Identification of a mesenchymal progenitor cell hierarchy in adipose tissue

Metabolic health depends on the capacity of adipose tissue progenitor cells to undergo de novo adipogenesis. The cellular hierarchy and mechanisms governing adipocyte progenitor differentiation are incompletely understood. Through single-cell RNA sequence analyses, we show that the lineage hierarchy of adipocyte progenitors consists of distinct mesenchymal cell types that are present in both mouse and human adipose tissues. Cells marked by dipeptidyl peptidase–4 (DPP4)/CD26 expression are highly proliferative, multipotent progenitors. During the development of subcutaneous adipose tissue in mice, these progenitor cells give rise to intercellular adhesion molecule–1 (ICAM1)/CD54–expressing (CD54+) committed preadipocytes and a related adipogenic cell population marked by Clec11a and F3/CD142 expression. Transforming growth factor–β maintains DPP4+ cell identity and inhibits adipogenic commitment of DPP4+ and CD142+ cells. Notably, DPP4+ progenitors reside in the reticular interstitium, a recently appreciated fluid-filled space within and between tissues, including adipose depots.

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Lack of cardiac fibrosis in a new model of high prorenin hyperaldosteronism

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01135.2008 ◽

2009 ◽

Vol 297 (5) ◽

pp. H1845-H1852 ◽

Cited By ~ 14

Author(s):

Jörg Peters ◽

Torsten Schlüter ◽

Thomas Riegel ◽

Barbara S. Peters ◽

Andreas Beineke ◽

...

Keyword(s):

Cardiac Fibrosis ◽

Transforming Growth Factor ◽

Renin Angiotensin System ◽

Transforming Growth Factor Β ◽

Collagen Type I ◽

Intercellular Adhesion Molecule ◽

Heart Weight ◽

Type I ◽

Intercellular Adhesion Molecule 1 ◽

Transgenic Rats

The aim of the present study was to test the hypothesis that elevation of prorenin in plasma is sufficient to induce cardiac fibrosis. Normotensive cyp1a1 ren-2 transgenic rats with normal plasma prorenin and aldosterone levels were given 0.125% indole-3-carbinol (I3C) orally for a period of 12 wk. Plasma prorenin and aldosterone levels were determined in 4-wk intervals, and cardiac marker enzymes for hypertrophy, fibrosis, and oxidative stress as well as cardiac pathology were investigated. In I3C-treated cyp1a1 ren-2 transgenic rats, plasma prorenin concentrations were >100-fold elevated (≥7.1 ± 2.6 μg ANG I·ml−1·h−1 vs. ≤0.07 ± 0.1; P < 0.001), whereas active renin levels were suppressed (0.09 ± 0.02 vs. 0.2 ± 0.1; P < 0.05). Aldosterone concentrations were elevated three- to fourfold for a period of >4 wk (574 ± 51 vs. 160 ± 68 pg/ml; P < 0.01). After 12 wk of I3C, rats exhibited moderate cardiac hypertrophy (heart weight/body weight 2.5 ± 0.04 vs. 3.1 ± 0.1 mg/g; P < 0.01). There was a slight increase in mRNA contents of endothelin 1 (1.21 ± 0.08 vs. 0.75 ± 0.007; P < 0.001), NADP oxidase-2 (1.03 ± 0.006 vs. 0.76 ± 0.04; P < 0.001), transforming growth factor-β (0.99 ± 0.06 vs. 0.84 ± 0.04; P < 0.05), collagen type I (1.32 ± 0.32 vs. 0.94 ± 0.18; P < 0.05), and intercellular adhesion molecule-1 (1.12 ± 0.12 vs. 0.84 ± 0.08; P < 0.05). These genes are known to be stimulated by the renin-angiotensin system. There were no histological signs of fibrosis in the heart. We found that prorenin and aldosterone alone are not sufficient to induce considerable cardiac fibrosis in the absence of sodium load.

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Leukocyte Function-associated Antigen-1/Intercellular Adhesion Molecule-1 Interaction Induces a Novel Genetic Signature Resulting in T-cells Refractory to Transforming Growth Factor-β Signaling

Journal of Biological Chemistry ◽

10.1074/jbc.m112.376616 ◽

2012 ◽

Vol 287 (32) ◽

pp. 27204-27216 ◽

Cited By ~ 22

Author(s):

Navin K. Verma ◽

Eugene Dempsey ◽

Aideen Long ◽

Anthony Davies ◽

Sean P. Barry ◽

...

Keyword(s):

T Cells ◽

Growth Factor ◽

Adhesion Molecule ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Intercellular Adhesion ◽

Intercellular Adhesion Molecule ◽

Intercellular Adhesion Molecule 1 ◽

Genetic Signature ◽

Leukocyte Function

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Fibroblasts Influence the Efficacy, Resistance, and Future Use of Vaccines and Immunotherapy in Cancer Treatment

Vaccines ◽

10.3390/vaccines9060634 ◽

2021 ◽

Vol 9 (6) ◽

pp. 634

Author(s):

Bailee H. Sliker ◽

Paul M. Campbell

Keyword(s):

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cell Types ◽

Fibroblast Activation Protein ◽

Cancer Associated Fibroblasts ◽

Cell Type ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

New Research ◽

Tumor Types

Tumors are composed of not only epithelial cells but also many other cell types that contribute to the tumor microenvironment (TME). Within this space, cancer-associated fibroblasts (CAFs) are a prominent cell type, and these cells are connected to an increase in tumor progression as well as alteration of the immune landscape present in and around the tumor. This is accomplished in part by their ability to alter the presence of both innate and adaptive immune cells as well as the release of various chemokines and cytokines, together leading to a more immunosuppressive TME. Furthermore, new research implicates CAFs as players in immunotherapy response in many different tumor types, typically by blunting their efficacy. Fibroblast activation protein (FAP) and transforming growth factor β (TGF-β), two major CAF proteins, are associated with the outcome of different immunotherapies and, additionally, have become new targets themselves for immune-based strategies directed at CAFs. This review will focus on CAFs and how they alter the immune landscape within tumors, how this affects response to current immunotherapy treatments, and how immune-based treatments are currently being harnessed to target the CAF population itself.

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Myostatin/Activin-A Signaling in the Vessel Wall and Vascular Calcification

Cells ◽

10.3390/cells10082070 ◽

2021 ◽

Vol 10 (8) ◽

pp. 2070

Author(s):

Pasquale Esposito ◽

Daniela Verzola ◽

Daniela Picciotto ◽

Leda Cipriani ◽

Francesca Viazzi ◽

...

Keyword(s):

Vascular Calcification ◽

Intracellular Signaling ◽

Transforming Growth Factor ◽

Vascular Inflammation ◽

Transforming Growth Factor Β ◽

Cell Types ◽

Activin A ◽

Premature Aging ◽

High Morbidity ◽

Type I

A current hypothesis is that transforming growth factor-β signaling ligands, such as activin-A and myostatin, play a role in vascular damage in atherosclerosis and chronic kidney disease (CKD). Myostatin and activin-A bind with different affinity the activin receptors (type I or II), activating distinct intracellular signaling pathways and finally leading to modulation of gene expression. Myostatin and activin-A are expressed by different cell types and tissues, including muscle, kidney, reproductive system, immune cells, heart, and vessels, where they exert pleiotropic effects. In arterial vessels, experimental evidence indicates that myostatin may mostly promote vascular inflammation and premature aging, while activin-A is involved in the pathogenesis of vascular calcification and CKD-related mineral bone disorders. In this review, we discuss novel insights into the biology and physiology of the role played by myostatin and activin in the vascular wall, focusing on the experimental and clinical data, which suggest the involvement of these molecules in vascular remodeling and calcification processes. Moreover, we describe the strategies that have been used to modulate the activin downward signal. Understanding the role of myostatin/activin signaling in vascular disease and bone metabolism may provide novel therapeutic opportunities to improve the treatment of conditions still associated with high morbidity and mortality.

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Transforming Growth Factor β-Mediated Transcriptional Repression of c-myc Is Dependent on Direct Binding of Smad3 to a Novel Repressive Smad Binding Element

Molecular and Cellular Biology ◽

10.1128/mcb.24.6.2546-2559.2004 ◽

2004 ◽

Vol 24 (6) ◽

pp. 2546-2559 ◽

Cited By ~ 159

Author(s):

Joshua P. Frederick ◽

Nicole T. Liberati ◽

David S. Waddell ◽

Yigong Shi ◽

Xiao-Fan Wang

Keyword(s):

Growth Factor ◽

Transcriptional Repression ◽

Molecular Mechanisms ◽

Target Genes ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cell Types ◽

Specific Cell ◽

Smad Proteins ◽

Smad Binding Element

ABSTRACT Smad proteins are the most well-characterized intracellular effectors of the transforming growth factor β (TGF-β) signal. The ability of the Smads to act as transcriptional activators via TGF-β-induced recruitment to Smad binding elements (SBE) within the promoters of TGF-β target genes has been firmly established. However, the elucidation of the molecular mechanisms involved in TGF-β-mediated transcriptional repression are only recently being uncovered. The proto-oncogene c-myc is repressed by TGF-β, and this repression is required for the manifestation of the TGF-β cytostatic program in specific cell types. We have shown that Smad3 is required for both TGF-β-induced repression of c-myc and subsequent growth arrest in keratinocytes. The transcriptional repression of c-myc is dependent on direct Smad3 binding to a novel Smad binding site, termed a repressive Smad binding element (RSBE), within the TGF-β inhibitory element (TIE) of the c-myc promoter. The c-myc TIE is a composite element, comprised of an overlapping RSBE and a consensus E2F site, that is capable of binding at least Smad3, Smad4, E2F-4, and p107. The RSBE is distinct from the previously defined SBE and may partially dictate, in conjunction with the promoter context of the overlapping E2F site, whether the Smad3-containing complex actively represses, as opposed to transactivates, the c-myc promoter.

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Abstract 447: Ac-SDKP Suppresses TNFα-induced ICAM-1 Expression In Endothelial Cells Via Inhibition Of IκB Kinase And NF-κB Activation

Hypertension ◽

10.1161/hyp.64.suppl_1.447 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Liping Zhu ◽

Xiao-Ping Yang ◽

Pablo Nakagawa ◽

Nour-Eddine Rhaleb ◽

Pamela Harding ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Types ◽

Intercellular Adhesion Molecule ◽

Intercellular Adhesion Molecule 1 ◽

Human Coronary Artery ◽

Mobility Shift ◽

Autoimmune Myocarditis ◽

Iκb Kinase ◽

Subsequent Degradation ◽

Mobility Shift Assay

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases. We previously showed that Ac-SDKP decreased transcription factor NF-κB activation in angiotensin II-induced hypertension and also reduced intercellular adhesion molecule-1 (ICAM-1) expression in an experimental autoimmune myocarditis and hypertension animal model. However, the mechanisms by which Ac-SDKP down-regulated ICAM-1 expression are unclear. TNFα is a proinflammatory cytokine that induces ICAM-1 expression on different cell types. We hypothesized that Ac-SDKP suppresses TNFα-induced ICAM-1 via inhibition of IκB kinase (IKK) and subsequently by blockade of NF-κB activation. Human coronary artery endothelial cells were treated with Ac-SDKP or vehicle and then stimulated with TNFα (0.5 ng/ml). ICAM-1 protein expression and phosphorylation of IKK (p-IKK), inhibitory κB (p-IκB), p38 (p-p38) and ERK (p-ERK) were measured by Western Blot. Activation of NF-κB was determined by electrophoretic mobility shift assay (EMSA). ICAM-1 expression was virtually undetectable under basal conditions, but greatly increased by TNFα. Ac-SDKP dose-dependently suppressed TNFα-induced ICAM-1 expression (set at a value of 1.0 arbitrary units, AU) to 0.67±0.13 (p<0.05), 0.51±0.12 (p<0.01) and 0.39±0.09 AU (p<0.01) at 0.1 nM, 1 nM and 10 nM, respectively. In addition, Ac-SDKP (10 nM) inhibited TNFα-induced p-IKK from 1.0 to 0.71±0.02 AU (p<0.01). Ac-SDKP also inhibited TNFα-induced IKKβ expression from 1.0 to 0.64±0.12 AU (p<0.05), without affecting IKKα expression. Furthermore, Ac-SDKP inhibited TNFα-induced p-IκB from 1.0 to 0.54±0.03 AU (p<0.01). EMSA results showed that Ac-SDKP inhibited TNFα-mediated activation of NF-κB, which was 0.63±0.04-fold of TNFα-treated cells. However, Ac-SDKP had no effect on TNFα-induced p-p38 and p-ERK. Thus, we conclude that Ac-SDKP inhibits TNFα-induced IKK and subsequent degradation of IκB, thereby preventing NF-κB activation and ICAM-1 expression. These inhibitory effects are independent of p38 and ERK.

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Transforming growth factor–β in tissue fibrosis

Journal of Experimental Medicine ◽

10.1084/jem.20190103 ◽

2020 ◽

Vol 217 (3) ◽

Cited By ~ 6

Author(s):

Nikolaos G. Frangogiannis

Keyword(s):

Extracellular Matrix ◽

Growth Factor ◽

Epithelial Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cell Types ◽

Cellular Targets ◽

Extracellular Matrix Molecules ◽

Interacting Networks

TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β–driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.

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Adipose Tissue-Derived Mesenchymal Stem Cell Modulates the Immune Response of Allergic Rhinitis in a Rat Model

International Journal of Molecular Sciences ◽

10.3390/ijms20040873 ◽

2019 ◽

Vol 20 (4) ◽

pp. 873 ◽

Cited By ~ 7

Author(s):

Nesrine Ebrahim ◽

Yasser Mandour ◽

Ayman Farid ◽

Ebtesam Nafie ◽

Amira Mohamed ◽

...

Keyword(s):

Allergic Rhinitis ◽

Adipose Tissue ◽

Rat Model ◽

Transforming Growth Factor ◽

Immunoglobulin E ◽

Physiological Saline ◽

Transforming Growth Factor Β ◽

Underlying Mechanism ◽

Albino Rats ◽

Microscopical Examination

This study was designed to investigate the potential effects and underlying mechanism of adipose tissue-derived mesenchymal stem cells (MSCs) on allergic inflammation compared to Montelukast as an antileukotriene drug in a rat model of allergic rhinitis (AR). The effect of MSCs was evaluated in albino rats that were randomly divided into four (control, AR, AR + Montelukast, and AR + MSCs) groups. Rats of AR group were sensitized by ovalbumin (OVA) and then challenged with daily nasal drops of OVA diluted in sterile physiological saline (50 μL/nostril, 100 mg/mL, 10% OVA) from day 15 to day 21 of treatment with/without Montelukast (1 h before each challenge) or MSCs I/P injection (1 × 106 MCSs; weekly for three constitutive weeks). Both Montelukast and MSCs treatment started from day 15 of the experiment. At the end of the 5th week, blood samples were collected from all rats for immunological assays, histological, and molecular biology examinations. Both oral Montelukast and intraperitoneal injection of MSCs significantly reduced allergic symptoms and OVA-specific immunoglobulin E (IgE), IgG1, IgG2a and histamine as well as increasing prostaglandin E2 (PGE2). Further analysis revealed that induction of nasal innate cytokines, such as interleukin (IL)-4 and TNF-α; and chemokines, such as CCL11 and vascular cell adhesion molecule-1 (VCAM-1), were suppressed; and transforming growth factor-β (TGF-β) was up-regulated in Montelukast and MSCs-treated groups with superior effect to MSCs, which explained their underlying mechanism. In addition, the adipose tissue-derived MSCs-treated group had more restoring effects on nasal mucosa structure demonstrated by electron microscopical examination.

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