Publications
366 results found
Forbes SJ, Rosenthal N, 2014, Preparing the ground for tissue regeneration: from mechanism to therapy, NATURE MEDICINE, Vol: 20, Pages: 857-869, ISSN: 1078-8956
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- Citations: 376
Rosenthal N, Zernicka-Goetz M, 2014, A tribute to Sir John Gurdon, DIFFERENTIATION, Vol: 88, Pages: 1-2, ISSN: 0301-4681
Wilson JL, Salimova E, Dissen GA, et al., 2014, Transgenic Mice Overexpressing Nerve Growth Factor (NGF) in the Ovary Exhibit Both Reproductive and Metabolic Alterations Characteristic of PCOS and a State of Sympathetic Hyperactivity, Publisher: ENDOCRINE SOC, ISSN: 0163-769X
Pinto AR, Godwin JW, Chandran A, et al., 2014, Age-related changes in tissue macrophages precede cardiac functional impairment, Aging-US, Vol: 6, Pages: 399-413, ISSN: 1945-4589
Cardiac tissue macrophages (cTMs) are abundant in the murine heart but the extent to which the cTM phenotype changes with age is unknown. This study characterizes aging-dependent phenotypic changes in cTM subsets. Using the Cx3cr1GFP/+ mouse reporter line where GFP marks cTMs, and the tissue macrophage marker Mrc1, we show that two major cardiac tissue macrophage subsets, Mrc1−GFPhi and Mrc1+GFPhi cTMs, are present in the young (<10 week old) mouse heart, and a third subset, Mrc1+GFPlo, comprises ~50% of total Mrc1+ cTMs from 30 weeks of age. Immunostaining and functional assays show that Mrc1+ cTMs are the principal myeloid sentinels in the mouse heart and that they retain proliferative capacity throughout life. Gene expression profiles of the two Mrc1+ subsets also reveal that Mrc1+GFPlo cTMs have a decreased number of immune response genes (Cx3cr1, Lpar6, CD9, Cxcr4, Itga6 and Tgfβr1), and an increased number of fibrogenic genes (Ltc4s, Retnla, Fgfr1, Mmp9 and Ccl24), consistent with a potential role for cTMs in cardiac fibrosis. These findings identify early age-dependent gene expression changes in cTMs, with significant implications for cardiac tissue injury responses and aging-associated cardiac fibrosis.
Furtado MB, Costa MW, Pranoto EA, et al., 2014, Cardiogenic genes expressed in cardiac fibroblasts contribute to heart development and repair, Circulation Research, Vol: 114, Pages: 1422-1434, ISSN: 0009-7330
Rationale:Cardiac fibroblasts are critical to proper heart function through multiple interactions with the myocardial compartment, but appreciation of their contribution has suffered from incomplete characterization and lack of cell-specific markers.Objective:To generate an unbiased comparative gene expression profile of the cardiac fibroblast pool, identify and characterize the role of key genes in cardiac fibroblast function, and determine their contribution to myocardial development and regeneration.Methods and Results:High-throughput cell surface and intracellular profiling of cardiac and tail fibroblasts identified canonical mesenchymal stem cell and a surprising number of cardiogenic genes, some expressed at higher levels than in whole heart. While genetically marked fibroblasts contributed heterogeneously to interstitial but not cardiomyocyte compartments in infarcted hearts, fibroblast-restricted depletion of one highly expressed cardiogenic marker, T-box 20, caused marked myocardial dysmorphology and perturbations in scar formation on myocardial infarction.Conclusions:The surprising transcriptional identity of cardiac fibroblasts, the adoption of cardiogenic gene programs, and direct contribution to cardiac development and repair provoke alternative interpretations for studies on more specialized cardiac progenitors, offering a novel perspective for reinterpreting cardiac regenerative therapies.
Carnevali L, Graiani G, Rossi S, et al., 2014, Signs of cardiac autonomic imbalance and proarrhythmic remodeling in FTO deficient mice, PLoS One, Vol: 9, Pages: 1-10, ISSN: 1932-6203
In humans, variants of the fat mass and obesity associated (FTO) gene have recently been associated with obesity. However, the physiological function of FTO is not well defined. Previous investigations in mice have linked FTO deficiency to growth retardation, loss of white adipose tissue, increased energy metabolism and enhanced systemic sympathetic activation. In this study we investigated for the first time the effects of global knockout of the mouse FTO gene on cardiac function and its autonomic neural regulation. ECG recordings were acquired via radiotelemetry in homozygous knockout (n = 12) and wild-type (n = 8) mice during resting and stress conditions, and analyzed by means of time- and frequency-domain indexes of heart rate variability. In the same animals, cardiac electrophysiological properties (assessed by epicardial mapping) and structural characteristics were investigated. Our data indicate that FTO knockout mice were characterized by (i) higher heart rate values during resting and stress conditions, (ii) heart rate variability changes (increased LF to HF ratio), (iii) larger vulnerability to stress-induced tachyarrhythmias, (iv) altered ventricular repolarization, and (v) cardiac hypertrophy compared to wild-type counterparts. We conclude that FTO deficiency in mice leads to an imbalance of the autonomic neural modulation of cardiac function in the sympathetic direction and to a potentially proarrhythmic remodeling of electrical and structural properties of the heart.
Godwin JW, Rosenthal N, 2014, Scar-free wound healing and regeneration in amphibians: Immunological influences on regenerative success, DIFFERENTIATION, Vol: 87, Pages: 66-75, ISSN: 0301-4681
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- Citations: 132
Rosenthal N, Santini MP, 2014, Stem Cells and the Regenerating Heart, Essentials of Stem Cell Biology: Third Edition, Pages: 281-289, ISBN: 9780124095038
The restricted regenerative capacity of the mammalian heart remains a perplexing exception. The regenerative response launched by other injured organs involves local populations of self-renewing precursor cells, or recruitment of circulating stem cells to replace or repair the injured areas. In response to functional stress, the heart can increase its muscle mass through cellular hypertrophy, but the damaged heart needs a rapid response to repair damage to the muscle wall and maintain adequate blood flow to the rest of the body. Paradoxically, this most critical organ cannot restore the muscle loss that accompanies myocardial infarction and ischemia-reperfusion injury. Instead, interruption of the coronary blood supply results in apoptosis and fibrotic scar formation at the cost of functional muscle. As a result, the remaining cardiomyocytes undergo cellular hypertrophy, leading to decompensated function and congestive heart failure, an increasingly prevalent disease in the industrialized world.
Poggioli T, Sarathchandra P, Rosenthal N, et al., 2014, Intramyocardial Cell Delivery: Observations in Murine Hearts, JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, ISSN: 1940-087X
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- Citations: 8
Zarrinpashneh E, Poggioli T, Sarathchandra P, et al., 2013, Ablation of SGK1 impairs endothelial cell migration and tube formation leading to decreased neo-angiogenesis following myocardial infarction, PLoS ONE, Vol: 8, ISSN: 1932-6203
Serum and glucocorticoid inducible kinase 1 (SGK1) plays a pivotal role in early angiogenesis during embryonic development. In this study, we sought to define the SGK1 downstream signalling pathways in the adult heart and to elucidate their role in cardiac neo-angiogenesis and wound healing after myocardial ischemia. To this end, we employed a viable SGK1 knockout mouse model generated in a 129/SvJ background. Ablation of SGK1 in these mice caused a significant decrease in phosphorylation of SGK1 target protein NDRG1, which correlated with alterations in NF-κB signalling and expression of its downstream target protein, VEGF-A. Disruption of these signalling pathways was accompanied by smaller heart and body size. Moreover, the lack of SGK1 led to defective endothelial cell (ECs) migration and tube formation in vitro, and increased scarring with decreased angiogenesis in vivo after myocardial infarct. This study underscores the importance of SGK1 signalling in cardiac neo-angiogenesis and wound healing after an ischemic insult in vivo.
Lexow J, Poggioli T, Sarathchandra P, et al., 2013, Cardiac fibrosis in mice expressing an inducible myocardial-specific Cre driver, DISEASE MODELS & MECHANISMS, Vol: 6, Pages: 1470-1476, ISSN: 1754-8403
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- Citations: 68
Costa MW, Rosenthal N, 2013, Molecular Tools in Cancer Research, Abeloff's Clinical Oncology: Fifth Edition, Pages: 2-21.e1, ISBN: 9781455728657
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- Citations: 1
Shavlakadze T, Chai J, Maley K, et al., 2013, A growth stimulus is needed for IGF-1 to induce skeletal muscle hypertrophy in vivo, Journal of Cell Science, Vol: 126, ISSN: 0021-9533
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- Citations: 1
Rosenthal N, Santini MP, 2013, Stem Cells and the Regenerating Heart, Handbook of Stem Cells, Pages: 595-601, ISBN: 9780123859426
Pinto AR, Chandran A, Rosenthal NA, et al., 2013, Isolation and analysis of single cells from the mouse heart, JOURNAL OF IMMUNOLOGICAL METHODS, Vol: 393, Pages: 74-80, ISSN: 0022-1759
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- Citations: 32
Godwin JW, Pinto AR, Rosenthal NA, 2013, Macrophages are required for adult salamander limb regeneration, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 9415-9420, ISSN: 0027-8424
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- Citations: 571
Costa MW, Guo G, Wolstein O, et al., 2013, Functional Characterization of a Novel Mutation in <i>NKX2</i>-<i>5</i> Associated With Congenital Heart Disease and Adult-Onset Cardiomyopathy, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 6, Pages: 238-247, ISSN: 1942-325X
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- Citations: 72
Lexow J, Poggioli T, Rosenthal N, et al., 2013, Combinatorial therapies for cardiac regeneration, Recent Patents on Regenerative Medicine, Vol: 3, Pages: 34-46, ISSN: 2210-2965
The mammalian heart has a limited capability of physiological cardiomyocyte turnover during adult life to substitute aged or damaged cells. While this regenerative mechanism has been preserved throughout mammalian evolution, it is insufficient to counteract more extensive tissue loss, which results in scar formation at the expense of cardiac function. In recent years, regenerative medicine studies investigated the efficiency of stem cells to regenerate the heart via cell-therapy, while pre-conditioning the hostile environment of the injured cardiac tissue by administration of cell survival and anti-inflammatory molecules. Indeed, post-infarct combinatorial therapies using cells and factors (including growth factors, chemokines and cytokines) increased cardiac function recovery and tissue regeneration. In addition, the use of factors and molecules capable of inducing adult cardiomyocytes to re-enter cell cycle was explored to overcome the intrinsic cell cycle block or the loss of mitogenic stimuli in the postnatal heart. Nevertheless, the field has yet to solve significant obstacles including the incomplete differentiation of stem cells (with the associated danger of tumor formation) and the paucity of tissue-specific stem cells (specifically in adult/aged organs). In this review, we describe the advances in cardiac regenerative studies and the patented designs of new tools to heal an injured heart. © 2013 Bentham Science Publishers.
Lam NT, Currie PD, Lieschke GJ, et al., 2012, Nerve growth factor stimulates cardiac regeneration via cardiomyocyte proliferation in experimental heart failure, PLoS One, Vol: 7, ISSN: 1932-6203
Although the adult heart likely retains some regenerative capacity, heart failure (HF) typically remains a progressive disorder. We hypothesise that alterations in the local environment contribute to the failure of regeneration in HF. Previously we showed that nerve growth factor (NGF) is deficient in the failing heart and here we hypothesise that diminished NGF limits the cardiac regenerative response in HF. The capacity of NGF to augment cardiac regeneration was tested in a zebrafish model of HF. Cardiac injury with a HF phenotype was induced in zebrafish larvae at 72 hours post fertilization (hpf) by exposure to aristolochic acid (AA, 2.5 µM, 72-75 hpf). By 168 hpf, AA induced HF and death in 37.5% and 20.8% of larvae respectively (p<0.001). NGF mRNA expression was reduced by 42% (p<0.05). The addition of NGF (50 ng/ml) after exposure to AA reduced the incidence of HF by 50% (p<0.01) and death by 65% (p<0.01). Mechanistically, AA mediated HF was characterised by reduced cardiomyocyte proliferation as reflected by a 6.4 fold decrease in BrdU+ cardiomyocytes (p<0.01) together with features of apoptosis and loss of cardiomyocytes. Following AA exposure, NGF increased the abundance of BrdU+ cardiomyocytes in the heart by 4.8 fold (p<0.05), and this was accompanied by a concomitant significant increase in cardiomyocyte numbers. The proliferative effect of NGF on cardiomyocytes was not associated with an anti-apoptotic effect. Taken together the study suggests that NGF stimulates a regenerative response in the failing zebrafish heart, mediated by stimulation of cardiomyocyte proliferation.
Hede MS, Salimova E, Piszczek A, et al., 2012, E-peptides control bioavailability of IGF-1, PLoS One, Vol: 7, Pages: 1-11, ISSN: 1932-6203
Insulin-like growth factor 1 (IGF-1) is a potent cytoprotective growth factor that has attracted considerable attention as a promising therapeutic agent. Transgenic over-expression of IGF-1 propeptides facilitates protection and repair in a broad range of tissues, although transgenic mice over-expressing IGF-1 propeptides display little or no increase in IGF-1 serum levels, even with high levels of transgene expression. IGF-1 propeptides are encoded by multiple alternatively spliced transcripts including C-terminal extension (E) peptides, which are highly positively charged. In the present study, we use decellularized mouse tissue to show that the E-peptides facilitate in vitro binding of murine IGF-1 to the extracellular matrix (ECM) with varying affinities. This property is independent of IGF-1, since proteins consisting of the E-peptides fused to relaxin, a related member of the insulin superfamily, bound equally avidly to decellularized ECM. Thus, the E-peptides control IGF-1 bioavailability by preventing systemic circulation, offering a potentially powerful way to tether IGF-1 and other therapeutic proteins to the site of synthesis and/or administration.
Murray SA, Eppig JT, Smedley D, et al., 2012, Beyond knockouts: cre resources for conditional mutagenesis (vol 23, pg 587, 2012), MAMMALIAN GENOME, Vol: 23, Pages: 791-791, ISSN: 0938-8990
Panse KD, Felkin LE, Lopez-Olaneta MM, et al., 2012, Follistatin-Like 3 Mediates Paracrine Fibroblast Activation by Cardiomyocytes, JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH, Vol: 5, Pages: 814-826, ISSN: 1937-5387
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- Citations: 31
Santini MP, Poudel B, Poggioli T, et al., 2012, Attenuation of Post-infarct Cardiac Hypertrophy by Allogeneic Cell-mediated Supplemental Igf-1 Propeptide Delivery, CIRCULATION, Vol: 126, ISSN: 0009-7322
Bradley A, Anastassiadis K, Ayadi A, et al., 2012, The mammalian gene function resource: the international knockout mouse consortium, Mammalian Genome, Vol: 23, Pages: 580-586, ISSN: 0938-8990
In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research.
Santini MP, Rosenthal N, 2012, Myocardial regenerative properties of macrophage populations and stem cells, Journal of Cardiovascular Translational Research, Vol: 5, Pages: 700-712, ISSN: 1937-5387
The capacity to regenerate damaged tissue and appendages is lost to some extent in higher vertebrates such as mammals, which form a scar tissue at the expenses of tissue reconstitution and functionality. Whereas this process can protect from further damage and elicit fast healing, it can lead to functional deterioration in organs such as the heart. Based on the analyses performed in the last years, stem cell therapies may not be sufficient to induce cardiac regeneration and additional approaches are required to overcome scar formation. Among these, the immune cells and their humoral response have become a key parameter in regenerative processes. In this review, we will describe the recent findings on the possible therapeutical use of progenitor and immune cells to rescue a damaged heart.
Murray SA, Eppig JT, Smedley D, et al., 2012, Beyond knockouts: cre resources for conditional mutagenesis, MAMMALIAN GENOME, Vol: 23, Pages: 587-599, ISSN: 0938-8990
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- Citations: 47
Lara-Pezzi E, Lopez-Olaneta MM, Gomez-Salinero J, et al., 2012, The calcineurin splicing variant CnAbeta1 induces recovery from myocardial infarction and reduces cardiac hypertrophy and fibrosis, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 491-491, ISSN: 0195-668X
Touvron M, Escoubet B, Mericskay M, et al., 2012, Locally expressed IGF1 propeptide improves mouse heart function in induced dilated cardiomyopathy by blocking myocardial fibrosis and SRF-dependent CTGF induction, DISEASE MODELS & MECHANISMS, Vol: 5, Pages: 481-491, ISSN: 1754-8403
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- Citations: 39
Chandras C, Zouberakis M, Salimova E, et al., 2012, CreZOO-the European virtual repository of Cre and other targeted conditional driver strains, Database: the journal of biological databases and curation, Vol: 2012, Pages: 1-5, ISSN: 1758-0463
The CreZOO (http://www.crezoo.org/) is the European virtual repository of Cre and other targeted conditional driver strains. These mice serve as tools for researchers to selectively ‘switch off’ gene expression in mouse models to examine gene function and disease pathology. CreZOO aims to capture and disseminate extant and new information on these Cre driver strains, such as genetic background and availability information, and details pertaining promoter, allele, inducibility and expression patterns, which are also presented. All transgenic strains carry detailed information according to MGI's official nomenclature, whereas their availability [e.g. live mice, cryopreserved embryos, sperm and embryonic stem (ES) cells] is clearly indicated with links to European and International databases and repositories (EMMA, MGI/IMSR, MMRRC, etc) and laboratories where the particular mouse strain is available together with the respective IDs. Each promoter/gene includes IDs and direct links to MGI, Entrez Gene, Ensembl, OMIM and RGD databases depending on their species origin, whereas allele information is presented with MGI IDs and active hyperlinks to redirect the user to the respective page in a new tab. The tissue/cell (special) and developmental (temporal) specificity expression patterns are clearly presented, whereas handling and genotyping details (in the form of documents or hyperlinks) together with all relevant publications are clearly presented with PMID(s) and direct PubMed links. CreZOO's design offers a user-friendly query interface and provides instant access to the list of conditional driver strains, promoters and inducibility details. Database access is free of charge and there are no registration requirements for data querying. CreZOO is being developed in the context of the CREATE consortium (http://www.creline.org/), a core of major European and international mouse database holders and research groups involved in conditional mutagenesis.
Pinto AR, Paolicelli R, Salimova E, et al., 2012, An abundant tissue macrophage population in the adult murine heart with a distinct alternatively-activated macrophage profile, PLoS One, Vol: 7, Pages: 1-11, ISSN: 1932-6203
Cardiac tissue macrophages (cTMs) are a previously uncharacterised cell type that we have identified and characterise here as an abundant GFP+ population within the adult Cx3cr1GFP/+ knock-in mouse heart. They comprise the predominant myeloid cell population in the myocardium, and are found throughout myocardial interstitial spaces interacting directly with capillary endothelial cells and cardiomyocytes. Flow cytometry-based immunophenotyping shows that cTMs exhibit canonical macrophage markers. Gene expression analysis shows that cTMs (CD45+CD11b+GFP+) are distinct from mononuclear CD45+CD11b+GFP+ cells sorted from the spleen and brain of adult Cx3cr1GFP/+ mice. Gene expression profiling reveals that cTMs closely resemble alternatively-activated anti-inflammatory M2 macrophages, expressing a number of M2 markers, including Mrc1, CD163, and Lyve-1. While cTMs perform normal tissue macrophage homeostatic functions, they also exhibit a distinct phenotype, involving secretion of salutary factors (including IGF-1) and immune modulation. In summary, the characterisation of cTMs at the cellular and molecular level defines a potentially important role for these cells in cardiac homeostasis.
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