The EGF-like Protein dlk1 Inhibits Notch Signaling and Potentiates Adipogenesis of Mesenchymal Cells

Nueda, María-Luisa; Baladrón, Victoriano; Sánchez-Solana, Beatriz; Ballesteros, María-Ángeles; Laborda, Jorge

doi:10.1016/j.jmb.2006.10.043

Cited by 116 publications

(140 citation statements)

References 66 publications

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“…Dlk1 is a modulator of adipogenesis. 52,53 Different isoforms of Dlk1 may have opposite roles in the control of adipogenesis; however, it is agreed that Dlk1 is elevated in the preadipocytic state. With age progression, an adi- pogenic program overcomes osteogenesis 54 (rat marrow cells) and myogenesis 55 (murine myoblasts).…”

Section: Discussionmentioning

confidence: 99%

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

Cieslik

Trial

Entman

2011

The American Journal of Pathology

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Cardiac fibroblasts are the most prevalent cell type in the heart. These cells exert a critical role in regulating normal myocardial function and in the adverse myocardial remodeling that occurs after myocardial infarction (MI). 1 Irreversible cardiomyocyte damage owing to cessation of oxygen supply during MI leads to necrosis, which stimulates inflammatory reactions that trigger reparative pathways and activate cells to form a scar. Cytokines released by inflammatory infiltrating leukocytes promote endogenous mesenchymal stem cell (MSC) proliferation and migration toward the infarct site, followed by differentiation into fibroblasts that deposit scar-forming collagen. The fibroblasts mature into myofibroblasts, expressing scar-contracting ␣-smooth muscle actin (␣-SMA). 2 Resident fibroblasts also become activated and participate in this process. After several weeks, a mature scar is formed, and most of the myofibroblasts undergo apoptosis. [3][4][5] We have previously established in a model of mouse MI that, compared with young animals, aged mice demonstrate greater infarct expansion and less effective myocardial repair. 6 Defective scar formation arises from a decreased number of myofibroblasts and diminished collagen deposition in the infarct, which results in a structurally unstable scar formed by loose connective tissue. 7 Evidence indicates that multipotent cells can be generated in vitro from several adult organs including the heart. 8 Tissue-resident progenitor cells of mesenchymal origin can differentiate into myogenic, adipocytic, chondrocytic, osteoblastic, and fibroblastic lineages. 9 -11 The potential of those stem cells to differentiate decreases

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Section: Discussionmentioning

confidence: 99%

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

Cieslik

Trial

Entman

2011

The American Journal of Pathology

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“…Delta-like protein-1 (DLK1) is an EGF-like protein that interacts with the NOTCH1 receptor through specific EGF-like repeats [11] and inhibits multiple NOTCH-mediated processes, such as adipogenesis or hematopoiesis [12][13][14][15]. DLK1 seems to function as a noncanonical NOTCH1 ligand, as it lacks the conserved DSL domain mediating classical NOTCH ligand-receptor interactions.…”

Section: Introductionmentioning

confidence: 99%

“…The NOTCH-RBP-J pathway seems to control the expression of typical pro-inflammatory genes characteristic of M1-type macrophages, including and Nos2 [8,9], leading to a stronger immune response of these cells, mediated, in part, by increased NF-κB activity [4,5]. RBP-J also regulates the translation of IRF8, a key transcription factor for M1 differentiation [10].Delta-like protein-1 (DLK1) is an EGF-like protein that interacts with the NOTCH1 receptor through specific EGF-like repeats [11] and inhibits multiple NOTCH-mediated processes, such as adipogenesis or hematopoiesis [12][13][14][15]. DLK1 seems to function as a noncanonical NOTCH1 ligand, as it lacks the conserved DSL domain mediating classical NOTCH ligand-receptor interactions.…”

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confidence: 99%

DLK1 is a novel inflammatory inhibitor which interferes with NOTCH1 signaling in TLR‐activated murine macrophages

González¹,

Ruiz-García²,

Monsalve³

et al. 2015

Eur J Immunol

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Delta-like protein 1 (DLK1) is a noncanonical ligand that inhibits NOTCH1 receptor activity and regulates multiple differentiation processes. In macrophages, NOTCH signaling increases TLR-induced expression of key pro-inflammatory mediators. We have investigated the role of DLK1 in macrophage activation and inflammation using Dlk1-deficient mice and Raw 264.7 cells overexpressing Dlk1. In the absence of Dlk1, NOTCH1 expression is increased and the activation of macrophages with TLR3 or TLR4 agonists leads to higher production of IFN-β and other pro-inflammatory cytokines, including TNF-α, IL-12, and IL-23. The expression of key proteins involved in IFN-β signaling, such as IRF3, IRF7, IRF1, or STAT1, as well as cRel, or RelB, which are responsible for the generation of IL-12 and IL-23, is enhanced in Dlk1 KO macrophages. Consistently, Dlk1 KO mice are more sensitive to LPS-induced endotoxic shock. These effects seem to be mediated through the modulation of NOTCH1 signaling. TLR4 activation reduces DLK1 expression, whereas increases NOTCH1 levels. In addition, DLK1 expression diminishes during differentiation of human U937 cells to macrophages. Overall, these results reveal a novel role for DLK1 as a regulator of NOTCH-mediated, pro-inflammatory macrophage activation, which could help to ensure a baseline level preventing constant tissue inflammation.Keywords: Cytokine r DLK1 r Inflammatory inhibitor r Macrophage r NOTCH signaling r TLR Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMacrophages are key cells in innate and adaptive immune response to pathogens. Toll-like receptors (TLR) recognize conserved microbial structures and induce the activation of macrophages, thus increasing their phagocytic and cytotoxic activities, and leading to the production of inflammatory cytokines, Correspondence: Dr. María J. Ruiz-Hidalgo and Dr. María J. M. Díaz-Guerra e-mail: Maria.RHidalgo@uclm.es; MariaJose.Martinez@uclm.es such as TNF-α and IL-1, and cytokines of the IL-6 and IL-12 families, which regulate T-cell differentiation [1].Macrophages display a remarkable plasticity and can change their functioning in response to environmental signals, which allows a fine-tuning of their activity to adapt to different situations. Unrestrained activation of TLR responses can lead to excessive inflammation and tissue damage and contribute to the pathogenesis of inflammatory disorders, such as septic shock. Multiple mechanisms are implicated in the control of macrophage activation, including inhibitory cytokines, transcriptional repressors, and epigenetic modifications [2,3].C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2616 María J. González et al. Eur. J. Immunol. 2015. 45: 2615-2627 In this line, a critical role for NOTCH signaling in macrophage activation and polarization has been evidenced [4][5][6]. Ligand binding to the NOTCH receptors triggers a two-step proteolytic cleavage causing the release of the NOTCH intracellular doma...

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“…Increased expression of DLK1 is the primary cause of muscle hypertrophy in callipyge sheep exhibiting overgrowth of fast-twitch muscles and reduced adiposity (Cao et al, 2010). The role of DLK1 in adipogenesis has been well-documented (Smas and Sul 1996;Nueda et al, 2007;Sul, 2009). Recently, DLK1 was shown to regulate the fate of myogenic cells (Andersen et al, 2009) and human skeletal stem cells (Abdallah et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Association between DLK1 and IGF-I gene expression and meat quality in sheep

Su¹,

Sun²,

Li³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. The aim of the present study was to detect delta-like 1 homolog (DLK1) and insulin-like growth factor-I (IGF-I) gene expression in the longissimus dorsi of Hu sheep at different growth stages and study the association between these genes and meat quality. The diameter and density of muscle fibers and tenderness of the longissimus dorsi were measured. Growth stage, but not sex, significantly affected DLK1 and IGF-I expression. DLK1 and IGF-I expression in the sheep longissimus dorsi gradually increased with growth, but also decreased during some periods. These results suggest that different growth stages significantly affect DLK1 and IGF-I gene expression in sheep muscle tissue. The expression of DLK1 and IGF-I genes were positively and significantly (P < 0.01) correlated with muscle fiber diameter and muscle fiber shear stress, and negatively and significantly (P < 0.01) correlated with muscle fiber density. Muscle fiber diameter was positively and significantly (P < 0.01) correlated with muscle fiber shear stress, and negatively and significantly (P < 0.01) correlated with muscle fiber density. In addition,

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The EGF-like Protein dlk1 Inhibits Notch Signaling and Potentiates Adipogenesis of Mesenchymal Cells

Cited by 116 publications

References 66 publications

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

DLK1 is a novel inflammatory inhibitor which interferes with NOTCH1 signaling in TLR‐activated murine macrophages

Association between DLK1 and IGF-I gene expression and meat quality in sheep

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