMC
November 2017

Macrophages Facilitate Electrical Conduction in the Heart.

Cell 2017 04;169(3):510-522.e20

Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11b mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.
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http://dx.doi.org/10.1016/j.cell.2017.03.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474950PMC
April 2017

Molecular MR Imaging of Myeloperoxidase Distinguishes Steatosis from Steatohepatitis in Nonalcoholic Fatty Liver Disease.

Radiology 2017 08 30;284(2):390-400. Epub 2017 Mar 30.

From the Center for Systems Biology (B.P., G.W., Y.I., M.A., M.W.Z., L.B., C.W., A.R.G., J.W.C.), Department of Radiology (B.P., A.R.G., J.W.C.), Liver Center and Gastrointestinal Division (Y.C., K.E.C.), and Department of Pathology (R.M.), Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge St, Boston, MA 02114.

Purpose To test whether MPO-Gd, an activatable molecular magnetic resonance (MR) imaging agent specific for myeloperoxidase (MPO) activity, could detect MPO activity in nonalcoholic steatohepatitis (NASH) mouse models and human liver biopsy samples. Materials and Methods In this study, 20 leptin receptor-deficient and three MPO knockout mice were injected with endotoxin (lipopolysaccharide) or fed a methionine and choline-deficient (MCD) diet to induce experimental NASH and underwent MR imaging with MPO-Gd. Saline-injected and control diet-fed leptin receptor-deficient mice were used as respective controls. MPO protein and activity measurements and histologic analyses were performed. Eleven human liver biopsy samples underwent MPO-Gd-enhanced MR imaging ex vivo and subsequent histologic evaluation. Results were compared with Student t test or Mann-Whitney U test. Results With endotoxin, a significantly increased contrast-to-noise ratio (CNR) was found compared with sham (mean CNR, 1.81 [95% confidence interval {CI}: 1.53, 2.10] vs 1.02 [95% CI: 0.89, 1.14]; P = .03) at MPO-Gd MR imaging. In the diet-induced NASH model, an increased CNR was also found compared with sham mice (mean CNR, 1.33 [95% CI: 1.27, 1.40] vs 0.98 [95% CI: 0.83, 1.12]; P = .008). Conversely, CNR remained at baseline in NASH mice imaged with gadopentetate dimeglumine and in MPO knockout NASH mice with MPO-Gd, which proves specificity of MPO-Gd. Ex vivo molecular MR imaging of liver biopsy samples from NASH and control patients confirmed results from animal studies (mean CNR for NASH vs control patients, 2.61 [95% CI: 1.48, 3.74] vs 1.29 [95% CI: 1.06, 1.52]; P = .004). Conclusion MPO-Gd showed elevated MPO activity in NAFLD mouse models and human liver biopsy samples. RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on April 6, 2017.
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http://dx.doi.org/10.1148/radiol.2017160588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548451PMC
August 2017

Polyglucose nanoparticles with renal elimination and macrophage avidity facilitate PET imaging in ischaemic heart disease.

Nat Commun 2017 01 16;8:14064. Epub 2017 Jan 16.

Center for Systems Biology and Department of Imaging, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, Massachusetts 02114, USA.

Tissue macrophage numbers vary during health versus disease. Abundant inflammatory macrophages destruct tissues, leading to atherosclerosis, myocardial infarction and heart failure. Emerging therapeutic options create interest in monitoring macrophages in patients. Here we describe positron emission tomography (PET) imaging with F-Macroflor, a modified polyglucose nanoparticle with high avidity for macrophages. Due to its small size, Macroflor is excreted renally, a prerequisite for imaging with the isotope flourine-18. The particle's short blood half-life, measured in three species, including a primate, enables macrophage imaging in inflamed cardiovascular tissues. Macroflor enriches in cardiac and plaque macrophages, thereby increasing PET signal in murine infarcts and both mouse and rabbit atherosclerotic plaques. In PET/magnetic resonance imaging (MRI) experiments, Macroflor PET imaging detects changes in macrophage population size while molecular MRI reports on increasing or resolving inflammation. These data suggest that Macroflor PET/MRI could be a clinical tool to non-invasively monitor macrophage biology.
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http://dx.doi.org/10.1038/ncomms14064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241815PMC
January 2017

Myeloperoxidase Inhibition Improves Ventricular Function and Remodeling After Experimental Myocardial Infarction.

JACC Basic Transl Sci 2016 Dec 26;1(7):633-643. Epub 2016 Dec 26.

Center for Systems Biology, and the Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

PF-1355 is an oral myeloperoxidase (MPO) inhibitor that successfully decreased elevated MPO activity in mouse myocardial infarction models. Short duration PF-1355 treatment for 7 days decreased the number of inflammatory cells and attenuated left ventricular dilation. Cardiac function and remodeling improved when treatment was increased to 21 days. Better therapeutic effect was further achieved with early compared with delayed treatment initiation (1 h vs. 24 h after infarction). In conclusion, PF-1355 treatment protected a mouse heart from acute and chronic effects of MI, and this study paves the way for future translational studies investigating this class of drugs in cardiovascular diseases.
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http://dx.doi.org/10.1016/j.jacbts.2016.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113523PMC
December 2016