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Wong CN, Lee SK, Liew KB, Chew YL, Chua AL. Mechanistic Insights into Propolis in Targeting Type 2 Diabetes Mellitus: A Systematic Review. PLANTA MEDICA 2025. [PMID: 40294604 DOI: 10.1055/a-2596-0010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Type 2 diabetes mellitus (T2DM) is a major global health concern characterized by insulin resistance and impaired glucose metabolism. Growing interest in natural therapies has led to the exploration of propolis, a resinous bee product, for its potential anti-diabetic effects. This review examines the mechanisms by which propolis may aid in T2DM management. A literature search was conducted in SCOPUS and PubMed using the terms (Propolis) AND (diabetes OR "insulin resistance" OR hyperglycemia), focusing on studies published from 2014 onwards. The search yielded 384 and 207 records in SCOPUS and PubMed, respectively. After screening and full-text review, 42 studies met the inclusion criteria. Key variables analyzed included the type and source of propolis, experimental models, dosage, treatment duration, and primary and secondary outcomes. Findings highlight multiple mechanisms through which propolis may benefit T2DM, including enhancing pancreatic β-cell function, improving insulin sensitivity, regulating glucose and lipid metabolism, modulating gut microbiota, and reducing oxidative stress and inflammation. Some studies also reported protective effects on renal and hepatic function. Overall, propolis exhibits promising potential as a complementary therapy for T2DM. However, further well-designed clinical trials are necessary to confirm its efficacy, determine optimal dosing, and identify key bioactive compounds responsible for its therapeutic effects. Future research should focus on optimizing its clinical application for diabetes management.
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Affiliation(s)
- Chee Ning Wong
- M. Kandiah Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang, Selangor, Malaysia
| | - Siew-Keah Lee
- M. Kandiah Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang, Selangor, Malaysia
| | - Kai Bin Liew
- Faculty of Pharmacy, University of Cyberjaya, Cyberjaya, Selangor, Malaysia
| | - Yik-Ling Chew
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Wilayah Persekutuan, Malaysia
| | - Ang-Lim Chua
- Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
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Jerab D, Blangero F, da Costa PCT, de Brito Alves JL, Kefi R, Jamoussi H, Morio B, Eljaafari A. Beneficial Effects of Omega-3 Fatty Acids on Obesity and Related Metabolic and Chronic Inflammatory Diseases. Nutrients 2025; 17:1253. [PMID: 40219010 PMCID: PMC11990730 DOI: 10.3390/nu17071253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/28/2025] [Accepted: 03/30/2025] [Indexed: 04/14/2025] Open
Abstract
Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are known to help resolve inflammation through generation of anti-inflammatory eicosanoids and specialized pro-resolving mediators, including resolvins, protectins, and maresins. Through binding to the GPR120/FFAR4 receptor, their beneficial effects result from phospholipid membrane remodeling, impairment of inflammatory signaling molecules clustering, subsequent inhibition of NF-κB and inflammasome activation, and a reduction in oxidative stress. Obesity, a chronic inflammatory disease that contributes to metabolic disorders, is alleviated by n-3 PUFAs. In the adipose tissue (AT) of individuals with obesity, n-3 PUFAs counteract hypoxia, inhibit immune cell infiltration and AT inflammation, improve insulin sensitivity, and reduce fat mass. Beyond AT, n-3 PUFAs also alleviate other metabolic disorders such as metabolic-associated steatotic liver disease (MASLD), gut dysbiosis, and/or renal dysfunction. In cardiovascular disease (CVD), they are mainly recommended as a secondary prevention for patients with coronary heart disease risks. This review provides an in-depth analysis of the benefits of n-3 PUFAs in obesity and related metabolic diseases, examining both the mechanistic and clinical aspects. Additionally, it also explores the effects of n-3 PUFAs in obesity-related chronic inflammatory conditions, including inflammatory bowel disease, psoriasis, rheumatoid arthritis, osteoarthritis, and multiple sclerosis, by targeting specific pathophysiological mechanisms. Clinical applications and limitations of n-3 PUFAs are discussed based on findings from human clinical trials.
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Affiliation(s)
- Donia Jerab
- CarMeN Laboratory, Institut National de Recherche pour l’ Agriculture, l’ Alimentation et l’Environnement, UMR1397, Institut National de la Santé et de la Recherche Médicale, U 1060, Université Claude Bernard Lyon I, 69310 Pierre-Bénite, France (B.M.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis 1002, Tunisia;
| | - Ferdinand Blangero
- CarMeN Laboratory, Institut National de Recherche pour l’ Agriculture, l’ Alimentation et l’Environnement, UMR1397, Institut National de la Santé et de la Recherche Médicale, U 1060, Université Claude Bernard Lyon I, 69310 Pierre-Bénite, France (B.M.)
| | - Paulo César Trindade da Costa
- Department of Nutrition, Health Sciences Center, Federal University of Paraíba, João Pessoa 58051-900, Brazil (J.L.d.B.A.)
| | - José Luiz de Brito Alves
- Department of Nutrition, Health Sciences Center, Federal University of Paraíba, João Pessoa 58051-900, Brazil (J.L.d.B.A.)
| | - Rym Kefi
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis 1002, Tunisia;
| | - Henda Jamoussi
- Research Unit “Obesity: Etiopathology and Treatment, UR18ES01”, Faculty of Medicine, Tunis El Manar University, Tunis 2092, Tunisia;
| | - Beatrice Morio
- CarMeN Laboratory, Institut National de Recherche pour l’ Agriculture, l’ Alimentation et l’Environnement, UMR1397, Institut National de la Santé et de la Recherche Médicale, U 1060, Université Claude Bernard Lyon I, 69310 Pierre-Bénite, France (B.M.)
| | - Assia Eljaafari
- CarMeN Laboratory, Institut National de Recherche pour l’ Agriculture, l’ Alimentation et l’Environnement, UMR1397, Institut National de la Santé et de la Recherche Médicale, U 1060, Université Claude Bernard Lyon I, 69310 Pierre-Bénite, France (B.M.)
- Department of Clinical Research, Hospices Civils de Lyon, 69002 Lyon, France
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3
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Miracle CE, McCallister CL, Egleton RD, Salisbury TB. Mechanisms by which obesity regulates inflammation and anti-tumor immunity in cancer. Biochem Biophys Res Commun 2024; 733:150437. [PMID: 39074412 PMCID: PMC11455618 DOI: 10.1016/j.bbrc.2024.150437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 07/12/2024] [Accepted: 07/22/2024] [Indexed: 07/31/2024]
Abstract
Obesity is associated with an increased risk for 13 different cancers. The increased risk for cancer in obesity is mediated by obesity-associated changes in the immune system. Obesity has distinct effects on different types of inflammation that are tied to tumorigenesis. For example, obesity promotes chronic inflammation in adipose tissue that is tumor-promoting in peripheral tissues. Conversely, obesity inhibits acute inflammation that rejects tumors. Obesity therefore promotes cancer by differentially regulating chronic versus acute inflammation. Given that obesity is chronic, the initial inflammation in adipose tissue will lead to systemic inflammation that could induce compensatory anti-inflammatory reactions in peripheral tissues to suppress chronic inflammation. The overall effect of obesity in peripheral tissues is therefore dependent on the duration and severity of obesity. Adipose tissue is a complex tissue that is composed of many cell types in addition to adipocytes. Further, adipose tissue cellularity is different at different anatomical sites throughout the body. Consequently, the sensitivity of adipose tissue to obesity is dependent on the anatomical location of the adipose depot. For example, obesity induces more inflammation in visceral than subcutaneous adipose tissue. Based on these studies, the mechanisms by which obesity promotes tumorigenesis are multifactorial and immune cell type-specific. The objective of our paper is to discuss the cellular mechanisms by which obesity promotes tumorigenesis by regulating distinct types of inflammation in adipose tissue and the tumor microenvironment.
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Affiliation(s)
- Cora E Miracle
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV, 25755, USA.
| | - Chelsea L McCallister
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV, 25755, USA.
| | - Richard D Egleton
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV, 25755, USA.
| | - Travis B Salisbury
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV, 25755, USA.
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Balcerczyk A, Eljaafari A, Pirola L. Adipose stem cells drive T cell infiltration in obesity. Trends Endocrinol Metab 2024; 35:931-933. [PMID: 38945796 DOI: 10.1016/j.tem.2024.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 07/02/2024]
Abstract
Obesity is often associated with adipose tissue (AT) inflammation and immune cell infiltration. Writing recently in Cell Reports, Liao et al. investigated the mechanisms of T cell infiltration of AT using single cell (sc)RNA-sequencing (RNA-seq), transplantation studies, in vitro co-cultures, and knock-out mice. They highlighted the crucial role of C-C motif chemokine ligand 5 (CCL5)-secreting adipose stem cells (ASCs), offering insights for potential therapies.
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Affiliation(s)
- Aneta Balcerczyk
- Department of Oncobiology and Epigenetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, Lodz 90-236, Poland
| | - Assia Eljaafari
- Carmen (Cardiometabolism and Nutrition) Laboratory, INSERM Unit 1060, Claude Bernard Lyon-1 University, 165 Chemin du Grand Revoyet, BP12, 69310, Pierre Bénite, France; Hospices Civils of Lyon, Department of Medical Research, Lyon South Hospital, 69310, Pierre Bénite, France
| | - Luciano Pirola
- Carmen (Cardiometabolism and Nutrition) Laboratory, INSERM Unit 1060, Claude Bernard Lyon-1 University, 165 Chemin du Grand Revoyet, BP12, 69310, Pierre Bénite, France.
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Pinho ACO, Barbosa P, Lazaro A, Tralhão JG, Pereira MJ, Paiva A, Laranjeira P, Carvalho E. Identification and characterization of circulating and adipose tissue infiltrated CD20 +T cells from subjects with obesity that undergo bariatric surgery. Immunol Lett 2024; 269:106911. [PMID: 39147242 DOI: 10.1016/j.imlet.2024.106911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 08/10/2024] [Accepted: 08/12/2024] [Indexed: 08/17/2024]
Abstract
T cells play critical roles in adipose tissue (AT) inflammation. The role of CD20+T cell in AT dysfunction and their contributing to insulin resistance (IR) and type 2 diabetes progression, is not known. The aim was to characterize CD20+T cells in omental (OAT), subcutaneous (SAT) and peripheral blood (PB) from subjects with obesity (OB, n = 42), by flow cytometry. Eight subjects were evaluated before (T1) and 12 months post (T2) bariatric/metabolic surgery (BMS). PB from subjects without obesity (nOB, n = 12) was also collected. Higher percentage of CD20+T cells was observed in OAT, compared to PB or SAT, in OB-T1. CD20 expression by PB CD4+T cells was inversely correlated with adiposity markers, while follicular-like CD20+T cells were positively correlated with impaired glucose tolerance (increased HbA1c). Notably, among OB-T1, IR establishment was marked by a lower percentage and absolute number of PB CD20+T cells, compared nOB. Obesity was associated with higher percentage of activated CD20+T cells; however, OAT-infiltrated CD20+T cells from OB-T1 with diabetes displayed the lowest activation. CD20+T cells infiltrating OAT from OB-T1 displayed a phenotype towards IFN-γ-producing Th1 and Tc1 cells. After BMS, the percentage of PB CD4+CD20+T cells increased, with reduced Th1 and increased Th17 phenotype. Whereas in OAT the percentage of CD20+T cells with Th1/17 and Tc1/17 phenotypes increased. Interestingly, OAT from OB pre/post BMS maintained higher frequency of effector memory CD20+T cells. In conclusion, CD20+T cells may play a prominent role in obesity-related AT inflammation.
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Affiliation(s)
- Aryane Cruz Oliveira Pinho
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504, Coimbra, Portugal; Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3000-456, Coimbra, Portugal
| | - Pedro Barbosa
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal
| | - André Lazaro
- General Surgery Unit, Centro Hospitalar e Universitário de Coimbra University of Coimbra, 3000-075, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal
| | - José G Tralhão
- General Surgery Unit, Centro Hospitalar e Universitário de Coimbra University of Coimbra, 3000-075, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal
| | - Maria João Pereira
- Department of Medical Sciences, Clinical Diabetology and Metabolism, Uppsala University, Uppsala, Sweden
| | - Artur Paiva
- CIBB - Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504, Coimbra, Portugal; Flow Cytometry Unit, Clinical Pathology Department, Hospitais da Universidade de Coimbra, Unidade Local de Saúde de Coimbra, 3000-076, Coimbra, Portugal; Instituto Politécnico de Coimbra, ESTESC-Coimbra Health School, Ciências Biomédicas Laboratoriais, 3046-854, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548, Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), 3000-061, Coimbra, Portugal
| | - Paula Laranjeira
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504, Coimbra, Portugal; Flow Cytometry Unit, Clinical Pathology Department, Hospitais da Universidade de Coimbra, Unidade Local de Saúde de Coimbra, 3000-076, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548, Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), 3000-061, Coimbra, Portugal.
| | - Eugenia Carvalho
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal; APDP-Portuguese Diabetes Association, Lisbon, Portugal.
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Abdelnabi MN, Hassan GS, Shoukry NH. Role of the type 3 cytokines IL-17 and IL-22 in modulating metabolic dysfunction-associated steatotic liver disease. Front Immunol 2024; 15:1437046. [PMID: 39156888 PMCID: PMC11327067 DOI: 10.3389/fimmu.2024.1437046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 07/12/2024] [Indexed: 08/20/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases that span simple steatosis, metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis and may progress to cirrhosis and cancer. The pathogenesis of MASLD is multifactorial and is driven by environmental, genetic, metabolic and immune factors. This review will focus on the role of the type 3 cytokines IL-17 and IL-22 in MASLD pathogenesis and progression. IL-17 and IL-22 are produced by similar adaptive and innate immune cells such as Th17 and innate lymphoid cells, respectively. IL-17-related signaling is upregulated during MASLD resulting in increased chemokines and proinflammatory cytokines in the liver microenvironment, enhanced recruitment of myeloid cells and T cells leading to exacerbation of inflammation and liver disease progression. IL-17 may also act directly by activating hepatic stellate cells resulting in increased fibrosis. In contrast, IL-22 is a pleiotropic cytokine with a dominantly protective signature in MASLD and is currently being tested as a therapeutic strategy. IL-22 also exhibits beneficial metabolic effects and abrogates MASH-related inflammation and fibrosis development via inducing the production of anti-oxidants and anti-apoptotic factors. A sex-dependent effect has been attributed to both cytokines, most importantly to IL-22 in MASLD or related conditions. Altogether, IL-17 and IL-22 are key effectors in MASLD pathogenesis and progression. We will review the role of these two cytokines and cells that produce them in the development of MASLD, their interaction with host factors driving MASLD including sexual dimorphism, and their potential therapeutic benefits.
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Affiliation(s)
- Mohamed N. Abdelnabi
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
| | - Ghada S. Hassan
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Naglaa H. Shoukry
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
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Wystrychowski G, Simka-Lampa K, Witkowska A, Sobecko E, Skubis-Sikora A, Sikora B, Wojtyna E, Golda A, Gwizdek K, Wróbel M, Sędek Ł, Górczyńska-Kosiorz S, Szweda-Gandor N, Trautsolt W, Francuz T, Kruszniewska-Rajs C, Gola J. Selected microRNA Expression and Protein Regulator Secretion by Adipose Tissue-Derived Mesenchymal Stem Cells and Metabolic Syndrome. Int J Mol Sci 2024; 25:6644. [PMID: 38928349 PMCID: PMC11204268 DOI: 10.3390/ijms25126644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 06/12/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
The role of adipose mesenchymal stem cells (Ad-MSCs) in metabolic syndrome remains unclear. We aimed to assess the expression of selected microRNAs in Ad-MSCs of non-diabetic adults in relation to Ad-MSC secretion of protein regulators and basic metabolic parameters. Ten obese, eight overweight, and five normal weight subjects were enrolled: 19 females and 4 males; aged 43.0 ± 8.9 years. Ad-MSCs were harvested from abdominal subcutaneous fat. Ad-MSC cellular expressions of four microRNAs (2-ΔCt values) and concentrations of IL-6, IL-10, VEGF, and IGF-1 in the Ad-MSC-conditioned medium were assessed. The expressions of miR-21, miR-122, or miR-192 did not correlate with clinical parameters (age, sex, BMI, visceral fat, HOMA-IR, fasting glycemia, HbA1c, serum lipids, CRP, and eGFR). Conversely, the expression of miR-155 was lowest in obese subjects (3.69 ± 2.67 × 10-3 vs. 7.07 ± 4.42 × 10-3 in overweight and 10.25 ± 7.05 × 10-3 in normal weight ones, p = 0.04). The expression of miR-155 correlated inversely with BMI (sex-adjusted r = -0.64; p < 0.01), visceral adiposity (r = -0.49; p = 0.03), and serum CRP (r = -0.63; p < 0.01), whereas it correlated positively with serum HDL cholesterol (r = 0.51; p = 0.02). Moreover, miR-155 synthesis was associated marginally negatively with Ad-MSC secretion of IGF-1 (r = -0.42; p = 0.05), and positively with that of IL-10 (r = 0.40; p = 0.06). Ad-MSC expression of miR-155 appears blunted in visceral obesity, which correlates with Ad-MSC IGF-1 hypersecretion and IL-10 hyposecretion, systemic microinflammation, and HDL dyslipidemia. Ad-MSC studies in metabolic syndrome should focus on miR-155.
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Affiliation(s)
| | - Klaudia Simka-Lampa
- Department of Biochemistry, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (K.S.-L.); (E.S.); (T.F.)
| | | | - Ewelina Sobecko
- Department of Biochemistry, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (K.S.-L.); (E.S.); (T.F.)
| | - Aleksandra Skubis-Sikora
- Department of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.S.-S.); (B.S.)
| | - Bartosz Sikora
- Department of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.S.-S.); (B.S.)
| | - Ewa Wojtyna
- Institute of Medical Sciences, University of Opole, 45-040 Opole, Poland;
| | - Agnieszka Golda
- Alfamed General Practice, 41-100 Siemianowice Slaskie, Poland;
| | - Katarzyna Gwizdek
- Department of Rehabilitation, Faculty of Health Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland;
| | - Marta Wróbel
- Department of Internal Medicine, Diabetology and Cardiometabolic Diseases, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland;
| | - Łukasz Sędek
- Department of Microbiology and Immunology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland;
| | - Sylwia Górczyńska-Kosiorz
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (S.G.-K.); (N.S.-G.); (W.T.)
| | - Nikola Szweda-Gandor
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (S.G.-K.); (N.S.-G.); (W.T.)
| | - Wanda Trautsolt
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (S.G.-K.); (N.S.-G.); (W.T.)
| | - Tomasz Francuz
- Department of Biochemistry, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (K.S.-L.); (E.S.); (T.F.)
| | - Celina Kruszniewska-Rajs
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland; (C.K.-R.); (J.G.)
| | - Joanna Gola
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland; (C.K.-R.); (J.G.)
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Badr OI, Kamal MM, El-Maraghy SA, Ghaiad HR. The effect of diabetes mellitus on differentiation of mesenchymal stem cells into insulin-producing cells. Biol Res 2024; 57:20. [PMID: 38698488 PMCID: PMC11067316 DOI: 10.1186/s40659-024-00502-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 04/16/2024] [Indexed: 05/05/2024] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is a global epidemic with increasing incidences. DM is a metabolic disease associated with chronic hyperglycemia. Aside from conventional treatments, there is no clinically approved cure for DM up till now. Differentiating mesenchymal stem cells (MSCs) into insulin-producing cells (IPCs) is a promising approach for curing DM. Our study was conducted to investigate the effect of DM on MSCs differentiation into IPCs in vivo and in vitro. METHODS We isolated adipose-derived mesenchymal stem cells (Ad-MSCs) from the epididymal fat of normal and STZ-induced diabetic Sprague-Dawley male rats. Afterwards, the in vitro differentiation of normal-Ad-MSCs (N-Ad-MSCs) and diabetic-Ad-MSCs (DM-Ad-MSCs) into IPCs was compared morphologically then through determining the gene expression of β-cell markers including neurogenin-3 (Ngn-3), homeobox protein (Nkx6.1), musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), and insulin-1 (Ins-1) and eventually, through performing glucose-stimulated insulin secretion test (GSIS). Finally, the therapeutic potential of N-Ad-MSCs and DM-Ad-MSCs transplantation was compared in vivo in STZ-induced diabetic animals. RESULTS Our results showed no significant difference in the characteristics of N-Ad-MSCs and DM-Ad-MSCs. However, we demonstrated a significant difference in their abilities to differentiate into IPCs in vitro morphologically in addition to β-cell markers expression, and functional assessment via GSIS test. Furthermore, the abilities of both Ad-MSCs to control hyperglycemia in diabetic rats in vivo was assessed through measuring fasting blood glucose (FBGs), body weight (BW), histopathological examination of both pancreas and liver and immunoexpression of insulin in pancreata of study groups. CONCLUSION Our findings reveal the effectiveness of N-Ad-MSCs in differentiating into IPCs in vitro and controlling the hyperglycemia of STZ-induced diabetic rats in vivo compared to DM-Ad-MSCs.
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Affiliation(s)
- Omar I Badr
- Pharmacology and Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
| | - Mohamed M Kamal
- Pharmacology and Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
- Drug Research and Development Group, Health Research Center of Excellence, The British University in Egypt, Cairo, Egypt
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Shohda A El-Maraghy
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Heba R Ghaiad
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
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Liao X, Zeng Q, Xie L, Zhang H, Hu W, Xiao L, Zhou H, Wang F, Xie W, Song J, Sun X, Wang D, Ding Y, Jiao Y, Mai W, Aini W, Hui X, Liu W, Hsueh WA, Deng T. Adipose stem cells control obesity-induced T cell infiltration into adipose tissue. Cell Rep 2024; 43:113963. [PMID: 38492218 DOI: 10.1016/j.celrep.2024.113963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/11/2024] [Accepted: 02/28/2024] [Indexed: 03/18/2024] Open
Abstract
T cell infiltration into white adipose tissue (WAT) drives obesity-induced adipose inflammation, but the mechanisms of obesity-induced T cell infiltration into WAT remain unclear. Our single-cell RNA sequencing reveals a significant impact of adipose stem cells (ASCs) on T cells. Transplanting ASCs from obese mice into WAT enhances T cell accumulation. C-C motif chemokine ligand 5 (CCL5) is upregulated in ASCs as early as 4 weeks of high-fat diet feeding, coinciding with the onset of T cell infiltration into WAT during obesity. ASCs and bone marrow transplantation experiments demonstrate that CCL5 from ASCs plays a crucial role in T cell accumulation during obesity. The production of CCL5 in ASCs is induced by tumor necrosis factor alpha via the nuclear factor κB pathway. Overall, our findings underscore the pivotal role of ASCs in regulating T cell accumulation in WAT during the early phases of obesity, emphasizing their importance in modulating adaptive immunity in obesity-induced adipose inflammation.
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Affiliation(s)
- Xiyan Liao
- National Clinical Research Center for Metabolic Diseases and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Qin Zeng
- National Clinical Research Center for Metabolic Diseases and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Limin Xie
- National Clinical Research Center for Metabolic Diseases and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Haowei Zhang
- The First Affiliated Hospital, Department of Orthopedics, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Wanyu Hu
- National Clinical Research Center for Metabolic Diseases and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Liuling Xiao
- Center for Translational Research in Hematological Malignancies, Neal Cancer Center, Houston Methodist Research Institute, Houston, TX 77080, USA
| | - Hui Zhou
- National Clinical Research Center for Metabolic Diseases and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Fanqi Wang
- National Clinical Research Center for Metabolic Diseases and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Wanqin Xie
- NHC Key Laboratory of Birth Defects for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, 53 Xiangchun Road, Changsha, Hunan 410028, China
| | - Jianfeng Song
- National Clinical Research Center for Metabolic Diseases and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Xiaoxiao Sun
- National Clinical Research Center for Metabolic Diseases and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Dandan Wang
- National Clinical Research Center for Metabolic Diseases and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Yujin Ding
- National Clinical Research Center for Metabolic Diseases and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Yayi Jiao
- National Clinical Research Center for Metabolic Diseases and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Wuqian Mai
- National Clinical Research Center for Metabolic Diseases and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Wufuer Aini
- National Clinical Research Center for Metabolic Diseases and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Xiaoyan Hui
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Wei Liu
- Department of Biliopancreatic Surgery and Bariatric Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Willa A Hsueh
- The Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Tuo Deng
- National Clinical Research Center for Metabolic Diseases and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Clinical Immunology Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
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10
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Engin A. Reappraisal of Adipose Tissue Inflammation in Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:297-327. [PMID: 39287856 DOI: 10.1007/978-3-031-63657-8_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Chronic low-grade inflammation is a central component in the pathogenesis of obesity-related expansion of adipose tissue and complications in other metabolic tissues. Five different signaling pathways are defined as dominant determinants of adipose tissue inflammation: These are increased circulating endotoxin due to dysregulation in the microbiota-gut-brain axis, systemic oxidative stress, macrophage accumulation, and adipocyte death. Finally, the nucleotide-binding and oligomerization domain (NOD) leucine-rich repeat family pyrin domain-containing 3 (NLRP3) inflammasome pathway is noted to be a key regulator of metabolic inflammation. The NLRP3 inflammasome and associated metabolic inflammation play an important role in the relationships among fatty acids and obesity. Several highly active molecules, including primarily leptin, resistin, adiponectin, visfatin, and classical cytokines, are abundantly released from adipocytes. The most important cytokines that are released by inflammatory cells infiltrating obese adipose tissue are tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) (CCL-2), and IL-1. All these molecules mentioned above act on immune cells, causing local and then general inflammation. Three metabolic pathways are noteworthy in the development of adipose tissue inflammation: toll-like receptor 4 (TLR4)/phosphatidylinositol-3'-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, endoplasmic reticulum (ER) stress-derived unfolded protein response (UPR), and inhibitor of nuclear factor kappa-B kinase beta (IKKβ)-nuclear factor kappa B (NF-κB) pathway. In fact, adipose tissue inflammation is an adaptive response that contributes to a visceral depot barrier that effectively filters gut-derived endotoxin. Excessive fatty acid release worsens adipose tissue inflammation and contributes to insulin resistance. However, suppression of adipose inflammation in obesity with anti-inflammatory drugs is not a rational solution and paradoxically promotes insulin resistance, despite beneficial effects on weight gain. Inflammatory pathways in adipocytes are indeed indispensable for maintaining systemic insulin sensitivity. Cannabinoid type 1 receptor (CB1R) is important in obesity-induced pro-inflammatory response; however, blockade of CB1R, contrary to anti-inflammatory drugs, breaks the links between insulin resistance and adipose tissue inflammation. Obesity, however, could be decreased by improving leptin signaling, white adipose tissue browning, gut microbiota interactions, and alleviating inflammation. Furthermore, capsaicin synthesized by chilies is thought to be a new and promising therapeutic option in obesity, as it prevents metabolic endotoxemia and systemic chronic low-grade inflammation caused by high-fat diet.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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11
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Mahmoud M, Abdel-Rasheed M, Galal ER, El-Awady RR. Factors Defining Human Adipose Stem/Stromal Cell Immunomodulation in Vitro. Stem Cell Rev Rep 2024; 20:175-205. [PMID: 37962697 PMCID: PMC10799834 DOI: 10.1007/s12015-023-10654-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2023] [Indexed: 11/15/2023]
Abstract
Human adipose tissue-derived stem/stromal cells (hASCs) are adult multipotent mesenchymal stem/stromal cells with immunomodulatory capacities. Here, we present up-to-date knowledge on the impact of different experimental and donor-related factors on hASC immunoregulatory functions in vitro. The experimental determinants include the immunological status of hASCs relative to target immune cells, contact vs. contactless interaction, and oxygen tension. Factors such as the ratio of hASCs to immune cells, the cellular context, the immune cell activation status, and coculture duration are also discussed. Conditioning of hASCs with different approaches before interaction with immune cells, hASC culture in xenogenic or xenofree culture medium, hASC culture in two-dimension vs. three-dimension with biomaterials, and the hASC passage number are among the experimental parameters that greatly may impact the hASC immunosuppressive potential in vitro, thus, they are also considered. Moreover, the influence of donor-related characteristics such as age, sex, and health status on hASC immunomodulation in vitro is reviewed. By analysis of the literature studies, most of the indicated determinants have been investigated in broad non-standardized ranges, so the results are not univocal. Clear conclusions cannot be drawn for the fine-tuned scenarios of many important factors to set a standard hASC immunopotency assay. Such variability needs to be carefully considered in further standardized research. Importantly, field experts' opinions may help to make it clearer.
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Affiliation(s)
- Marwa Mahmoud
- Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, 33 El Buhouth St, Ad Doqi, Dokki, 12622, Cairo Governorate, Egypt.
- Department of Medical Molecular Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
| | - Mazen Abdel-Rasheed
- Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, 33 El Buhouth St, Ad Doqi, Dokki, 12622, Cairo Governorate, Egypt
- Department of Reproductive Health Research, National Research Centre, Cairo, Egypt
| | - Eman Reda Galal
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Rehab R El-Awady
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
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12
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Liu Y, Ouyang Y, You W, Liu W, Cheng Y, Mai X, Shen Z. Physiological roles of human interleukin-17 family. Exp Dermatol 2024; 33:e14964. [PMID: 37905720 DOI: 10.1111/exd.14964] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 10/08/2023] [Accepted: 10/13/2023] [Indexed: 11/02/2023]
Abstract
Interleukin-17 s (IL-17s) are well-known proinflammatory cytokines, and their antagonists perform excellently in the treatment of inflammatory skin diseases such as psoriasis. However, their physiological functions have not been given sufficient attention by clinicians. IL-17s can protect the host from extracellular pathogens, maintain epithelial integrity, regulate cognitive processes and modulate adipocyte activity through distinct mechanisms. Here, we present a systematic review concerning the physiological functions of IL-17s. Our goal is not to negate the therapeutic effect of IL-17 antagonists, but to ensure their safe use and reasonably explain the possible adverse events that may occur in their application.
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Affiliation(s)
- Yucong Liu
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Ye Ouyang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Wanchun You
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Wenqi Liu
- Department of Dermatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Yufan Cheng
- Department of Dermatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Xinming Mai
- Medical School, Shenzhen University, Shenzhen, China
| | - Zhu Shen
- Department of Dermatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
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13
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Mahmoud M, Abdel-Rasheed M. Influence of type 2 diabetes and obesity on adipose mesenchymal stem/stromal cell immunoregulation. Cell Tissue Res 2023; 394:33-53. [PMID: 37462786 PMCID: PMC10558386 DOI: 10.1007/s00441-023-03801-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 06/21/2023] [Indexed: 10/07/2023]
Abstract
Type 2 diabetes (T2D), associated with obesity, represents a state of metabolic inflammation and oxidative stress leading to insulin resistance and progressive insulin deficiency. Adipose-derived stem cells (ASCs) are adult mesenchymal stem/stromal cells identified within the stromal vascular fraction of adipose tissue. These cells can regulate the immune system and possess anti-inflammatory properties. ASCs are a potential therapeutic modality for inflammatory diseases including T2D. Patient-derived (autologous) rather than allogeneic ASCs may be a relatively safer approach in clinical perspectives, to avoid occasional anti-donor immune responses. However, patient characteristics such as body mass index (BMI), inflammatory status, and disease duration and severity may limit the therapeutic utility of ASCs. The current review presents human ASC (hASC) immunoregulatory mechanisms with special emphasis on those related to T lymphocytes, hASC implications in T2D treatment, and the impact of T2D and obesity on hASC immunoregulatory potential. hASCs can modulate the proliferation, activation, and functions of diverse innate and adaptive immune cells via direct cell-to-cell contact and secretion of paracrine mediators and extracellular vesicles. Preclinical studies recommend the therapeutic potential of hASCs to improve inflammation and metabolic indices in a high-fat diet (HFD)-induced T2D disease model. Discordant data have been reported to unravel intact or detrimentally affected immunomodulatory functions of ASCs, isolated from patients with obesity and/or T2D patients, in vitro and in vivo. Numerous preconditioning strategies have been introduced to potentiate hASC immunomodulation; they are also discussed here as possible options to potentiate the immunoregulatory functions of hASCs isolated from patients with obesity and T2D.
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Affiliation(s)
- Marwa Mahmoud
- Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, 33 El Buhouth St, Ad Doqi, Dokki, 12622, Cairo Governorate, Egypt.
- Department of Medical Molecular Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
| | - Mazen Abdel-Rasheed
- Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, 33 El Buhouth St, Ad Doqi, Dokki, 12622, Cairo Governorate, Egypt
- Department of Reproductive Health Research, National Research Centre, Cairo, Egypt
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14
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Pestel J, Blangero F, Watson J, Pirola L, Eljaafari A. Adipokines in obesity and metabolic-related-diseases. Biochimie 2023; 212:48-59. [PMID: 37068579 DOI: 10.1016/j.biochi.2023.04.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 04/03/2023] [Accepted: 04/13/2023] [Indexed: 04/19/2023]
Abstract
The discovery of leptin in the 1990s led to a reconsideration of adipose tissue (AT) as not only a fatty acid storage organ, but also a proper endocrine tissue. AT is indeed capable of secreting bioactive molecules called adipokines for white AT or batokines for brown/beige AT, which allow communication with numerous organs, especially brain, heart, liver, pancreas, and/or the vascular system. Adipokines exert pro or anti-inflammatory activities. An equilibrated balance between these two sets ensures homeostasis of numerous tissues and organs. During the development of obesity, AT remodelling leads to an alteration of its endocrine activity, with increased secretion of pro-inflammatory adipokines relative to the anti-inflammatory ones, as shown in the graphical abstract. Pro-inflammatory adipokines take part in the initiation of local and systemic inflammation during obesity and contribute to comorbidities associated to obesity, as detailed in the present review.
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Affiliation(s)
- Julien Pestel
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France
| | - Ferdinand Blangero
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France
| | - Julia Watson
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France
| | - Luciano Pirola
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France
| | - Assia Eljaafari
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France; Hospices Civils de Lyon: 2 quai des Célestins, 69001 Lyon, France.
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15
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Blangero F, Robert M, Andraud T, Dumontet C, Vidal H, Eljaafari A. Contribution of Mesenchymal Stem Cells from Obese Adipose Tissue to PD-L1 Over-Expression and Breast Cancer Progression through Pathogenic Th17 Cell Activation. Cancers (Basel) 2023; 15:cancers15112963. [PMID: 37296927 DOI: 10.3390/cancers15112963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/09/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Obesity is a well-known risk factor for cancer. We have previously reported the role of adipose-tissue-derived mesenchymal stem cells from obese individuals (ob-ASC) in the promotion of pathogenic Th17 cells and immune check point (ICP) upregulation. Thus, we postulated herein that this mechanism could contribute to breast cancer (BC) aggressiveness. METHODS Conditioning medium (CM) from mitogen-activated ob-ASC and immune cell co-cultures were added to two human breast cancer cell line (BCCL) cultures. Expressions of pro-inflammatory cytokines, angiogenesis markers, metalloproteinases, and PD-L1 (a major ICP) were measured at the mRNA and/or protein levels. BCCL migration was explored in wound healing assays. Anti-cytokine neutralizing antibodies (Ab) were added to co-cultures. RESULTS CM from ob-ASC/MNC co-cultures increased IL-1β, IL-8, IL-6, VEGF-A, MMP-9, and PD-L1 expressions in both BCCLs and accelerated their migration. The use of Abs demonstrated differential effects for IL-17A and IFNγ on BCCL pro-inflammatory cytokine over-expression or PD-L1 upregulation, respectively, but potentiating effects on BCCL migration. Finally, co-cultures with ob-ASC, but not lean ASC, enhanced PD-L1 expression. CONCLUSIONS Our results demonstrate increased inflammation and ICP markers and accelerated BCCL migration following the activation of pathogenic Th17 cells by ob-ASC, which could represent a new mechanism linking obesity with BC progression.
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Affiliation(s)
- Ferdinand Blangero
- CarMeN Laboratory, INSERM U1060, INRAE U1397, University Claude Bernard Lyon 1, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, 69310 Pïerre Bénite, France
| | - Maud Robert
- CarMeN Laboratory, INSERM U1060, INRAE U1397, University Claude Bernard Lyon 1, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, 69310 Pïerre Bénite, France
- Bariatric Surgery Department, Edouard Herriot Hospital, 69003 Lyon, France
| | - Thomas Andraud
- CarMeN Laboratory, INSERM U1060, INRAE U1397, University Claude Bernard Lyon 1, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, 69310 Pïerre Bénite, France
| | - Charles Dumontet
- Center of Research in Cancerology of Lyon, INSERM U1052, CNRS 5286, University Claude Bernard Lyon 1, Centre Léon Berard, 69008 Lyon, France
| | - Hubert Vidal
- CarMeN Laboratory, INSERM U1060, INRAE U1397, University Claude Bernard Lyon 1, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, 69310 Pïerre Bénite, France
| | - Assia Eljaafari
- CarMeN Laboratory, INSERM U1060, INRAE U1397, University Claude Bernard Lyon 1, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, 69310 Pïerre Bénite, France
- Research Department, Hospices Civils de Lyon, 69002 Lyon, France
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16
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Pathogenic Role of Adipose Tissue-Derived Mesenchymal Stem Cells in Obesity and Obesity-Related Inflammatory Diseases. Cells 2023; 12:cells12030348. [PMID: 36766689 PMCID: PMC9913687 DOI: 10.3390/cells12030348] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/12/2023] [Accepted: 01/14/2023] [Indexed: 01/19/2023] Open
Abstract
Adipose tissue-derived mesenchymal stem cells (ASCs) are adult stem cells, endowed with self-renewal, multipotent capacities, and immunomodulatory properties, as mesenchymal stem cells (MSCs) from other origins. However, in a pathological context, ASCs like MSCs can exhibit pro-inflammatory properties and attract inflammatory immune cells at their neighborhood. Subsequently, this creates an inflammatory microenvironment leading to ASCs' or MSCs' dysfunctions. One such example is given by obesity where adipogenesis is impaired and insulin resistance is initiated. These opposite properties have led to the classification of MSCs into two categories defined as pro-inflammatory ASC1 or anti-inflammatory ASC2, in which plasticity depends on the micro-environmental stimuli. The aim of this review is to (i) highlight the pathogenic role of ASCs during obesity and obesity-related inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, and cancer; and (ii) describe some of the mechanisms leading to ASCs dysfunctions. Thus, the role of soluble factors, adhesion molecules; TLRs, Th17, and Th22 cells; γδ T cells; and immune checkpoint overexpression will be addressed.
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17
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Miller D, Grant A, Durgam S, El-Hayek K, Flanigan DC, Malanga G, Vasileff WK, Baria MR. Adipose-Derived Stem Cells, Obesity, and Inflammation: A Systematic Review and Implications for Osteoarthritis Treatment. Am J Phys Med Rehabil 2022; 101:879-887. [PMID: 35978456 DOI: 10.1097/phm.0000000000001930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
ABSTRACT Adipose is a known source of mesenchymal stem cells that can be used to treat musculoskeletal disorders, such as osteoarthritis. Because obesity often coexists with osteoarthritis, excess adiposity may be a useful source of mesenchymal stem cells. However, obesity is associated with systemic inflammation, which may influence the quality of adipose-derived stem cells. We performed a systematic review of the literature examining adipose-derived stem cell behavior, cytokine, and growth factor profiles from obese and nonobese patients. Two independent reviewers applied the inclusion/exclusion criteria and independently extracted data including mesenchymal stem cell count/viability/behavior, growth factor, and/or cytokine expression. Twenty-two articles met criteria for inclusion. Samples from obese patients had increased mesenchymal stem cell content (n = 6), but decreased proliferative ability (n = 3), and increased expression of interleukin 1 (n = 3), interleukin 6 (n = 3), and tumor necrosis factor α (n = 6). There was also greater macrophage content (n = 4). Weight loss normalized cellular function. In vitro behavior and quality of adipose-derived stem cell are significantly different between obese and nonobese patients. Samples from obese patients had greater adipose-derived stem cell content, lower proliferative ability, increased senescence, and increased proinflammatory cytokine expression. Differences in cellular function should be considered when using adipose to treat musculoskeletal pathology in obese and nonobese patients.
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Affiliation(s)
- Dana Miller
- From the Department of Physical Medicine and Rehabilitation, The Ohio State University, Columbus, Ohio (DM, AG); Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio (SD); Divisions General Surgery and Surgical Oncology, MetroHealth System, Case Western Reserve University School of Medicine, Cleveland, Ohio (KE-H); Department of Orthopaedics, Sports Medicine Research Institute, The Ohio State University, Columbus, Ohio (DCF, WKV); Department of Physical Medicine and Rehabilitation, Rutgers School of Medicine-New Jersey Medical School, Newark, New Jersey (GM); and Department of Physical Medicine and Rehabilitation, Sports Medicine Research Institute, The Ohio State University, Columbus, Ohio (MRB)
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18
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Ritter A, Kreis NN, Hoock SC, Solbach C, Louwen F, Yuan J. Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells, Obesity and the Tumor Microenvironment of Breast Cancer. Cancers (Basel) 2022; 14:3908. [PMID: 36010901 PMCID: PMC9405791 DOI: 10.3390/cancers14163908] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/01/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
Breast cancer is the most frequently diagnosed cancer and a common cause of cancer-related death in women. It is well recognized that obesity is associated with an enhanced risk of more aggressive breast cancer as well as reduced patient survival. Adipose tissue is the major microenvironment of breast cancer. Obesity changes the composition, structure, and function of adipose tissue, which is associated with inflammation and metabolic dysfunction. Interestingly, adipose tissue is rich in ASCs/MSCs, and obesity alters the properties and functions of these cells. As a key component of the mammary stroma, ASCs play essential roles in the breast cancer microenvironment. The crosstalk between ASCs and breast cancer cells is multilateral and can occur both directly through cell-cell contact and indirectly via the secretome released by ASC/MSC, which is considered to be the main effector of their supportive, angiogenic, and immunomodulatory functions. In this narrative review, we aim to address the impact of obesity on ASCs/MSCs, summarize the current knowledge regarding the potential pathological roles of ASCs/MSCs in the development of breast cancer, discuss related molecular mechanisms, underline the possible clinical significance, and highlight related research perspectives. In particular, we underscore the roles of ASCs/MSCs in breast cancer cell progression, including proliferation and survival, angiogenesis, migration and invasion, the epithelial-mesenchymal transition, cancer stem cell development, immune evasion, therapy resistance, and the potential impact of breast cancer cells on ASCS/MSCs by educating them to become cancer-associated fibroblasts. We conclude that ASCs/MSCs, especially obese ASCs/MSCs, may be key players in the breast cancer microenvironment. Targeting these cells may provide a new path of effective breast cancer treatment.
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Affiliation(s)
- Andreas Ritter
- Obstetrics and Prenatal Medicine, Gynecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany
| | | | | | | | | | - Juping Yuan
- Obstetrics and Prenatal Medicine, Gynecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany
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19
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Kuca-Warnawin E, Plebańczyk M, Ciechomska M, Olesińska M, Szczęsny P, Kontny E. Impact of Adipose-Derived Mesenchymal Stem Cells (ASCs) of Rheumatic Disease Patients on T Helper Cell Differentiation. Int J Mol Sci 2022; 23:ijms23105317. [PMID: 35628127 PMCID: PMC9140468 DOI: 10.3390/ijms23105317] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/27/2022] [Accepted: 05/03/2022] [Indexed: 11/16/2022] Open
Abstract
Complex pathogenesis of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is associated with an imbalance of various Th-cell subpopulations. Mesenchymal stem cells (MSCs) have the ability to restore this balance. However, bone marrow-derived MSCs of SLE and SSc patients exhibit many abnormalities, whereas the properties of adipose derived mesenchymal stem cells (ASCS) are much less known. Therefore, we examined the effect of ASCs obtained from SLE (SLE/ASCs) and SSc (SSc/ASCs) patients on Th subset differentiation, using cells from healthy donors (HD/ASCs) as controls. ASCs were co-cultured with activated CD4+ T cells or peripheral blood mononuclear cells. Expression of transcription factors defining Th1, Th2, Th17, and regulatory T cell (Tregs) subsets, i.e., T-bet, GATA3, RORc, and FoxP3, were analysed by quantitative RT-PCR, the concentrations of subset-specific cytokines were measured by ELISA, and Tregs formation by flow cytometry. Compared with HD/ASCs, SLE/ASCs and especially SSc/ASCs triggered Th differentiation which was disturbed at the transcription levels of genes encoding Th1- and Tregs-related transcription factors. However, we failed to find functional consequences of this abnormality, because all tested ASCs similarly switched differentiation from Th1 to Th2 direction with accompanying IFNγ/IL-4 ratio decrease, up-regulated Th17 formation and IL-17 secretion, and up-regulated classical Tregs generation.
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Affiliation(s)
- Ewa Kuca-Warnawin
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland; (M.P.); (M.C.); (E.K.)
- Correspondence:
| | - Magdalena Plebańczyk
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland; (M.P.); (M.C.); (E.K.)
| | - Marzena Ciechomska
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland; (M.P.); (M.C.); (E.K.)
| | - Marzena Olesińska
- Clinic of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (M.O.); (P.S.)
| | - Piotr Szczęsny
- Clinic of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (M.O.); (P.S.)
| | - Ewa Kontny
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland; (M.P.); (M.C.); (E.K.)
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20
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Zhou ZY, Deng Y, Wen YL, Cheng YQ, Li KX, Chen HP. Chronic low-grade inflammation is involved in TLR4 knockout-induced spontaneous obesity in aged mice. Biomed Pharmacother 2022; 147:112637. [PMID: 35093760 DOI: 10.1016/j.biopha.2022.112637] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 01/01/2022] [Accepted: 01/12/2022] [Indexed: 02/09/2023] Open
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21
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CD40L-expressing CD4+ T cells prime adipose-derived stromal cells to produce inflammatory chemokines. Cytotherapy 2022; 24:500-507. [DOI: 10.1016/j.jcyt.2022.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 12/21/2021] [Accepted: 01/20/2022] [Indexed: 11/18/2022]
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22
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Negrini TDC, Carlos IZ, Duque C, Caiaffa KS, Arthur RA. Interplay Among the Oral Microbiome, Oral Cavity Conditions, the Host Immune Response, Diabetes Mellitus, and Its Associated-Risk Factors-An Overview. FRONTIERS IN ORAL HEALTH 2022; 2:697428. [PMID: 35048037 PMCID: PMC8757730 DOI: 10.3389/froh.2021.697428] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 08/16/2021] [Indexed: 12/12/2022] Open
Abstract
This comprehensive review of the literature aimed to investigate the interplay between the oral microbiome, oral cavity conditions, and host immune response in Diabetes mellitus (DM). Moreover, this review also aimed to investigate how DM related risk factors, such as advanced age, hyperglycemia, hyperlipidemia, obesity, hypertension and polycystic ovary syndrome (PCOS), act in promoting or modifying specific mechanisms that could potentially perpetuate both altered systemic and oral conditions. We found that poorly controlled glycemic index may exert a negative effect on the immune system of affected individuals, leading to a deficient immune response or to an exacerbation of the inflammatory response exacerbating DM-related complications. Hyperglycemia induces alterations in the oral microbiome since poor glycemic control is associated with increased levels and frequencies of periodontal pathogens in the subgingival biofilm of individuals with DM. A bidirectional relationship between periodontal diseases and DM has been suggested: DM patients may have an exaggerated inflammatory response, poor repair and bone resorption that aggravates periodontal disease whereas the increased levels of systemic pro-inflammatory mediators found in individuals affected with periodontal disease exacerbates insulin resistance. SARS-CoV-2 infection may represent an aggravating factor for individuals with DM. Individuals with DM tend to have low salivary flow and a high prevalence of xerostomia, but the association between prevalence/experience of dental caries and DM is still unclear. DM has also been associated to the development of lesions in the oral mucosa, especially potentially malignant ones and those associated with fungal infections. Obesity plays an important role in the induction and progression of DM. Co-affected obese and DM individuals tend to present worse oral health conditions. A decrease in HDL and, an increase in triglycerides bloodstream levels seem to be associated with an increase on the load of periodontopathogens on oral cavity. Moreover, DM may increase the likelihood of halitosis. Prevalence of impaired taste perception and impaired smell recognition tend to be greater in DM patients. An important interplay among oral cavity microbiome, DM, obesity and hypertension has been proposed as the reduction of nitrate into nitrite, in addition to contribute to lowering of blood pressure, reduces oxidative stress and increases insulin secretion, being these effects desirable for the control of obesity and DM. Women with PCOS tend to present a distinct oral microbial composition and an elevated systemic response to selective members of this microbial community, but the association between oral microbiome, PCOS are DM is still unknown. The results of the studies presented in this review suggest the interplay among the oral microbiome, oral cavity conditions, host immune response and DM and some of the DM associated risk factors exist. DM individuals need to be encouraged and motivated for an adequate oral health care. In addition, these results show the importance of adopting multidisciplinary management of DM and of strengthening physicians-dentists relationship focusing on both systemic and on oral cavity conditions of DM patients.
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Affiliation(s)
- Thais de Cássia Negrini
- Department of Clinical Analysis, School of Pharmaceutical Sciences, São Paulo State University, Araraquara, Brazil
| | - Iracilda Zeppone Carlos
- Department of Clinical Analysis, School of Pharmaceutical Sciences, São Paulo State University, Araraquara, Brazil
| | - Cristiane Duque
- Department of Restorative and Preventive Dentistry, Araçatuba Dental School, São Paulo State University, Araçatuba, Brazil
| | - Karina Sampaio Caiaffa
- Department of Restorative and Preventive Dentistry, Araçatuba Dental School, São Paulo State University, Araçatuba, Brazil
| | - Rodrigo Alex Arthur
- Department of Preventive and Community Dentistry, Dental School, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
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23
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Liu L, Hu J, Wang Y, Lei H, Xu D. The role and research progress of the balance and interaction between regulatory T cells and other immune cells in obesity with insulin resistance. Adipocyte 2021; 10:66-79. [PMID: 33472506 PMCID: PMC7834085 DOI: 10.1080/21623945.2021.1876375] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Metabolic homoeostasis in adipose tissue plays a major role in obesity-related insulin resistance (IR). Regulatory T (Treg) cells have been recorded to regulate metabolic homoeostasis in adipose tissue. However, their specific mechanism is not yet known. This review aims to present the role of Treg cells and other immune cells in obesity-associated IR, focusing on the balance of numbers and functions of Treg cells and other immune cells as well as the crucial role of their interactions in maintaining adipose tissue homoeostasis. Th1 cells, Th17 cells, CD8+ T cells, and pro-inflammatory macrophages mediate the occurrence of obesity and IR by antagonizing Treg cells, while anti-inflammatory dendritic cells, eosinophils and type 2 innate lymphoid cells (ILC2s) regulate the metabolic homoeostasis of adipose tissue by promoting the proliferation and differentiation of Treg cells. γ δ T cells and invariant natural killer T (iNKT) cells have complex effects on Treg cells, and their roles in obesity-associated IR are controversial. The balance of Treg cells and other immune cells can help maintain the metabolic homoeostasis of adipose tissue. Further research needs to explore more specific molecular mechanisms, thus providing more precise directions for the treatment of obesity with IR.
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Affiliation(s)
- Leiling Liu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jiahui Hu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yating Wang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hao Lei
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Danyan Xu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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24
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The Hepatic Stellate Cells (HSTCs) and Adipose-derived Mesenchymal Stem Cells (ASCs) Axis as a Potential Major Driver of Metabolic Syndrome - Novel Concept and Therapeutic Implications. Stem Cell Rev Rep 2021; 18:1417-1422. [PMID: 34822062 PMCID: PMC9033713 DOI: 10.1007/s12015-021-10304-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2021] [Indexed: 11/27/2022]
Abstract
Abstract Herein, we would like to introduce a novel concept for the prevention and treatment of metabolic syndrome, which is based on molecular relationship between liver and adipose tissue. Particularly, we believe, that unravelling the molecular crosstalk between hepatokines and adipokines will allow to better understand the pathophysiology of metabolic diseases and allow to develop novel, effective therapeutic solutions against obesity and metabolic syndrome. Graphical Abstract Inter-organ communication on the level of stem progenitor cells-hepatic stellate cells (HSTCs) and adipose-derived progenitors (ASCs) could represents a key mechanism involved in controlling glucose tolerance as well as insulin sensitivity. ![]()
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25
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Neuro-immune-metabolism: The tripod system of homeostasis. Immunol Lett 2021; 240:77-97. [PMID: 34655659 DOI: 10.1016/j.imlet.2021.10.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 09/30/2021] [Accepted: 10/08/2021] [Indexed: 11/20/2022]
Abstract
Homeostatic regulation of cellular and molecular processes is essential for the efficient physiological functioning of body organs. It requires an intricate balance of several networks throughout the body, most notable being the nervous, immune and metabolic systems. Several studies have reported the interactions between neuro-immune, immune-metabolic and neuro-metabolic pathways. Current review aims to integrate the information and show that neuro, immune and metabolic systems form the triumvirate of homeostasis. It focuses on the cellular and molecular interactions occurring in the extremities and intestine, which are innervated by the peripheral nervous system and for the intestine in particular the enteric nervous system. While the interdependence of neuro-immune-metabolic pathways provides a fallback mechanism in case of disruption of homeostasis, in chronic pathologies of continued disequilibrium, the collapse of one system spreads to the other interacting networks as well. Current review illustrates this domino-effect using diabetes as the main example. Together, this review attempts to provide a holistic picture of the integrated network of neuro-immune-metabolism and attempts to broaden the outlook when devising a scientific study or a treatment strategy.
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26
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Li L, Xia Y, Ji X, Wang H, Zhang Z, Lu P, Ding Q, Wang D, Liu M. MIG/CXCL9 exacerbates the progression of metabolic-associated fatty liver disease by disrupting Treg/Th17 balance. Exp Cell Res 2021; 407:112801. [PMID: 34461107 DOI: 10.1016/j.yexcr.2021.112801] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/21/2021] [Accepted: 08/22/2021] [Indexed: 12/12/2022]
Abstract
CD4+CD25+ regulatory T (Treg) cells and Th17 cells play important roles in the progression of metabolic-associated fatty liver disease (MAFLD). However, the contribution of monokine induced by interferon-gamma (MIG)/CXCL9 to the Treg/Th17 imbalance in MAFLD is only partially understood. In the present study, we detected increased levels of MIG/CXCL9 and a Treg/Th17 imbalance in the setting of metabolic-associated steatohepatitis (MASH). Recombinant adeno-associated virus-mediated gene transfer and silencing of MIG/CXCL9 expression in mice alleviated MASH and increased the Treg/Th17 ratio. Furthermore, the percentage of Th17 cells, but not Treg cells, differentiated from splenic CD4+ T cells was significantly increased by administration of MIG/CXCL9. MIG/CXCL9 also promoted Th17 cell proliferation, and its effects were dose dependent. Levels of phosphorylated c-Jun N-terminal kinase (JNK) decreased dramatically when MIG/CXCL9 was inhibited in a murine MASH model. In cultured Treg cells, phosphorylated JNK levels decreased dose-dependently in response to MIG/CXCL9 inhibition, but increased in cultured Th17 cells. This effect was blocked in the presence of a JNK inhibitor. These findings underline the fundamental importance of MIG/CXCL9 in maintaining the Treg/Th17 balance in MAFLD and provide the foundations for a novel approach to preventing and treating MAFLD.
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Affiliation(s)
- Lili Li
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Yujia Xia
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Xiaoyu Ji
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Zerui Zhang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Panpan Lu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Qiang Ding
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Deqiong Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
| | - Mei Liu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
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27
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Eljaafari A, Pestel J, Le Magueresse-Battistoni B, Chanon S, Watson J, Robert M, Disse E, Vidal H. Adipose-Tissue-Derived Mesenchymal Stem Cells Mediate PD-L1 Overexpression in the White Adipose Tissue of Obese Individuals, Resulting in T Cell Dysfunction. Cells 2021; 10:cells10102645. [PMID: 34685625 PMCID: PMC8534339 DOI: 10.3390/cells10102645] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/20/2021] [Accepted: 09/26/2021] [Indexed: 12/25/2022] Open
Abstract
The PD-L1/PD-1 immune checkpoint axis is the strongest T cell exhaustion inducer. As immune dysfunction occurs during obesity, we analyzed the impact of obesity on PD-L1/PD-1 expression in white adipose tissue (WAT) in mice and in human white adipocytes. We found that PD-L1 was overexpressed in WAT of diet-induced obese mice and was associated with increased expression of PD-1 in visceral but not subcutaneous WAT. Human in vitro cocultures with adipose-tissue-derived mesenchymal stem cells (ASC) and mononuclear cells demonstrated that the presence of ASC harvested from obese WAT (i) enhanced PD-L1 expression as compared with ASC from lean WAT, (ii) decreased Th1 cell cytokine secretion, and (iii) resulted in decreased cytolytic activity towards adipocytes. Moreover, (iv) the implication of PD-L1 in obese ASC-mediated T cell dysfunction was demonstrated through PD-L1 blockade. Finally, (v) conditioned media gathered from these cocultures enhanced PD-L1 expression in freshly differentiated adipocytes, depending on IFNγ. Altogether, our results suggest that PD-L1 is overexpressed in the WAT of obese individuals during IFNγ secretion, leading to T cell dysfunction and notably reduced cytolytic activity. Such a mechanism could shed light on why adipose-tissue-infiltrating viruses, such as SARS-CoV-2, can worsen disease in obese individuals.
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Affiliation(s)
- Assia Eljaafari
- Inserm U1060, University Claude Bernard Lyon 1, INRAE U1397, 69310 Pierre Bénite, France; (J.P.); (B.L.M.-B.); (S.C.); (J.W.); (M.R.); (E.D.); (H.V.)
- CarMeN Laboratory, Centre Hospitalier Lyon Sud, 69310 Pierre Bénite, France
- Direction des Affaires Médicales, Hospices Civils de Lyon (HCL), 69002 Lyon, France
- Correspondence:
| | - Julien Pestel
- Inserm U1060, University Claude Bernard Lyon 1, INRAE U1397, 69310 Pierre Bénite, France; (J.P.); (B.L.M.-B.); (S.C.); (J.W.); (M.R.); (E.D.); (H.V.)
- CarMeN Laboratory, Centre Hospitalier Lyon Sud, 69310 Pierre Bénite, France
| | - Brigitte Le Magueresse-Battistoni
- Inserm U1060, University Claude Bernard Lyon 1, INRAE U1397, 69310 Pierre Bénite, France; (J.P.); (B.L.M.-B.); (S.C.); (J.W.); (M.R.); (E.D.); (H.V.)
- CarMeN Laboratory, Centre Hospitalier Lyon Sud, 69310 Pierre Bénite, France
| | - Stephanie Chanon
- Inserm U1060, University Claude Bernard Lyon 1, INRAE U1397, 69310 Pierre Bénite, France; (J.P.); (B.L.M.-B.); (S.C.); (J.W.); (M.R.); (E.D.); (H.V.)
- CarMeN Laboratory, Centre Hospitalier Lyon Sud, 69310 Pierre Bénite, France
| | - Julia Watson
- Inserm U1060, University Claude Bernard Lyon 1, INRAE U1397, 69310 Pierre Bénite, France; (J.P.); (B.L.M.-B.); (S.C.); (J.W.); (M.R.); (E.D.); (H.V.)
- CarMeN Laboratory, Centre Hospitalier Lyon Sud, 69310 Pierre Bénite, France
| | - Maud Robert
- Inserm U1060, University Claude Bernard Lyon 1, INRAE U1397, 69310 Pierre Bénite, France; (J.P.); (B.L.M.-B.); (S.C.); (J.W.); (M.R.); (E.D.); (H.V.)
- CarMeN Laboratory, Centre Hospitalier Lyon Sud, 69310 Pierre Bénite, France
- Bariatric Surgery Department, Edouard Herriot Hospital, 69003 Lyon, France
| | - Emmanuel Disse
- Inserm U1060, University Claude Bernard Lyon 1, INRAE U1397, 69310 Pierre Bénite, France; (J.P.); (B.L.M.-B.); (S.C.); (J.W.); (M.R.); (E.D.); (H.V.)
- CarMeN Laboratory, Centre Hospitalier Lyon Sud, 69310 Pierre Bénite, France
- Endocrinology Department, Lyon Sud, 69310 Pierre Bénite, France
| | - Hubert Vidal
- Inserm U1060, University Claude Bernard Lyon 1, INRAE U1397, 69310 Pierre Bénite, France; (J.P.); (B.L.M.-B.); (S.C.); (J.W.); (M.R.); (E.D.); (H.V.)
- CarMeN Laboratory, Centre Hospitalier Lyon Sud, 69310 Pierre Bénite, France
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28
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Lefevre C, Chartoire D, Ferraz JC, Verdier T, Pinteur C, Chanon S, Pesenti S, Vieille-Marchiset A, Genestier L, Vidal H, Mey A. Obesity activates immunomodulating properties of mesenchymal stem cells in adipose tissue with differences between localizations. FASEB J 2021; 35:e21650. [PMID: 33993539 DOI: 10.1096/fj.202002046rr] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 04/21/2021] [Accepted: 04/21/2021] [Indexed: 01/02/2023]
Abstract
Mesenchymal stem cells from healthy adipose tissue are adipocytes progenitors with immunosuppressive potential that are used for years in cell therapy. Whether adipose stem cells (ASC) may prevent inflammation in early obesity is not known. To address this question, we performed a kinetic study of high-fat (HF) diet induced obesity in mice to follow the immune regulating functions of adipose stem cells (ASC) isolated from the subcutaneous (SAT) and the visceral adipose tissue (VAT). Our results show that, early in obesity and before inflammation was detected, HF diet durably and differently activated ASC from SAT and VAT. Subcutaneous ASC from HF-fed mice strongly inhibited the proliferation of activated T lymphocytes, whereas visceral ASC selectively inhibited TNFα expression by macrophages and simultaneously released higher concentrations of IL6. These depot specific differences may contribute to the low-grade inflammation that develops with obesity in VAT while inflammation in SAT is delayed. The mechanisms involved differ from those already described for naïve cells activation with inflammatory cytokines and probably engaged metabolic activation. These results evidence that adipose stem cells are metabolic sensors acquiring an obesity-primed immunocompetent state in answer to depot-specific intrinsic features with overnutrition, placing these cells ahead of inflammation in the local dialog with immune cells.
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Affiliation(s)
- Camille Lefevre
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
| | - Dimitri Chartoire
- CRCL, Equipe Labellisée Ligue Contre le Cancer, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Faculté de Médecine Lyon Sud, Université Claude Bernard Lyon I, Oullins Cedex, France
| | - Jose Candido Ferraz
- Department of Physical Education and Sports Science, CAV, Federal University of Pernambuco (UFPE), Vitoria de Santo Antão, Brazil
| | - Thomas Verdier
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
| | - Claudie Pinteur
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
| | - Stéphanie Chanon
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
| | - Sandra Pesenti
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
| | - Aurélie Vieille-Marchiset
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
| | - Laurent Genestier
- CRCL, Equipe Labellisée Ligue Contre le Cancer, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Faculté de Médecine Lyon Sud, Université Claude Bernard Lyon I, Oullins Cedex, France
| | - Hubert Vidal
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
| | - Anne Mey
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
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Zhang S, Gang X, Yang S, Cui M, Sun L, Li Z, Wang G. The Alterations in and the Role of the Th17/Treg Balance in Metabolic Diseases. Front Immunol 2021; 12:678355. [PMID: 34322117 PMCID: PMC8311559 DOI: 10.3389/fimmu.2021.678355] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 06/22/2021] [Indexed: 12/17/2022] Open
Abstract
Chronic inflammation plays an important role in the development of metabolic diseases. These include obesity, type 2 diabetes mellitus, and metabolic dysfunction-associated fatty liver disease. The proinflammatory environment maintained by the innate immunity, including macrophages and related cytokines, can be influenced by adaptive immunity. The function of T helper 17 (Th17) and regulatory T (Treg) cells in this process has attracted attention. The Th17/Treg balance is regulated by inflammatory cytokines and various metabolic factors, including those associated with cellular energy metabolism. The possible underlying mechanisms include metabolism-related signaling pathways and epigenetic regulation. Several studies conducted on human and animal models have shown marked differences in and the important roles of Th17/Treg in chronic inflammation associated with obesity and metabolic diseases. Moreover, Th17/Treg seems to be a bridge linking the gut microbiota to host metabolic disorders. In this review, we have provided an overview of the alterations in and the functions of the Th17/Treg balance in metabolic diseases and its role in regulating immune response-related glucose and lipid metabolism.
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Affiliation(s)
- Siwen Zhang
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Xiaokun Gang
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Shuo Yang
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Mengzhao Cui
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Lin Sun
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Zhuo Li
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Guixia Wang
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China
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Hsu WT, Huang WJ, Chiang BL, Tseng PH. Butyrate modulates adipose-derived stem cells isolated from polygenic obese and diabetic mice to drive enhanced immunosuppression. Cytotherapy 2021; 23:567-581. [PMID: 33875384 DOI: 10.1016/j.jcyt.2021.01.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 12/24/2020] [Accepted: 01/27/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND AIMS Adipose-derived stem cells (ASCs) offer promising therapeutic possibilities for immunomodulation. Butyrate (BA) exerts potent anti-inflammatory effects and exhibits multiple regulatory functionalities in adipose tissue (AT). The authors aimed to explore whether BA modulates ASCs to augment their immunosuppressive capabilities. METHODS The authors examined the potency of BA and ASCs for controlling anti-CD3 plus CD28-stimulated splenocyte proliferation in vitro, both in combination and with pre-treatment. Further, the authors investigated genes specifically upregulated by BA-treated ASCs, which were harvested from ASC-splenocyte co-culture after the removal of floating splenocytes. In addition, the authors investigated the influence of oral BA supplementation on the ex vivo immunosuppressive potency of ASCs from BALB/c and Tsumura, Suzuki, obese, diabetes (TSOD) mice. RESULTS BA enhanced the immunosuppressive potency of ASCs when directly added to ASC-splenocyte co-cultures or via pre-conditioning treatment. The percentages of ASC-induced Foxp3+ regulatory T cells increased, whereas the numbers of ASC-suppressed T helper 17 cells further decreased after BA exposure. The messenger RNA expression levels of inducible nitric oxide (NO) synthase (iNOS), chemokines, IL-10 and amphiregulin in ASCs co-cultured with activated splenocytes were upregulated after incubation with BA. This was accompanied by an amplification of iNOS-inducing cytokines, interferon gamma and tumor necrosis factor alpha in the ASC-splenocyte co-culture, triggering ASCs to produce high NO levels under the influence of BA. Mechanistically, the authors detected BA-mediated acetylated histone H3 in ASCs. BA treatment consistently improved the immunosuppressive potency of ASCs derived from both BALB/c and TSOD mice. CONCLUSIONS The use of BA to counteract metaflammation by restoring the defective immunomodulation of ASCs from dysregulated AT in obese donors is recommended.
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Affiliation(s)
- Wan-Tseng Hsu
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
| | - Wei-Jan Huang
- Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan
| | - Bor-Luen Chiang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ping-Huei Tseng
- Department of Internal Medicine, Division of Gastroenterology, National Taiwan University Hospital, Taipei, Taiwan
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31
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Hatasa M, Yoshida S, Takahashi H, Tanaka K, Kubotsu Y, Ohsugi Y, Katagiri T, Iwata T, Katagiri S. Relationship between NAFLD and Periodontal Disease from the View of Clinical and Basic Research, and Immunological Response. Int J Mol Sci 2021; 22:3728. [PMID: 33918456 PMCID: PMC8038294 DOI: 10.3390/ijms22073728] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/31/2021] [Accepted: 04/01/2021] [Indexed: 12/22/2022] Open
Abstract
Periodontal disease is an inflammatory disease caused by pathogenic oral microorganisms that leads to the destruction of alveolar bone and connective tissues around the teeth. Although many studies have shown that periodontal disease is a risk factor for systemic diseases, such as type 2 diabetes and cardiovascular diseases, the relationship between nonalcoholic fatty liver disease (NAFLD) and periodontal disease has not yet been clarified. Thus, the purpose of this review was to reveal the relationship between NAFLD and periodontal disease based on epidemiological studies, basic research, and immunology. Many cross-sectional and prospective epidemiological studies have indicated that periodontal disease is a risk factor for NAFLD. An in vivo animal model revealed that infection with periodontopathic bacteria accelerates the progression of NAFLD accompanied by enhanced steatosis. Moreover, the detection of periodontopathic bacteria in the liver may demonstrate that the bacteria have a direct impact on NAFLD. Furthermore, Porphyromonas gingivalis lipopolysaccharide induces inflammation and accumulation of intracellular lipids in hepatocytes. Th17 may be a key molecule for explaining the relationship between periodontal disease and NAFLD. In this review, we attempted to establish that oral health is essential for systemic health, especially in patients with NAFLD.
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Affiliation(s)
- Masahiro Hatasa
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
| | - Sumiko Yoshida
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (K.T.); (Y.K.)
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Kenichi Tanaka
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (K.T.); (Y.K.)
| | - Yoshihito Kubotsu
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (K.T.); (Y.K.)
| | - Yujin Ohsugi
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
| | - Takaharu Katagiri
- Department of Biochemistry, Toho University School of Medicine, Tokyo 143-8540, Japan;
- Division of Rheumatology, Department of Internal Medicine, Ohashi Medical Center, Tokyo 153-8515, Japan
| | - Takanori Iwata
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
| | - Sayaka Katagiri
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
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Yu Q, Wang T, Wang F, Yang Y, He C, Yang W, Zhang J, Zou Z. High n-3 fatty acids counteract hyperglycemia-induced insulin resistance in fat-1 mice via pre-adipocyte NLRP3 inflammasome inhibition. Food Funct 2021; 12:230-240. [PMID: 33295913 DOI: 10.1039/d0fo02092c] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Although n-3 polyunsaturated fatty acids (n-3 PUFAs) have potential anti-insulin resistance activity, the mechanism remains largely unknown. In this study, increased glucose resistance, insulin sensitivity, and lower glycemia were observed upon streptozotocin (STZ) treatment in n-3 PUFA-enriched fat-1 mice compared to wild type (WT) mice. Endogenous n-3 PUFAs in fat-1 mice were found to impair hyperglycemia or high glucose level-induced nucleotide-binding domain and leucine-rich repeat pyrin 3 domain (NLRP3) inflammasome activation and inhibit IL-1β secretion in adipose tissues. In addition, endogenous n-3 PUFAs also inhibited high glucose-induced caspase-1 activity and IL-1β secretion in pre-adipocyte-enriched stromal vascular fractions (SVF) isolated from adipose tissues. Furthermore, in 3T3-L1 pre-adipocytes, high levels of glucose induced thioredoxin interacting protein (TXNIP) expression and activated the NLRP3 inflammasome, which was counteracted by docosahexaenoic acid (DHA), the major n-3 PUFA in fat-1 mice, by downregulating TXNIP via the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. Our results suggest that n-3 PUFA-mediated insulin sensitivity is at least partly associated with inflammasome inhibition in pre-adipocytes. Our findings highlight the potential clinical use of dietary n-3 PUFAs in the prevention or intervention of T2D and other NLRP3 inflammasome-driven inflammatory diseases.
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Affiliation(s)
- Qingyao Yu
- College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang 315211, China.
| | - Tiantian Wang
- College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang 315211, China.
| | - Feng Wang
- Department of Laboratory Medicine, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang 315040, China
| | - Yong Yang
- Department of Clinical laboratory, the affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315020, China
| | - Canxia He
- Zhejiang Key Laboratory of Pathophysiology, Medical School, Ningbo University, Ningbo, Zhejiang 315211, China.
| | - Wenge Yang
- College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang 315211, China.
| | - JinJie Zhang
- College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang 315211, China.
| | - Zuquan Zou
- Zhejiang Key Laboratory of Pathophysiology, Medical School, Ningbo University, Ningbo, Zhejiang 315211, China.
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Abdelazeem AH, Abuelsaad ASA, Abdel-Moniem A, Abdel-Gabbar M. Association of metabolic syndrome components with alterations in oxidative stress and cytokines expression. JOURNAL OF TAIBAH UNIVERSITY FOR SCIENCE 2021. [DOI: 10.1080/16583655.2021.2009680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Ahmed H. Abdelazeem
- Biochemistry Department Faculty of Science, Beni-Suef University, Beni Suef, Egypt
| | | | - Adel Abdel-Moniem
- Molecular Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
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Pestel J, Robert M, Corbin S, Vidal H, Eljaafari A. Involvement of glycated albumin in adipose-derived-stem cell-mediated interleukin 17 secreting T helper cell activation. World J Stem Cells 2020; 12:621-632. [PMID: 32843918 PMCID: PMC7415245 DOI: 10.4252/wjsc.v12.i7.621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/19/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Advanced glycation end products (AGE) are a marker of various diseases including diabetes, in which they participate to vascular damages such as retinopathy, nephropathy and coronaropathy. Besides those vascular complications, AGE are involved in altered metabolism in many tissues, including adipose tissue (AT) where they contribute to reduced glucose uptake and attenuation of insulin sensitivity. AGE are known to contribute to type 1 diabetes (T1D) through promotion of interleukin (IL)-17 secreting T helper (Th17) cells.
AIM To investigate whether lean adipose-derived stem cells (ASC) could be able to induce IL-17A secretion, with the help of AGE.
METHODS As we have recently demonstrated that ASC are involved in Th17 cell promotion when they are harvested from obese AT, we used the same co-culture model to measure the impact of glycated human serum albumin (G-HSA) on human lean ASC interacting with blood mononuclear cells. IL-17A and pro-inflammatory cytokine secretion were measured by ELISA. Receptor of AGE (RAGE) together with intercellular adhesion molecule 1 (ICAM-1), human leukocyte Antigen (HLA)-DR, cluster of differentiation (CD) 41, and CD62P surface expressions were measured by cytofluorometry. Anti-RAGE specific monoclonal antibody was added to co-cultures in order to evaluate the role of RAGE in IL-17A production.
RESULTS Results showed that whereas 1% G-HSA only weakly potentiated the production of IL-17A by T cells interacting with ASC harvested from obese subjects, it markedly increased IL-17A, but also interferon gamma and tumor necrosis factor alpha production in the presence of ASC harvested from lean individuals. This was associated with increased expression of RAGE and HLA-DR molecule by co-cultured cells. Moreover, RAGE blockade experiments demonstrated RAGE specific involvement in lean ASC-mediated Th-17 cell activation. Finally, platelet aggregation and ICAM-1, which are known to be induced by AGE, were not involved in these processes.
CONCLUSION Thus, our results demonstrated that G-HSA potentiated lean ASC-mediated IL-17A production in AT, suggesting a new mechanism by which AGE could contribute to T1D pathophysiology.
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Affiliation(s)
- Julien Pestel
- INSERM U1060 CarMen, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
- Faculty of Medicine, Université Claude Bernard Lyon 1, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
| | - Maud Robert
- INSERM U1060 CarMen, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
- Faculty of Medicine, Université Claude Bernard Lyon 1, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
- Department of Surgery in Gastro-enterology, Edouard Herriot Hospital, Lyon 69003, France
| | - Sara Corbin
- Public Health Department, Hospices Civils de Lyon, 1 quai des célestins Lyon 69002, France
| | - Hubert Vidal
- INSERM U1060 CarMen, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
- Faculty of Medicine, Université Claude Bernard Lyon 1, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
| | - Assia Eljaafari
- INSERM U1060 CarMen, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
- Faculty of Medicine, Université Claude Bernard Lyon 1, Batiment CENS-ELI, Centre Hospitalier Lyon Sud, Pierre Bénite 69310, France
- DO-IT Research Team, Hospices Civils de Lyon, 1 quai des célestins, Lyon 69002, France
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Development of novel human in vitro vascularized adipose tissue model with functional macrophages. Cytotechnology 2020; 72:665-683. [PMID: 32524217 PMCID: PMC7547925 DOI: 10.1007/s10616-020-00407-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Accepted: 06/04/2020] [Indexed: 01/16/2023] Open
Abstract
Inflammation has been proven significant factor in development of type 2 diabetes. So far, most of the adipose tissue related research has been performed in animals, mainly rodent models. The relevance of translation of animal results to humans is questionable. However, in vitro model with relevant human cell source, such as human adipose tissue stromal cells (hASC), can be developed and should be utilized for human adipose tissue research. We developed in vitro models of human adipose tissue utilizing hASC, endothelial cells and monocytes/macrophages. By isolating endothelial cells and macrophages from same adipose tissue as hASC, we were able to provide method for constructing personalized models of adipose tissue. With these models, we studied the effect of macrophages on adipogenesis and protein secretion, with and without vasculature. The models were analyzed for immunocytochemical markers, cell number, triglyceride accumulation and protein secretion. We found that lipid accumulation was greater in adipocytes in the presence of macrophages. Interferon gamma increased this difference between adipocyte culture and Adipocyte-Macrophage co-culture. Protein secretion was affected more by macrophages when vasculature was not present compared to the mild effect when vasculature was present. The vascularized adipose model with macrophages is valuable tool for human adipose tissue research, especially for the personalized medicine approaches; for choosing the right treatments and for studying rare medical conditions.
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Quoc Lam B, Shrivastava SK, Shrivastava A, Shankar S, Srivastava RK. The Impact of obesity and diabetes mellitus on pancreatic cancer: Molecular mechanisms and clinical perspectives. J Cell Mol Med 2020; 24:7706-7716. [PMID: 32458441 PMCID: PMC7348166 DOI: 10.1111/jcmm.15413] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 04/24/2020] [Indexed: 01/18/2023] Open
Abstract
The incidence of obesity and type 2 diabetes (T2DM) in the Western world has increased dramatically during the recent decades. According to the American Cancer Society, pancreatic cancer (PC) is the fourth leading cause of cancer‐related death in the United States. The relationship among obesity, T2DM and PC is complex. Due to increase in obesity, diabetes, alcohol consumption and sedentary lifestyle, the mortality due to PC is expected to rise significantly by year 2040. The underlying mechanisms by which diabetes and obesity contribute to pancreatic tumorigenesis are not well understood. Furthermore, metabolism and microenvironment within the pancreas can also modulate pancreatic carcinogenesis. The risk of PC on a population level may be reduced by modifiable lifestyle risk factors. In this review, the interactions of diabetes and obesity to PC development were summarized, and novel strategies for the prevention and treatment of diabetes and PC were discussed.
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Affiliation(s)
- Bao Quoc Lam
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Sushant K Shrivastava
- Department of Pharmaceutics, Indian Institute of Technology, Banaras Hindu University, Varanasi, UP, India
| | - Anju Shrivastava
- Department of Oncology, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA
| | - Sharmila Shankar
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.,Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.,Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA
| | - Rakesh K Srivastava
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.,Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA
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Vyas KS, Bole M, Vasconez HC, Banuelos JM, Martinez-Jorge J, Tran N, Lemaine V, Mardini S, Bakri K. Profile of Adipose-Derived Stem Cells in Obese and Lean Environments. Aesthetic Plast Surg 2019; 43:1635-1645. [PMID: 31267153 DOI: 10.1007/s00266-019-01397-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Accepted: 05/04/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND With the demand for stem cells in regenerative medicine, new methods of isolating stem cells are highly sought. Adipose tissue is a readily available and non-controversial source of multipotent stem cells that carries a low risk for potential donors. However, elevated donor body mass index has been associated with an altered cellular microenvironment and thus has implications for stem cell efficacy in recipients. This review explored the literature on adipose-derived stem cells (ASCs) and the effect of donor obesity on cellular function. METHODS A review of published articles on obesity and ASCs was conducted with the PubMed database and the following search terms: obesity, overweight, adipose-derived stem cells and ASCs. Two investigators screened and reviewed the relevant abstracts. RESULTS There is agreement on reduced ASC function in response to obesity in terms of angiogenic differentiation, proliferation, migration, viability, and an altered and inflammatory transcriptome. Osteogenic differentiation and cell yield do not show reasonable agreement. Weight loss partially rescues some of the aforementioned features. CONCLUSIONS Generally, obesity reduces ASC qualities and may have an effect on the therapeutic value of ASCs. Because weight loss and some biomolecules have been shown to rescue these qualities, further research should be conducted on methods to return obese-derived ASCs to baseline. LEVEL V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors- www.springer.com/00266.
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Affiliation(s)
- Krishna S Vyas
- Division of Plastic Surgery, Department of Surgery, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA.
| | - Madhav Bole
- Division of Orthopaedic Surgery, London Health Sciences Centre, University Hospital, 339 Windermere Rd., London, ON, N6A 5A5, Canada
| | - Henry C Vasconez
- Division of Plastic Surgery, University of Kentucky, Lexington, KY, USA
| | - Joseph M Banuelos
- Division of Plastic Surgery, Department of Surgery, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA
| | - Jorys Martinez-Jorge
- Division of Plastic Surgery, Department of Surgery, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA
| | - Nho Tran
- Division of Plastic Surgery, Department of Surgery, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA
| | - Valerie Lemaine
- Division of Plastic Surgery, Department of Surgery, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA
| | - Samir Mardini
- Division of Plastic Surgery, Department of Surgery, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA
| | - Karim Bakri
- Division of Plastic Surgery, Department of Surgery, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA
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Vorotnikov AV, Stafeev IS, Menshikov MY, Shestakova MV, Parfyonova YV. Latent Inflammation and Defect in Adipocyte Renewal as a Mechanism of Obesity-Associated Insulin Resistance. BIOCHEMISTRY (MOSCOW) 2019; 84:1329-1345. [DOI: 10.1134/s0006297919110099] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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IL-17A contributes to propagation of inflammation but does not impair adipogenesis and/or insulin response, in adipose tissue of obese individuals. Cytokine 2019; 126:154865. [PMID: 31629101 DOI: 10.1016/j.cyto.2019.154865] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 09/24/2019] [Accepted: 09/25/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Adipose tissue is infiltrated with various immune cells, including Th17 lymphocytes and monocytes/macrophages, in obese individuals. We have previously demonstrated the role of obese adipose-derived stem cells (ob-ASC) and adipocytes (AD) in the mediation of inflammation through promotion of Th17 cells and activation of monocytes. Such an inflammation resulted in impaired ob-ASC adipogenesis and AD insulin response. In the present study, we investigated the role of IL-17A in the impairment of these functions. METHODS With this aim, we used Secukinumab, a potent human anti-IL17A monoclonal antibody which has been approved for the treatment of some IL-17A related inflammatory diseases, notably Psoriasis. This antibody was added or not to phytohemagglutinin A-activated co-cultures of ob-ASC and mononuclear cells. The conditioning media of those co-cultures were harvested and added to AD ongoing differentiation from ob-ASC. Adipogenesis, insulin sensitivity and secretion of inflammatory cytokines were then measured using qRT-PCR, Western blots and ELISAs, respectively. RESULTS Surprisingly, we did not observe any direct effect of IL-17A on ob-ASC adipogenesis, despite sensitivity of ob-ASC to IL-17A. Moreover, IL-17A blockade, with the help of Secukinumab, did not lead to the recovery of adipogenesis and insulin response, when these functions were impaired by the presence of an inflammatory conditioning medium. However, the up-regulation of IL6 and IL1B mRNA expression by AD submitted to inflammatory conditioning medium was inhibited in the presence of Secukinumab, which indicates that IL-17A may play a role in the propagation of inflammation towards AD. IN CONCLUSION we show herein that IL-17A does not play a major role in the impairment of adipogenesis and/or insulin resistance mediated by an inflammatory environment, but contributes to the propagation of inflammation in human obese adipose tissues. This suggests a beneficial effect of anti-IL17A mAb in inflammatory pathologies, where obesity contributes to poorer response to biologic treatments.
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6-Bromoindirubin-3′-Oxime Suppresses LPS-Induced Inflammation via Inhibition of the TLR4/NF-κB and TLR4/MAPK Signaling Pathways. Inflammation 2019; 42:2192-2204. [DOI: 10.1007/s10753-019-01083-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Qi Y, Ma J, Li S, Liu W. Applicability of adipose-derived mesenchymal stem cells in treatment of patients with type 2 diabetes. Stem Cell Res Ther 2019; 10:274. [PMID: 31455405 PMCID: PMC6712852 DOI: 10.1186/s13287-019-1362-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is mainly characterized by insulin resistance (IR) and impaired insulin secretion. The chronic inflammatory process contributed to IR and could also hamper pancreatic β cell function. However, currently applied treatment cannot reverse β cell damage or alleviate inflammation. Mesenchymal stem cells (MSCs), the cell-based therapy for their self-renewable, differentiation potential, and immunosuppressive properties, have been demonstrated in displaying therapeutic effects in T2DM. Adipose-derived MSCs (AD-MSCs) attracted more attention due to less harvested inconvenience and ethical issues commonly accompany with bone marrow-derived MSCs (BM-MSCs) and fetal annex-derived MSCs. Both AD-MSC therapy studies and mechanism explorations in T2DM animals presented that AD-MSCs could translate to clinical application. However, hyperglycemia, hyperinsulinemia, and metabolic disturbance in T2DM are crucial for impairment of AD-MSC function, which may limit the therapeutical effects of MSCs. This review focuses on the outcomes and the molecular mechanisms of MSC therapies in T2DM which light up the hope of AD-MSCs as an innovative strategy to cure T2DM.
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Affiliation(s)
- Yicheng Qi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, RenJi Hospital, School of Medicine, Shanghai Jiaotong University, 160# Pujian Road, Pudong, Shanghai, 200127, China
| | - Jing Ma
- Division of Endocrinology and Metabolism, Department of Internal Medicine, RenJi Hospital, School of Medicine, Shanghai Jiaotong University, 160# Pujian Road, Pudong, Shanghai, 200127, China
| | - Shengxian Li
- Division of Endocrinology and Metabolism, Department of Internal Medicine, RenJi Hospital, School of Medicine, Shanghai Jiaotong University, 160# Pujian Road, Pudong, Shanghai, 200127, China
| | - Wei Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, RenJi Hospital, School of Medicine, Shanghai Jiaotong University, 160# Pujian Road, Pudong, Shanghai, 200127, China.
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Abstract
Adipose stem cells (ASCs) are the basis of procedures intended for tissue regeneration. These cells are heterogeneous, owing to various factors, including the donor age, sex, body mass index, and clinical condition; the isolation procedure (liposuction or fat excision); the place from where the cells were sampled (body site and depth of each adipose depot); culture surface; type of medium (whether supplemented with fetal bovine serum or xeno-free), that affect the principal phenotypic features of ASCs. The features related to ASCs heterogeneity are relevant for the success of therapeutic procedures; these features include proliferation capacity, differentiation potential, immunophenotype, and the secretome. These are important characteristics for the success of regenerative tissue engineering, not only because of their effects upon the reconstruction and healing exerted by ASCs themselves, but also because of the paracrine signaling of ASCs and its impact on recipient tissues. Knowledge of sources of heterogeneity will be helpful in the standardization of ASCs-based procedures. New avenues of research could include evaluation of the effects of the use of more homo1geneous ASCs for specific purposes, the study of ASCs-recipient interactions in heterologous cell transplantation, and the characterization of epigenetic changes in ASCs, as well as investigations of the effect of the metabolome upon ASCs behavior in culture.
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43
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Machacek M, Saunders H, Zhang Z, Tan EP, Li J, Li T, Villar MT, Artigues A, Lydic T, Cork G, Slawson C, Fields PE. Elevated O-GlcNAcylation enhances pro-inflammatory Th17 function by altering the intracellular lipid microenvironment. J Biol Chem 2019; 294:8973-8990. [PMID: 31010828 PMCID: PMC6552434 DOI: 10.1074/jbc.ra119.008373] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 04/11/2019] [Indexed: 01/09/2023] Open
Abstract
Chronic, low-grade inflammation increases the risk for atherosclerosis, cancer, and autoimmunity in diseases such as obesity and diabetes. Levels of CD4+ T helper 17 (Th17) cells, which secrete interleukin 17A (IL-17A), are increased in obesity and contribute to the inflammatory milieu; however, the relationship between signaling events triggered by excess nutrient levels and IL-17A-mediated inflammation is unclear. Here, using cytokine, quantitative real-time PCR, immunoprecipitation, and ChIP assays, along with lipidomics and MS-based approaches, we show that increased levels of the nutrient-responsive, post-translational protein modification, O-GlcNAc, are present in naive CD4+ T cells from a diet-induced obesity murine model and that elevated O-GlcNAc levels increase IL-17A production. We also found that increased binding of the Th17 master transcription factor RAR-related orphan receptor γ t variant (RORγt) at the IL-17 gene promoter and enhancer, as well as significant alterations in the intracellular lipid microenvironment, elevates the production of ligands capable of increasing RORγt transcriptional activity. Importantly, the rate-limiting enzyme of fatty acid biosynthesis, acetyl-CoA carboxylase 1 (ACC1), is O-GlcNAcylated and necessary for production of these RORγt-activating ligands. Our results suggest that increased O-GlcNAcylation of cellular proteins may be a potential link between excess nutrient levels and pathological inflammation.
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Affiliation(s)
- Miranda Machacek
- From the Departments of Pathology and Laboratory Medicine.,Biochemistry and Molecular Biology, and
| | - Harmony Saunders
- From the Departments of Pathology and Laboratory Medicine.,Biochemistry and Molecular Biology, and
| | | | | | - Jibiao Li
- Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160 and
| | - Tiangang Li
- Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160 and
| | | | | | - Todd Lydic
- the Department of Physiology, Collaborative Mass Spectrometry Core, Michigan State University, East Lansing, Michigan 48824
| | - Gentry Cork
- From the Departments of Pathology and Laboratory Medicine.,Biochemistry and Molecular Biology, and
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44
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Chehimi M, Ward R, Pestel J, Robert M, Pesenti S, Bendridi N, Michalski MC, Laville M, Vidal H, Eljaafari A. Omega-3 Polyunsaturated Fatty Acids Inhibit IL-17A Secretion through Decreased ICAM-1 Expression in T Cells Co-Cultured with Adipose-Derived Stem Cells Harvested from Adipose Tissues of Obese Subjects. Mol Nutr Food Res 2019; 63:e1801148. [PMID: 30848861 DOI: 10.1002/mnfr.201801148] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 02/22/2019] [Indexed: 12/12/2022]
Abstract
SCOPE Obese adipose tissue (AT) is infiltrated by inflammatory immune cells including IL-17A-producing-T (Th17) cells. It has been previously demonstrated that adipose-derived stem cells from obese (ob-ASCs), but not lean AT promote Th17 cells. Because n-3 PUFAs are known to inhibit obese AT inflammation, it is tested here whether they could inhibit ob-ASC-mediated IL-17A secretion. METHODS AND RESULTS The n-3 PUFA precursor, alpha-linolenic acid (ALA), or its derivatives, eicosapentaenoic, or docosahexaenoic acid, is added to co-cultures of human ob-ASCs and mononuclear cells (MNCs). All three inhibited IL-17A, but not IL-1β, IL-6, nor TNFα secretion. As a control, palmitic acid (PA), a saturated fatty acid, did not inhibit IL-17A secretion. ALA also inhibited IL-17A secretion mediated by adipocytes differentiated from ob-ASCs. Toll-like-receptor 4 is shown to be involved in ob-ASC-mediated-IL-17A secretion, and to be inhibited by ALA, together with Cyclo-Oxygenase-2 and Signal-Transducer-and-Activator-of-transcription-3. In addition, ALA down-regulated Intercellular-Adhesion-Molecule-1 (ICAM-1) expression in both monocytes and ASCs, which resulted in decreased interactions between ob-ASCs and MNCs, and inhibition of IL-17A secretion. CONCLUSION It is demonstrated herein that ALA inhibits Th17 cell promotion, through decreased ICAM-1expression in both ob-ASCs and monocytes. This novel mechanism may contribute to explain the beneficial effects of n-3 PUFA in IL-17A-related inflammatory pathologies.
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Affiliation(s)
- Marwa Chehimi
- INSERM U 1060-CarMen, University Claude Bernard Lyon I, 165 Chemin du Grand Revoyet, 69310, Pierre Bénite, France
| | - Robert Ward
- Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Old Main Hill, Logan, Utah, 84322, USA
| | - Julien Pestel
- INSERM U 1060-CarMen, University Claude Bernard Lyon I, 165 Chemin du Grand Revoyet, 69310, Pierre Bénite, France
| | - Maud Robert
- Department of Surgery in Gastro-enterology, Edouard Herriot Hospital, 1 place d'Arsonval, 69003, Lyon, France
| | - Sandra Pesenti
- INSERM U 1060-CarMen, University Claude Bernard Lyon I, 165 Chemin du Grand Revoyet, 69310, Pierre Bénite, France
| | - Nadia Bendridi
- INSERM U 1060-CarMen, University Claude Bernard Lyon I, 165 Chemin du Grand Revoyet, 69310, Pierre Bénite, France
| | - Marie-Caroline Michalski
- INSERM U 1060-CarMen, University Claude Bernard Lyon I, 165 Chemin du Grand Revoyet, 69310, Pierre Bénite, France
| | - Martine Laville
- INSERM U 1060-CarMen, University Claude Bernard Lyon I, 165 Chemin du Grand Revoyet, 69310, Pierre Bénite, France.,Department of Nutrition, South Lyon Hospital, Hospices Civils de Lyon, 165 Chemin du Grand Revoyet, 69310, Pierre Bénite, France
| | - Hubert Vidal
- INSERM U 1060-CarMen, University Claude Bernard Lyon I, 165 Chemin du Grand Revoyet, 69310, Pierre Bénite, France
| | - Assia Eljaafari
- INSERM U 1060-CarMen, University Claude Bernard Lyon I, 165 Chemin du Grand Revoyet, 69310, Pierre Bénite, France.,Research DO-IT Team, Hospices Civils de Lyon, Faculte de Medecine Lyon Sud, Inserm U1060-CarMen, 165 Chemin du Grand Revoyet, 69310, Pierre Bénite, France
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45
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Abstract
Adipose-derived stem cells (ADSC) have come to be viewed as a ubiquitous solution for aesthetic and reconstructive problems involving loss of tissue volume and age or radiation-induced loss of tissue pliability and vascularity. As the theoretical potential of "stem cell therapy" has captured the public imagination, so the commercial potential of novel therapies is being exploited beyond scientifically sound, hypothesis-driven paradigms and in the absence of evidence establishing clinical efficacy and safety. Moreover, with variations in methods of isolation, manipulation, and reintroduction described, it is unclear how the practitioner with an interest in ADSC can harness the clinical potential in reproducible and scientifically measurable ways. This Continuing Medical Education (CME) article presents a summary of our understanding of what ADSC are, their utility within the field of aesthetic surgery, and the current and future directions for adipose stem cell research.
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Affiliation(s)
- Graeme Ewan Glass
- Attending Plastic and Craniofacial Surgeon, Department of Surgery, Sidra Medicine, Doha, Qatar; and Weill Cornell Medical College, Ar-Rayyan, Qatar
| | - Patrizia Ferretti
- Professor of Regenerative Biology, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
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46
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Chehimi M, Ward R, Vidal H, Eljaafari A. Les acides gras poly-insaturés de type oméga 3 inhibent la production d’IL-17A médiée par les cellules souches du tissu adipeux, en diminuant l’expression d’ICAM-1, chez le sujet obèse. NUTR CLIN METAB 2019. [DOI: 10.1016/j.nupar.2019.01.282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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High-Fat Diet Alters Immunogenic Properties of Circulating and Adipose Tissue-Associated Myeloid-Derived CD45 +DDR2 + Cells. Mediators Inflamm 2019; 2019:1648614. [PMID: 31015794 PMCID: PMC6421777 DOI: 10.1155/2019/1648614] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 01/04/2019] [Accepted: 01/15/2019] [Indexed: 12/26/2022] Open
Abstract
Chronic inflammation is evident in the adipose tissue and periphery of patients with obesity, as well as mouse models of obesity. T cell subsets in obese adipose tissue are skewed towards Th1- and Th17-associated phenotypes and their secreted cytokines contribute to obesity-associated inflammation. Our lab recently identified a novel, myeloid-derived CD45+DDR2+ cell subset that modulates T cell activity. The current study sought to determine how these myeloid-derived CD45+DDR2+ cells are altered in the adipose tissue and peripheral blood of preobese mice and how this population modulates T cell activity. C57BL/6 mice were fed with a diet high in milkfat (60%·kcal, HFD) ad libitum until a 20% increase in total body weight was reached, and myeloid-derived CD45+DDR2+ cells and CD4+ T cells in visceral adipose tissue (VAT), mammary gland-associated adipose tissue (MGAT), and peripheral blood (PB) were phenotypically analyzed. Also analyzed was whether mediators from MGAT-primed myeloid-derived CD45+DDR2+ cells stimulate normal CD4+ T cell cytokine production. A higher percentage of myeloid-derived CD45+DDR2+ cells expressed the activation markers MHC II and CD80 in both VAT and MGAT of preobese mice. CD4+ T cells were preferentially skewed towards Th1- and Th17-associated phenotypes in the adipose tissue and periphery of preobese mice. In vitro, MGAT from HFD-fed mice triggered myeloid-derived CD45+DDR2+ cells to induce CD4+ T cell IFN-γ and TNF-α production. Taken together, this study shows that myeloid-derived CD45+DDR2+ cells express markers of immune activation and suggests that they play an immune modulatory role in the adipose tissue of preobese mice.
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48
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Van Herck MA, Weyler J, Kwanten WJ, Dirinck EL, De Winter BY, Francque SM, Vonghia L. The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity. Front Immunol 2019; 10:82. [PMID: 30787925 PMCID: PMC6372559 DOI: 10.3389/fimmu.2019.00082] [Citation(s) in RCA: 175] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 01/11/2019] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) constitutes a spectrum of disease states characterized by hepatic steatosis and is closely associated to obesity and the metabolic syndrome. In non-alcoholic steatohepatitis (NASH), additionally, inflammatory changes and hepatocellular damage are present, representing a more severe condition, for which the treatment is an unmet medical need. Pathophysiologically, the immune system is one of the main drivers of NAFLD progression and other obesity-related comorbidities, and both the innate and adaptive immune system are involved. T cells form the cellular component of the adaptive immune system and consist of multiple differentially active subsets, i.e., T helper (Th) cells, regulatory T (Treg) cells, and cytotoxic T (Tc) cells, as well as several innate T-cell subsets. This review focuses on the role of these T-cell subsets in the pathogenesis of NAFLD, as well as the association with obesity and type 2 diabetes mellitus, reviewing the available evidence from both animal and human studies. Briefly, Th1, Th2, Th17, and Th22 cells seem to have an attenuating effect on adiposity. Th2, Th22, and Treg cells seem to decrease insulin resistance, whereas Th1, Th17, and Tc cells have an aggravating effect. Concerning NAFLD, both Th22 and Treg cells appear to have an overall tempering effect, whereas Th17 and Tc cells seem to induce more liver damage and fibrosis progression. The evidence regarding the role of the innate T-cell subsets is more controversial and warrants further exploration.
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Affiliation(s)
- Mikhaïl A Van Herck
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Jonas Weyler
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Wilhelmus J Kwanten
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Eveline L Dirinck
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Antwerp, Belgium
| | - Benedicte Y De Winter
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium
| | - Sven M Francque
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Luisa Vonghia
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
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49
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Stafeev I, Podkuychenko N, Michurina S, Sklyanik I, Panevina A, Shestakova E, Yah'yaev K, Fedenko V, Ratner E, Vorotnikov A, Menshikov M, Yashkov Y, Parfyonova Y, Shestakova M. Low proliferative potential of adipose-derived stromal cells associates with hypertrophy and inflammation in subcutaneous and omental adipose tissue of patients with type 2 diabetes mellitus. J Diabetes Complications 2019; 33:148-159. [PMID: 30482492 DOI: 10.1016/j.jdiacomp.2018.10.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/25/2018] [Accepted: 10/16/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Obesity and type 2 diabetes mellitus (T2DM) are among the most important morbidity factors. In this study we tested the hypothesis that low proliferative potential of adipose derived stromal cells (ADSC) associates with reduced formation of new fat depots, excess accumulation of fat in the functional adipocytes and their hypertrophy, resulting in fat inflammation and insulin resistance. METHODS We screened two groups of obese patients with or without T2DM, matched for BMI, age, and duration of obesity to test the hypothesis that hypertrophy and decreased renewal of adipocytes may underlie transition from obesity to T2DM. All patients were matched for carbohydrate metabolism (fasting blood glucose level, glycated hemoglobin, HOMA-IR index and M-index). The subcutaneous and omental fat tissue biopsies were obtained during bariatric surgery from obese individuals with or without T2DM. The morphology and immunophenotype of subcutaneous and omental fat was assessed in frozen tissue sections. ADSC were isolated from both types of fat tissue biopsies and screened for morphology, proliferative potential and inflammatory status. RESULTS The non-diabetic patients had normal carbohydrate metabolism and moderate insulin resistance measured by HOMA-IR and hyperinsulinemic clamp (M-index), while T2DM patients were extremely insulin resistant by both indexes. The average size of diabetic adipocytes was higher than that of non-diabetic in both subcutaneous and omental fat tissues, indicating adipocyte hypertrophy in T2DM. Both these tissues contained higher level of macrophage infiltration and increased M1-like to M2-like ratio of macrophage subpopulations, suggesting increased fat inflammation in T2DM. This was confirmed by increased activatory phosphorylation of stress-induced JNK1/2 in diabetic ADSC. CONCLUSION These results suggest that blunted proliferation and increased hypertrophy of diabetic ADSC may lead to reduced insulin sensitivity via increased inflammation mediated by M1 macrophages and JNK1/2 pathway.
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Affiliation(s)
- I Stafeev
- National Medical Research Centre for Cardiology, Moscow, Russia; M.V. Lomonosov Moscow State University, Moscow, Russia; Endocrinology Research Centre, Moscow, Russia.
| | - N Podkuychenko
- National Medical Research Centre for Cardiology, Moscow, Russia; M.V. Lomonosov Moscow State University, Moscow, Russia; Endocrinology Research Centre, Moscow, Russia
| | - S Michurina
- National Medical Research Centre for Cardiology, Moscow, Russia; M.V. Lomonosov Moscow State University, Moscow, Russia
| | - I Sklyanik
- Endocrinology Research Centre, Moscow, Russia
| | - A Panevina
- Endocrinology Research Centre, Moscow, Russia
| | | | - K Yah'yaev
- Central Clinical Hospital #1 of LLC Russian Railways, Moscow, Russia
| | - V Fedenko
- V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Moscow, Russia
| | - E Ratner
- National Medical Research Centre for Cardiology, Moscow, Russia; Endocrinology Research Centre, Moscow, Russia
| | - A Vorotnikov
- National Medical Research Centre for Cardiology, Moscow, Russia
| | - M Menshikov
- National Medical Research Centre for Cardiology, Moscow, Russia
| | - Y Yashkov
- V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Moscow, Russia
| | - Ye Parfyonova
- National Medical Research Centre for Cardiology, Moscow, Russia; M.V. Lomonosov Moscow State University, Moscow, Russia
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50
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PDGF enhances the protective effect of adipose stem cell-derived extracellular vesicles in a model of acute hindlimb ischemia. Sci Rep 2018; 8:17458. [PMID: 30514962 PMCID: PMC6279818 DOI: 10.1038/s41598-018-36143-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 11/09/2018] [Indexed: 12/14/2022] Open
Abstract
We previously have shown that platelet-derived growth factor (PDGF) modulates the biological activity of extracellular vesicles released by adipose-derived mesenchymal stem cells (ASC-EVs). ASC-EVs may interact with blood and vessel cells by transferring proteins and nucleic acids and regulate their functions. In this study, we investigated immunomodulatory activity and protection from acute hindlimb ischemia of EVs released by PDGF-stimulated ASC (PDGF-EVs). PDGF treatment of ASC changed protein and RNA composition of released EVs by enhancing the expression of anti-inflammatory and immunomodulatory factors. In vitro, control EVs (cEVs) derived from non-stimulated ASC increased the secretion of both the IL-1b, IL-17, IFNγ, TNFα pro-inflammatory factors and the IL-10 anti-inflammatory factor, and enhanced the in vitro peripheral blood mononuclear cell (PBMC) adhesion on endothelium. In contrast, PDGF-EVs enhanced IL-10 secretion and induced TGF-β1 secretion by PBMC. Moreover, PDGF-EVs stimulated the formation of T regulatory cells. In vivo, PDGF-EVs protected muscle tissue from acute ischemia, reduced infiltration of inflammatory cells and increased T regulatory cell infiltration in respect to cEVs. Our results suggest that PDGF-EVs are enriched in anti-inflammatory and immunomodulatory factors and induced in PBMC an enhanced production of IL-10 and TGF-β1 resulting in protection of muscle from acute ischemia in vivo.
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