Publications
54 results found
Noseda M, Harada M, McSweeney S, et al., 2015, PDGFRα demarcates the cardiogenic clonogenic Sca1(+) stem/progenitor cell in adult murine myocardium, Nature Communications, Vol: 6, ISSN: 2041-1723
Cardiac progenitor/stem cells in adult hearts represent an attractive therapeutic target for heart regeneration, though (inter)-relationships among reported cells remain obscure. Using single-cell qRT-PCR and clonal analyses, here we define four subpopulations of cardiac progenitor/stem cells in adult mouse myocardium all sharing stem cell antigen-1 (Sca1), based on side population (SP) phenotype, PECAM-1 (CD31) and platelet-derived growth factor receptor-α (PDGFRα) expression. SP status predicts clonogenicity and cardiogenic gene expression (Gata4/6, Hand2 and Tbx5/20), properties segregating more specifically to PDGFRα(+) cells. Clonal progeny of single Sca1(+) SP cells show cardiomyocyte, endothelial and smooth muscle lineage potential after cardiac grafting, augmenting cardiac function although durable engraftment is rare. PDGFRα(-) cells are characterized by Kdr/Flk1, Cdh5, CD31 and lack of clonogenicity. PDGFRα(+)/CD31(-) cells derive from cells formerly expressing Mesp1, Nkx2-5, Isl1, Gata5 and Wt1, distinct from PDGFRα(-)/CD31(+) cells (Gata5 low; Flk1 and Tie2 high). Thus, PDGFRα demarcates the clonogenic cardiogenic Sca1(+) stem/progenitor cell.
Noseda M, Harada M, Mcsweeney S, et al., 2014, PDGFRalpha demarcates the cardiogenic and clonogenic Sca-1+stem cell, 3rd Congress of the ESC-Council-on-Basic-Cardiovascular-Science on Frontiers in Cardio Vascular Biology, Publisher: OXFORD UNIV PRESS, ISSN: 0008-6363
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- Citations: 2
Belian E, Noseda M, Leja T, et al., 2012, Is Myocardin a limiting factor for cardiac programming?, Scientific Sessions of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: E386-E386, ISSN: 0009-7330
Noseda M, De Smith AJ, Leia T, et al., 2012, The Cdkn2a/2b Tumour Suppressor Locus is a Hot Spot for Genome Instability in Mouse Cardiac Progenitor Cells, CIRCULATION, Vol: 126, ISSN: 0009-7322
Noseda M, Harada M, McSweeney SJ, et al., 2012, Unmasking Phenotypic Micro-heterogeneities in Adult Cardiac Progenitor Cells: Clonal Analysis, Single Cell QRT-PCR, and Fate Mapping, CIRCULATION, Vol: 126, ISSN: 0009-7322
Chang L, Noseda M, Higginson M, et al., 2012, Differentiation of vascular smooth muscle cells from local precursors during embryonic and adult arteriogenesis requires Notch signaling., Proc Natl Acad Sci U S A, Vol: 109, Pages: 6993-6998
Vascular smooth muscle cells (VSMC) have been suggested to arise from various developmental sources during embryogenesis, depending on the vascular bed. However, evidence also points to a common subpopulation of vascular progenitor cells predisposed to VSMC fate in the embryo. In the present study, we use binary transgenic reporter mice to identify a Tie1(+)CD31(dim)vascular endothelial (VE)-cadherin(-)CD45(-) precursor that gives rise to VSMC in vivo in all vascular beds examined. This precursor does not represent a mature endothelial cell, because a VE-cadherin promoter-driven reporter shows no expression in VSMC during murine development. Blockade of Notch signaling in the Tie1(+) precursor cell, but not the VE-cadherin(+) endothelial cell, decreases VSMC investment of developing arteries, leading to localized hemorrhage in the embryo at the time of vascular maturation. However, Notch signaling is not required in the Tie1(+) precursor after establishment of a stable artery. Thus, Notch activity is required in the differentiation of a Tie1(+) local precursor to VSMC in a spatiotemporal fashion across all vascular beds.
Noseda M, Mcsweeney SJ, Leja T, et al., 2012, Mutually exclusive expression of key cardiogenic transcription factors in single cardiac progenitor cells, 2nd Congress of the European-Society-of-Cardiology Council on Basic Cardiovascular Science - Frontiers in Cardiovascular Biology, Publisher: OXFORD UNIV PRESS, Pages: S16-S16, ISSN: 0008-6363
Noseda M, De Smith AJ, Leja T, et al., 2012, The Cdkn2a/2b tumour suppressor locus is a hot spot for genome instability in mouse cardiac progenitor cells, 2nd Congress of the European-Society-of-Cardiology Council on Basic Cardiovascular Science - Frontiers in Cardiovascular Biology, Publisher: OXFORD UNIV PRESS, Pages: S59-S59, ISSN: 0008-6363
Noseda M, Peterkin T, Simoes FC, et al., 2011, Cardiopoietic Factors Extracellular Signals for Cardiac Lineage Commitment, CIRCULATION RESEARCH, Vol: 108, Pages: 129-152, ISSN: 0009-7330
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- Citations: 93
Lin S-C, Dolle P, Ryckebuesch L, et al., 2010, Endogenous retinoic acid regulates cardiac progenitor differentiation, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 107, Pages: 9234-9239, ISSN: 0027-8424
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- Citations: 83
Noseda M, Schneider MD, 2010, Unleashing Cardiopoiesis: A Novel Role for G-CSF, CELL STEM CELL, Vol: 6, Pages: 188-189, ISSN: 1934-5909
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- Citations: 3
Noseda M, Schneider MD, 2009, Fibroblasts inform the heart: Control of cardiomyocyte cycling and size by age-dependent paracrine signals, DEV CELL, Vol: 16, Pages: 161-162, ISSN: 1534-5807
Within the developing and adult heart, the fibroblast is often dismissed as merely a structural element, important just to mechanical integrity or to scarring when excessive in disease. leda et al. in this issue of Developmental Cell now report an essential program of paracrine factor production in cardiac fibroblasts that controls heart muscle cell growth, driving cycling or enlargement depending on the fibroblasts' developmental stage.
Lombardi R, Bell A, Senthil V, et al., 2008, Differential interactions of thin filament proteins in two cardiac troponin T mouse models of hypertrophic and dilated cardiomyopathies., Cardiovasc Res, Vol: 79, Pages: 109-117, ISSN: 0008-6363
AIM: Mutations in a sarcomeric protein can cause hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM), the opposite ends of a spectrum of phenotypic responses of the heart to mutations. We posit the contracting phenotypes could result from differential effects of the mutant proteins on interactions among the sarcomeric proteins. To test the hypothesis, we generated transgenic mice expressing either cardiac troponin T (cTnT)-Q92 or cTnT-W141, known to cause HCM and DCM, respectively, in the heart. METHODS AND RESULTS: We phenotyped the mice by echocardiography, histology and immunoblotting, and real-time polymerase chain reaction. We detected interactions between the sarcomeric proteins by co-immunoprecipitation and determined Ca2+ sensitivity of myofibrillar protein ATPase activity by Carter assay. The cTnT-W141 mice exhibited dilated hearts and decreased systolic function. In contrast, the cTnT-Q92 mice showed smaller ventricles and enhanced systolic function. Levels of cardiac troponin I, cardiac alpha-actin, alpha-tropomyosin, and cardiac troponin C co-immunoprecipitated with anti-cTnT antibodies were higher in the cTnT-W141 than in the cTnT-Q92 mice, as were levels of alpha-tropomyosin co-immunoprecipitated with an anti-cardiac alpha-actin antibody. In contrast, levels of cardiac troponin I co-immunoprecipitated with an anti-cardiac alpha-actin antibody were higher in the cTnT-Q92 mice. Ca2+ sensitivity of myofibrillar ATPase activity was increased in HCM but decreased in DCM mice compared with non-transgenic mice. CONCLUSION: Differential interactions among the sarcomeric proteins containing cTnT-Q92 or cTnT-W141 are responsible for the contrasting phenotypes of HCM or DCM, respectively.
Noseda M, McLean GR, 2008, Where did the scientific method go?, NATURE BIOTECHNOLOGY, Vol: 26, Pages: 28-29, ISSN: 1087-0156
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- Citations: 4
Noseda M, Karsan A, 2006, Notch and minichromosome maintenance (MCM) proteins: integration of two ancestral pathways in cell cycle control., Cell Cycle, Vol: 5, Pages: 2704-2709
Notch transmembrane receptors govern a highly evolutionarily conserved intercellular signaling mechanism activated by the engagement of Notch receptors by their cognate ligands expressed on neighboring cells. The subsequently cleaved intracellular domain of Notch receptors translocates to the nucleus where it interacts with the transcriptional regulator CSL, thereby regulating expression of target genes. The Notch pathway controls cell fate by regulating proliferation, differentiation, and apoptosis. Mini-chromosome maintenance (MCM) proteins are components of the prereplicative complex (pre-RC) that are essential for DNA replication. It has recently been shown that activated Notch downregulates mini-chromosome-maintenance (MCM) proteins MCM2 and MCM6 by a CSL-dependent mechanism. Here, we review the canonical pathway mediated by Notch receptors and discuss recent findings connecting the Notch pathway with the ancestral MCM complex during cell cycle progression.
Noseda M, Fu Y, Niessen K, et al., 2006, Smooth Muscle alpha-actin is a direct target of Notch/CSL., Circ Res, Vol: 98, Pages: 1468-1470
Intercellular signaling mediated by Notch receptors is essential for proper cardiovascular development and homeostasis. Notch regulates cell fate decisions that affect proliferation, survival, and differentiation of endothelial and smooth muscle cells. It has been reported that Jagged1-Notch interactions may participate in endocardial cushion formation by inducing endothelial-to-mesenchymal transformation. Here, we show that Notch directly regulates expression of the mesenchymal and smooth muscle cell marker smooth muscle alpha-actin (SMA) in endothelial and vascular smooth muscle cells via activation of its major effector, CSL. Notch/CSL activation induces SMA expression during endothelial-to-mesenchymal transformation, and Notch activation is required for expression of SMA in vascular smooth muscle cells. CSL directly binds a conserved cis element in the SMA promoter, and this consensus sequence is required for Notch-mediated SMA induction. This is the first evidence of the requirement for Notch activation in the regulation of SMA expression.
Noseda M, Niessen K, McLean G, et al., 2005, Notch-dependent cell cycle arrest is associated with downregulation of minichromosome maintenance proteins., Circ Res, Vol: 97, Pages: 102-104
Perturbation of the Notch signaling pathway has been implicated in the pathogenesis of human cardiovascular diseases, and animal models have confirmed the requirement of Notch during cardiovascular development. We recently demonstrated that Notch activation delays S-phase entry and contributes to endothelial contact inhibition. Minichromosome maintenance (MCM) proteins, components of the prereplicative complex (pre-RC), are essential for DNA replication. Here, we report that Notch-mediated cell cycle arrest is associated with downregulation of MCM2 and MCM6 in endothelial cells and human fibroblasts. Downregulation of MCM proteins is also observed on activation of C promoter binding factor (CBF1) and is mediated by inhibition of Rb phosphorylation, as demonstrated using a constitutively active Rb mutant. Although the effects of the Notch pathway are cell-type specific and context-dependent, in cell types where Notch has an antiproliferative effect, downregulation of MCM proteins may be a common mechanism to inhibit DNA replication.
McLean GR, Torres M, Trotter B, et al., 2005, A point mutation in the CH3 domain of human IgG3 inhibits antibody secretion without affecting antigen specificity, MOLECULAR IMMUNOLOGY, Vol: 42, Pages: 1111-1119, ISSN: 0161-5890
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- Citations: 3
Noseda M, Chang L, McLean G, et al., 2004, Notch activation induces endothelial cell cycle arrest and participates in contact inhibition: role of p21Cip1 repression., Mol Cell Biol, Vol: 24, Pages: 8813-8822, ISSN: 0270-7306
Although previous studies demonstrate that appropriate Notch signaling is required during angiogenesis and in vascular homeostasis, the mechanisms by which Notch regulates vascular function remain to be elucidated. Here, we show that activation of the Notch pathway by the ligand Jagged1 reduces the proliferation of endothelial cells. Notch activation inhibits proliferation of endothelial cells in a cell-autonomous manner by inhibiting phosphorylation of the retinoblastoma protein (Rb). During cell cycle entry, p21Cip1 is upregulated in endothelial cells. Activated Notch inhibits mitogen-induced upregulation of p21Cip1 and delays cyclin D-cdk4-mediated Rb phosphorylation. Notch-dependent repression of p21Cip1 prevents nuclear localization of cyclin D and cdk4. The necessity of p21Cip1 for nuclear translocation of cyclin D-cdk4 and S-phase entry in endothelial cells was demonstrated by targeted downregulation of p21Cip1 by using RNA interference. We further demonstrate that when endothelial cells reach confluence, Notch is activated and p21Cip1 is downregulated. Inhibition of the Notch pathway at confluence prevents p21Cip1 downregulation and induces Rb phosphorylation. We suggest that Notch activation contributes to contact inhibition of endothelial cells, in part through repression of p21Cip1 expression.
Noseda M, McLean G, Niessen K, et al., 2004, Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation., Circ Res, Vol: 94, Pages: 910-917
Various studies have identified a critical role for Notch signaling in cardiovascular development. In this and other systems, Notch receptors and ligands are expressed in regions that undergo epithelial-to-mesenchymal transformation. However, there is no direct evidence that Notch activation can induce mesenchymal transdifferentiation. In this study we show that Notch activation in endothelial cells results in morphological, phenotypic, and functional changes consistent with mesenchymal transformation. These changes include downregulation of endothelial markers (vascular endothelial [VE]-cadherin, Tie1, Tie2, platelet-endothelial cell adhesion molecule-1, and endothelial NO synthase), upregulation of mesenchymal markers (alpha-smooth muscle actin, fibronectin, and platelet-derived growth factor receptors), and migration toward platelet-derived growth factor-BB. Notch-induced endothelial-to-mesenchymal transformation does not seem to require external regulation and is restricted to cells expressing activated Notch. Jagged1 stimulation of endothelial cells induces a similar mesenchymal transformation, and Jagged1, Notch1, and Notch4 are expressed in the ventricular outflow tract during stages of endocardial cushion formation. This is the first evidence that Jagged1-Notch interactions induce endothelial-to-mesenchymal transformation, and our findings suggest that Notch signaling may be required for proper endocardial cushion differentiation and/or vascular smooth muscle cell development.
MacKenzie F, Duriez P, Wong F, et al., 2004, Notch4 inhibits endothelial apoptosis via RBP-Jkappa-dependent and -independent pathways., J Biol Chem, Vol: 279, Pages: 11657-11663, ISSN: 0021-9258
Notch4, a member of the Notch family of transmembrane receptors, is expressed primarily on endothelial cells. Activation of Notch in various cell systems has been shown to regulate cell fate decisions, partly by regulating the propensity of cells to live or die. Various studies have demonstrated a role for Notch1 in modulating apoptosis, either in a positive or negative manner. In this study, we determined that constitutively active Notch4 (Notch4 intracellular domain) inhibited endothelial apoptosis triggered by lipopolysaccharide. Notch signals are transmitted by derepression and coactivation of the transcriptional repressor, RBP-Jkappa, as well as by less well defined mechanisms that are independent of RBP-Jkappa. A Notch mutant lacking the N-terminal RAM domain showed only partial antiapoptotic activity relative to Notch4 intracellular domain but stimulated equivalent RBP-Jkappa-dependent transcriptional activity. Similarly, constitutively active RBP-Jkappa activated a full transcriptional response but only demonstrated partial antiapoptotic activity. Additional studies suggest that Notch4 provides endothelial protection in two ways: inhibition of the JNK-dependent proapoptotic pathway in an RBP-Jkappa-dependent manner and induction of an antiapoptotic pathway through an RBP-Jkappa-independent up-regulation of Bcl-2. Our findings demonstrate that Notch4 activation inhibits apoptosis through multiple pathways and provides one mechanism to explain the remarkable capacity of endothelial cells to withstand apoptosis.
Harfouche R, Gratton J-P, Yancopoulos GD, et al., 2003, Angiopoietin-1 activates both anti- and proapoptotic mitogen-activated protein kinases., FASEB J, Vol: 17, Pages: 1523-1525
In this study, we identified whether mitogen-activated protein kinases (MAPKs) mediate the effects of angiopoietin-1 (Ang-1) on endothelial cell apoptosis. Exposure of human umbilical vein endothelial cells to Ang-1 (300 ng/ml) evoked within 15-30 min a 15-fold and a 5-fold increase in phosphorylation of ERK1/2 and p38 MAPKs, respectively. Inhibitors of the PI-3 kinase pathway attenuated Ang-1-induced ERK1/2 phosphorylation at a level up-stream from Raf and MEK1/2, but these inhibitors augmented Ang-1-induced p38 phosphorylation. When serum and growth supplements were withdrawn, the percentage of endothelial apoptosis tripled over 24 h compared with control cells. The presence of Ang-1 (300 ng/ml) significantly attenuated endothelial cell apoptosis and inhibited caspase-9, -7, and -3 activation. These antiapoptotic effects were augmented when a p38 inhibitor was combined with Ang-1, whereas inhibition of ERK1/2 eliminated the antiapoptotic properties of Ang-1. We conclude that both anti- (ERK1/2) and pro- (p38) apoptotic members of MAPKs are simultaneously activated by Ang-1 in endothelial cells and that activation of ERK1/2 by Ang-1 is mediated through the PI-3 kinase pathway. The strong antiapoptotic effects of the ERK and the PI-3 kinase pathways mask the proapoptotic function of p38 MAPKs resulting in net attenuation of apoptosis by Ang-1.
Leong KG, Hu X, Li L, et al., 2002, Activated Notch4 inhibits angiogenesis: role of beta 1-integrin activation., Mol Cell Biol, Vol: 22, Pages: 2830-2841, ISSN: 0270-7306
Notch4 is a member of the Notch family of transmembrane receptors that is expressed primarily on endothelial cells. Activation of Notch in various cell systems has been shown to regulate cell fate decisions. The sprouting of endothelial cells from microvessels, or angiogenesis, involves the modulation of the endothelial cell phenotype. Based on the function of other Notch family members and the expression pattern of Notch4, we postulated that Notch4 activation would modulate angiogenesis. Using an in vitro endothelial-sprouting assay, we show that expression of constitutively active Notch4 in human dermal microvascular endothelial cells (HMEC-1) inhibits endothelial sprouting. We also show that activated Notch4 inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis in the chick chorioallantoic membrane in vivo. Activated Notch4 does not inhibit HMEC-1 proliferation or migration through fibrinogen. However, migration through collagen is inhibited. Our data show that Notch4 cells exhibit increased beta1-integrin-mediated adhesion to collagen. HMEC-1 expressing activated Notch4 do not have increased surface expression of beta 1-integrins. Rather, we demonstrate that Notch4-expressing cells display beta1-integrin in an active, high-affinity conformation. Furthermore, using function-activating beta 1-integrin antibodies, we demonstrate that activation of beta1-integrins is sufficient to inhibit VEGF-induced endothelial sprouting in vitro and angiogenesis in vivo. Our findings suggest that constitutive Notch4 activation in endothelial cells inhibits angiogenesis in part by promoting beta 1-integrin-mediated adhesion to the underlying matrix.
Lasorella A, Noseda M, Beyna M, et al., 2000, Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins., Nature, Vol: 407, Pages: 592-598, ISSN: 0028-0836
In mammalian cells, Id proteins coordinate proliferation and differentiation. Id2 is a dominant-negative antagonist of basic helix-loop-helix transcription factors and proteins of the retinoblastoma (Rb) family. Here we show that Id2-Rb double knockout embryos survive to term with minimal or no defects in neurogenesis and haematopoiesis, but they die at birth from severe reduction of muscle tissue. In neuroblastoma, an embryonal tumour derived from the neural crest, Id2 is overexpressed in cells carrying extra copies of the N-myc gene. In these cells, Id2 is in molar excess of the active form of Rb. The overexpression of Id2 results from transcriptional activation by oncoproteins of the Myc family. Cell-cycle progression induced by Myc oncoproteins requires inactivation of Rb by Id2. Thus, a dual connection links Id2 and Rb: during normal cell-cycle, Rb prohibits the action of Id2 on its natural targets, but oncogenic activation of the Myc-Id2 transcriptional pathway overrides the tumour-suppressor function of Rb.
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