Publications
366 results found
Harrison DE, Strong R, Reifsnyder P, et al., 2024, Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used., Geroscience, Vol: 46, Pages: 795-816
In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% (p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% (p = 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± SE (n) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang-Allison test. Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging.
Racine JJ, Misherghi A, Dwyer JR, et al., 2023, HLA-DQ8 Supports Development of Insulitis Mediated by Insulin-Reactive Human TCR-Transgenic T Cells in Nonobese Diabetic Mice., J Immunol, Vol: 211, Pages: 1792-1805
In an effort to improve HLA-"humanized" mouse models for type 1 diabetes (T1D) therapy development, we previously generated directly in the NOD strain CRISPR/Cas9-mediated deletions of various combinations of murine MHC genes. These new models improved upon previously available platforms by retaining β2-microglobulin functionality in FcRn and nonclassical MHC class I formation. As proof of concept, we generated H2-Db/H2-Kd double knockout NOD mice expressing human HLA-A*0201 or HLA-B*3906 class I variants that both supported autoreactive diabetogenic CD8+ T cell responses. In this follow-up work, we now describe the creation of 10 new NOD-based mouse models expressing various combinations of HLA genes with and without chimeric transgenic human TCRs reactive to proinsulin/insulin. The new TCR-transgenic models develop differing levels of insulitis mediated by HLA-DQ8-restricted insulin-reactive T cells. Additionally, these transgenic T cells can transfer insulitis to newly developed NSG mice lacking classical murine MHC molecules, but expressing HLA-DQ8. These new models can be used to test potential therapeutics for a possible capacity to reduce islet infiltration or change the phenotype of T cells expressing type 1 diabetes patient-derived β cell autoantigen-specific TCRs.
Robertson SJ, Bedard O, McNally KL, et al., 2023, Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19, NATURE COMMUNICATIONS, Vol: 14
Chella Krishnan K, El Hachem E-J, Keller MP, et al., 2023, Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy., Elife, Vol: 12
Mitochondria play an important role in both normal heart function and disease etiology. We report analysis of common genetic variations contributing to mitochondrial and heart functions using an integrative proteomics approach in a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). We performed a whole heart proteome study in the HMDP (72 strains, n=2-3 mice) and retrieved 848 mitochondrial proteins (quantified in ≥50 strains). High-resolution association mapping on their relative abundance levels revealed three trans-acting genetic loci on chromosomes (chr) 7, 13 and 17 that regulate distinct classes of mitochondrial proteins as well as cardiac hypertrophy. DAVID enrichment analyses of genes regulated by each of the loci revealed that the chr13 locus was highly enriched for complex-I proteins (24 proteins, P=2.2E-61), the chr17 locus for mitochondrial ribonucleoprotein complex (17 proteins, P=3.1E-25) and the chr7 locus for ubiquinone biosynthesis (3 proteins, P=6.9E-05). Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively, and both experimental and statistical analyses supported their causal roles. Furthermore, a large cohort of Diversity Outbred mice was used to corroborate Lrpprc gene as a driver of mitochondrial DNA (mtDNA)-encoded gene regulation, and to show that the chr17 locus is specific to heart. Variations in all three loci were associated with heart mass in at least one of two independent heart stress models, namely, isoproterenol-induced heart failure and diet-induced obesity. These findings suggest that common variations in certain mitochondrial proteins can act in trans to influence tissue-specific mitochondrial functions and contribute to heart hypertrophy, elucidating mechanisms that may underlie genetic susceptibility to heart failure in human populations.
Snyder JM, Casey KM, Galecki A, et al., 2023, Canagliflozin retards age-related lesions in heart, kidney, liver, and adrenal gland in genetically heterogenous male mice, GEROSCIENCE, Vol: 45, Pages: 385-397, ISSN: 2509-2715
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- Citations: 7
Strong R, Miller RA, Cheng CJ, et al., 2022, Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice., Aging Cell, Vol: 21
Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice receiving both drugs was neither higher nor lower than that seen previously in Rapa only, perhaps reflecting the limited survival benefits seen in prior cohorts of females receiving Aca alone. Capt led to a significant, though small (4% or 5%), increase in female lifespan. Capt also showed some possible benefits in male mice, but the interpretation was complicated by the unusually low survival of controls at one of the three test sites. BD seemed to produce a small (2%) increase in females, but only if the analysis included data from the site with unusually short-lived controls. None of the other 4 tested agents led to any lifespan benefit. The C2017 ITP dataset shows that combinations of anti-aging drugs may have effects that surpass the benefits produced by either drug used alone, and that additional studies of captopril, over a wider range of doses, are likely to be rewarding.
Svenson KL, Krasinski SD, Ellis M, et al., 2022, Animals, quality and the pursuit of relevance, DISEASE MODELS & MECHANISMS, Vol: 15, ISSN: 1754-8403
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- Citations: 2
Debuque RJ, Nowoshilow S, Chan KE, et al., 2022, Distinct toll-like receptor signaling in the salamander response to tissue damage, DEVELOPMENTAL DYNAMICS, Vol: 251, Pages: 988-1003, ISSN: 1058-8388
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- Citations: 9
Auchampach J, Han L, Huang GN, et al., 2022, Measuring cardiomyocyte cell-cycle activity and proliferation in the age of heart regeneration, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, Vol: 322, Pages: H579-H596, ISSN: 0363-6135
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- Citations: 11
Squiers GT, McLellan MA, Ilinykh A, et al., 2022, Corrigendum to: Cardiac cellularity is dependent upon biological sex and is regulated by gonadal hormones., Cardiovasc Res, Vol: 118
Forte E, Ramialison M, Nim HT, et al., 2022, Adult mouse fibroblasts retain organ-specific transcriptomic identity, ELIFE, Vol: 11, ISSN: 2050-084X
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- Citations: 7
Kuraitis D, Rosenthal N, Boh E, et al., 2022, Macrophages in dermatology: pathogenic roles and targeted therapeutics, ARCHIVES OF DERMATOLOGICAL RESEARCH, Vol: 314, Pages: 133-140, ISSN: 0340-3696
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- Citations: 7
Mohenska M, Tan NM, Tokolyi A, et al., 2022, 3D-cardiomics: A spatial transcriptional atlas of the mammalian heart, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 163, Pages: 20-32, ISSN: 0022-2828
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- Citations: 7
Brito L, Mylonaki I, Grigsby CL, et al., 2021, Genetic Enhancement of Epicardial Paracrine Signalling for Cardiac Regeneration, Annual Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Debuque RJ, Hart AJ, Johnson GH, et al., 2021, Identification of the Adult Hematopoietic Liver as the Primary Reservoir for the Recruitment of Pro-regenerative Macrophages Required for Salamander Limb Regeneration, FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, Vol: 9, ISSN: 2296-634X
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- Citations: 4
Squiers GT, McLellan MA, Ilinykh A, et al., 2021, Cardiac cellularity is dependent upon biological sex and is regulated by gonadal hormones, CARDIOVASCULAR RESEARCH, Vol: 117, Pages: 2252-2261, ISSN: 0008-6363
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- Citations: 19
Plikus M, Wang X, Sinha S, et al., 2021, Fibroblasts: Origins, definitions, and functions in health and disease, CELL, Vol: 184, Pages: 3852-3872, ISSN: 0092-8674
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- Citations: 194
Harrison DE, Strong R, Reifsnyder P, et al., 2021, 17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex, AGING CELL, Vol: 20, ISSN: 1474-9718
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- Citations: 34
Forte E, McLellan MA, Skelly DA, et al., 2021, <i>Ex uno, plures</i>-From One Tissue to Many Cells: A Review of Single-Cell Transcriptomics in Cardiovascular Biology, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 22
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- Citations: 1
Tombor LS, John D, Glaser SF, et al., 2021, Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction, NATURE COMMUNICATIONS, Vol: 12
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- Citations: 100
Macchiarini F, Miller RA, Strong R, et al., 2021, NIA Interventions Testing Program: A collaborative approach for investigating interventions to promote healthy aging, Handbook of the Biology of Aging, Pages: 219-235, ISBN: 9780128159620
The NIA Interventions Testing Program (ITP) investigates the potential of dietary interventions to promote healthy aging and provides preliminary data on cellular mechanisms and pathways that affect aging. Members of the research community propose compounds for study, and lifespan and health studies are performed at three sites to demonstrate the degree of reproducibility. A genetically heterogeneous mouse model is used to reduce the influence of strain-specific characteristics on the outcomes, and sufficient mice are used to detect a 10% change in mean lifespan with 80% power if at least two sites contribute data. There have been several positive findings that have prompted additional studies within the ITP and from the broader research community, including data on rapamycin, acarbose, 17α-estradiol, nordihydroguaiaretic acid, Protandim, and glycine. This chapter describes the ITP structure, summarizes findings to date and how they have led to additional studies, and discusses the future role of the ITP in promoting research on antiaging interventions.
Forte E, Panahi M, Baxan N, et al., 2021, Type 2 MI induced by a single high dose of isoproterenol in C57BL/6J mice triggers a persistent adaptive immune response against the heart, Journal of Cellular and Molecular Medicine, Vol: 25, Pages: 229-243, ISSN: 1582-1838
Heart failure is the common final pathway of several cardiovascular conditions and a major cause of morbidity and mortality worldwide. Aberrant activation of the adaptive immune system in response to myocardial necrosis has recently been implicated in the development of heart failure. The ß-adrenergic agonist isoproterenol hydrochloride is used for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis. To assess whether isoproterenol-induced cardiomyocyte necrosis triggers an adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of isoproterenol. We confirmed tissue damage reminiscent of human type 2 myocardial infarction. This is followed by an adaptive immune response targeting the heart as demonstrated by the activation of T cells, the presence of anti-heart auto-antibodies in the serum as late as 12 weeks after initial challenge and IgG deposition in the myocardium. All of these are hallmark signs of an established autoimmune response. Adoptive transfer of splenocytes from isoproterenol-treated mice induces left ventricular dilation and impairs cardiac function in healthy recipients. In summary, a single administration of a high dose of isoproterenol is a suitable high-throughput model for future studies of the pathological mechanisms of anti-heart autoimmunity and to test potential immunomodulatory therapeutic approaches.
Yucel N, Chang AC, Day JW, et al., 2020, Humanizing the mdx mouse model of DMD: the long and the short of it (vol 3, 4, 2018), NPJ REGENERATIVE MEDICINE, Vol: 5
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- Citations: 1
Forte E, Perkins B, Sintou A, et al., 2020, Cross-priming dendritic cells exacerbate immunopathology after ischemic tissue damage in the heart, Circulation, Vol: 143, Pages: 821-836, ISSN: 0009-7322
Background: Ischemic heart disease is a leading cause of heart failure and despite advanced therapeutic options, morbidity and mortality rates remain high. Although acute inflammation in response to myocardial cell death has been extensively studied, subsequent adaptive immune activity and anti-heart autoimmunity may also contribute to the development of HF. After ischemic injury to the myocardium, dendritic cells (DC) respond to cardiomyocyte necrosis, present cardiac antigen to T cells and potentially initiate a persistent autoimmune response against the heart. Cross-priming DC have the ability to activate both CD4+ helperand CD8+ cytotoxic T cells in response to necrotic cells and may thus be crucial players in exacerbating autoimmunity targeting the heart. This study investigates a role for cross priming DC in post-MI myocardial impairment through presentation of self-antigen fromnecrotic cardiomyocytes to cytotoxic CD8+ T cells.Methods: We induced type-2 myocardial infarction (MI)-like ischemic injury in the heart by treatment with a single high dose of the beta-adrenergic agonist isoproterenol. We characterized the DC population in the heart and mediastinal lymph nodes and analyzed long term cardiac immunopathology and functional decline in wild type and Clec9a-depleted mice lacking DC cross-priming function.Results: A diverse DC population, including cross-priming DC, is present in the heart and activated after ischemic injury. Clec9a -/- mice deficient in DC cross-priming are protected from long-term immune-mediated myocardial damage and decline of cardiac function, likely dueto dampened activation of cytotoxic CD8+ T cells.Conclusion: Activation of cytotoxic CD8+ T cells by cross-priming DC contributes to exacerbation of post-ischemic inflammatory damage of the myocardium and corresponding decline in cardiac function. Importantly, this provides novel therapeutic targets to prevent immune-mediated worsening of post-ischemic HF.
Miller RA, Harrison DE, Allison DB, et al., 2020, Canagliflozin extends life span in genetically heterogeneous male but not female mice, JCI INSIGHT, Vol: 5
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- Citations: 39
McLellan MA, Skelly DA, Dona MSI, et al., 2020, High-resolution transcriptomic profiling of the heart during chronic stress reveals cellular drivers of cardiac fibrosis and hypertrophy, Circulation, Vol: 142, Pages: 1448-1463, ISSN: 0009-7322
BACKGROUND: Cardiac fibrosis is a key antecedent to many types of cardiac dysfunction including heart failure. Physiological factors leading to cardiac fibrosis have been recognized for decades. However, the specific cellular and molecular mediators that drive cardiac fibrosis, and the relative effect of disparate cell populations on cardiac fibrosis, remain unclear. METHODS: We developed a novel cardiac single-cell transcriptomic strategy to characterize the cardiac cellulome, the network of cells that forms the heart. This method was used to profile the cardiac cellular ecosystem in response to 2 weeks of continuous administration of angiotensin II, a profibrotic stimulus that drives pathological cardiac remodeling. RESULTS: Our analysis provides a comprehensive map of the cardiac cellular landscape uncovering multiple cell populations that contribute to pathological remodeling of the extracellular matrix of the heart. Two phenotypically distinct fibroblast populations, Fibroblast-Cilp and Fibroblast-Thbs4, emerged after induction of tissue stress to promote fibrosis in the absence of smooth muscle actin-expressing myofibroblasts, a key profibrotic cell population. After angiotensin II treatment, Fibroblast-Cilp develops as the most abundant fibroblast subpopulation and the predominant fibrogenic cell type. Mapping intercellular communication networks within the heart, we identified key intercellular trophic relationships and shifts in cellular communication after angiotensin II treatment that promote the development of a profibrotic cellular microenvironment. Furthermore, the cellular responses to angiotensin II and the relative abundance of fibrogenic cells were sexually dimorphic. CONCLUSIONS: These results offer a valuable resource for exploring the cardiac cellular landscape in health and after chronic cardiovascular stress. These data provide insights into the cellular and molecular mechanisms that promote pathological remodeling of the mammalian heart, high
Forte E, Daigle S, Rosenthal NA, 2020, Protocol for Isolation of Cardiac Interstitial Cells from Adult Murine Hearts for Unbiased Single Cell Profiling, STAR PROTOCOLS, Vol: 1, ISSN: 2666-1667
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- Citations: 2
Sintou A, Mansfield C, Iacob A-O, et al., 2020, Mediastinal lymphadenopathy, class-switched auto-antibodies and myocardial immune-complexes during heart failure in rodents and humans, Frontiers in Cell and Developmental Biology, Vol: 8, Pages: 1-12, ISSN: 2296-634X
Mediastinal lymphadenopathy and auto-antibodies are clinical phenomena during ischemicheart failure pointing to an autoimmune response against the heart. T and B cell have beenconvincingly demonstrated to be activated after myocardial infarction, a prerequisite for thegeneration of mature auto-antibodies. Yet, little is known about the immunoglobulin isotyperepertoire thus pathological potential of anti-heart auto-antibodies during heart failure.We obtained human myocardial tissue from ischemic heart failure patients and inducedexperimental MI in rats. We found that anti-heart autoimmunity persists during heart failure.Rat mediastinal lymph nodes are enlarged and contain active secondary follicles with matureisotype-switched IgG2a B cells. Mature IgG2a auto-antibodies specific for cardiac antigens arepresent in rat heart failure serum, and IgG and complement C3 deposits are evident in heartfailure tissue of both rats and human patients.Previously established myocardial inflammation, and the herein provided proof of B cellmaturation in lymph nodes and myocardial deposition of mature auto-antibodies, provide allthe hallmark signs of an established autoimmune response in chronic heart failure.
Bouvet M, Claude O, Roux M, et al., 2020, Anti-integrin αv therapy improves cardiac fibrosis after myocardial infarction by blunting cardiac PW1+ stromal cells., Scientific Reports, Vol: 10, Pages: 11404-11404, ISSN: 2045-2322
There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure. We have recently shown that cardiac fibrosis post-myocardial infarction (MI) can be regulated by resident cardiac cells with a fibrogenic signature and identified by the expression of PW1 (Peg3). Here we identify αV-integrin (CD51) as an essential regulator of cardiac PW1+ cells fibrogenic behavior. We used transcriptomic and proteomic approaches to identify specific cell-surface markers for cardiac PW1+ cells and found that αV-integrin (CD51) was expressed in almost all cardiac PW1+ cells (93% ± 1%), predominantly as the αVβ1 complex. αV-integrin is a subunit member of the integrin family of cell adhesion receptors and was found to activate complex of latent transforming growth factor beta (TGFβ at the surface of cardiac PW1+ cells. Pharmacological inhibition of αV-integrin reduced the profibrotic action of cardiac PW1+CD51+ cells and was associated with improved cardiac function and animal survival following MI coupled with a reduced infarct size and fibrotic lesion. These data identify a targetable pathway that regulates cardiac fibrosis in response to an ischemic injury and demonstrate that pharmacological inhibition of αV-integrin could reduce pathological outcomes following cardiac ischemia.
Epstein JA, Rosenthal N, Feldman AM, 2020, Teasing the immune system to repair the heart, New England Journal of Medicine, Vol: 382, Pages: 1660-1662, ISSN: 0028-4793
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