scholarly journals CXCL2 Impairs Functions of Bone Marrow Mesenchymal Stem Cells and Can Serve as a Serum Marker in High-Fat Diet-Fed Rats

2021 ◽  
Vol 9 ◽  
Author(s):  
Jianhai Bi ◽  
Qiuchen Li ◽  
Zhigang Yang ◽  
Lei Cai ◽  
Tao Lv ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Inflammatory Cytokines ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Serum Marker ◽  
Cytokine Signaling ◽  
Low Grade ◽  
High Fat

In modern society excessive consumption of a high-fat diet (HFD) is a significant risk factor for many diseases such as diabetes, osteoarthritis and certain cancers. Resolving cellular and molecular mechanisms underlying HFD-associated disorders is of great importance to human health. Mesenchymal stem cells (MSCs) are key players in tissue homeostasis and adversely affected by prolonged HFD feeding. Low-grade systemic inflammation induced by HFD is characterized by increased levels of pro-inflammatory cytokines and alters homeostasis in many organs. However, whether, which and how HFD associated inflammatory cytokines impair MSCs remain unclear. Here we demonstrated that HFD induced serum cytokines disturbances, especially a continuous elevation of serum CXCL2 level in rats. Coincidentally, the differentially expressed genes (DEGs) of bone marrow MSCs (BMSCs) which functions were impaired in HFD rats were enriched in cytokine signaling. Further mechanism analysis revealed that CXCL2 treatment in vitro suppresses the adipogenic potential of BMSCs via Rac1 activation, and promoted BMSC migration and senescence by inducing over-production of ELMO1 and reactive oxygen species (ROS) respectively. Moreover, we found that although glycolipid metabolism indicators can be corrected, the CXCL2 elevation and BMSC dysfunctions cannot be fully rescued by diet correction and anti-inflammatory aspirin treatment, indicating the long-lasting deleterious effects of HFD on serum CXCL2 levels and BMSC functions. Altogether, our findings identify CXCL2 as an important regulator in BMSCs functions and may serve as a serum marker to indicate the BMSC dysfunctions induced by HFD. In addition, our findings underscore the intricate link among high-fat intake, chronic inflammation and BMSC dysfunction which may facilitate development of protective strategies for HFD associated diseases.

scholarly journals Interleukin-6 Knockout Inhibits Senescence of Bone Mesenchymal Stem Cells in High-Fat Diet-Induced Bone Loss

2021 ◽  
Vol 11 ◽  
Author(s):  
Yujue Li ◽  
Lingyun Lu ◽  
Ying Xie ◽  
Xiang Chen ◽  
Li Tian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Bone Loss ◽  
Interleukin 6 ◽  
High Fat Diet ◽  
Cell Senescence ◽  
Low Grade ◽  
High Fat ◽  
Bone Mesenchymal Stem Cells

Obesity, a chronic low-grade inflammatory state, not only promotes bone loss, but also accelerates cell senescence. However, little is known about the mechanisms that link obesity, bone loss, and cell senescence. Interleukin-6 (IL-6), a pivotal inflammatory mediator increased during obesity, is a candidate for promoting cell senescence and an important part of senescence-associated secretory phenotype (SASP). Here, wild type (WT) and (IL-6 KO) mice were fed with high-fat diet (HFD) for 12 weeks. The results showed IL-6 KO mice gain less weight on HFD than WT mice. HFD induced trabecular bone loss, enhanced expansion of bone marrow adipose tissue (BMAT), increased adipogenesis in bone marrow (BM), and reduced the bone formation in WT mice, but it failed to do so in IL-6 KO mice. Furthermore, IL-6 KO inhibited HFD-induced clone formation of bone marrow cells (BMCs), and expression of senescence markers (p53 and p21). IL-6 antibody inhibited the activation of STAT3 and the senescence of bone mesenchymal stem cells (BMSCs) from WT mice in vitro, while rescued IL-6 induced senescence of BMSCs from IL-6 KO mice through the STAT3/p53/p21 pathway. In summary, our data demonstrated that IL-6 KO may maintain the balance between osteogenesis and adipogenesis in BM, and restrain senescence of BMSCs in HFD-induced bone loss.

scholarly journals Metabolic and Pancreatic Effects of Bone Marrow Mesenchymal Stem Cells Transplantation in Mice Fed High-Fat Diet

PLoS ONE ◽  
2015 ◽  
Vol 10 (4) ◽  
pp. e0124369 ◽  
Author(s):  
Patricia de Godoy Bueno ◽  
Juliana Navarro Ueda Yochite ◽  
Graziela Fernanda Derigge-Pisani ◽  
Kelen Cristina Ribeiro Malmegrim de Farias ◽  
Lucimar Retto da Silva de Avó ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
High Fat Diet ◽  
High Fat ◽  
Marrow Mesenchymal Stem Cells ◽  
Stem Cells Transplantation

A High-Fat Diet Increases IL-1, IL-6, and TNF-α Production by Increasing NF-κB and Attenuating PPAR-γ Expression in Bone Marrow Mesenchymal Stem Cells

Inflammation ◽  
2012 ◽  
Vol 36 (2) ◽  
pp. 379-386 ◽  
Author(s):  
Mayara Cortez ◽  
Luciana Simão Carmo ◽  
Marcelo Macedo Rogero ◽  
Primavera Borelli ◽  
Ricardo Ambrósio Fock
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
High Fat Diet ◽  
High Fat ◽  
Ppar Γ ◽  
Tnf Α ◽  
Marrow Mesenchymal Stem Cells

High-carbohydrate, High-fat Diet-induced Hyperlipidemia Hampers the Differentiation Balance of Bone Marrow Mesenchymal Stem Cells by Suppressing Autophagy via the AMPK/ mTOR Pathway in Rat Models

2020 ◽  
Author(s):  
Zhenzhen Shang ◽  
Ting Zhang ◽  
Mengyang Jiang ◽  
Xiaojie Yin ◽  
Hui Qiang Sun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Bone Metabolism ◽  
High Fat Diet ◽  
High Fat ◽  
Rat Models ◽  
High Carbohydrate ◽  
Marrow Mesenchymal Stem Cells

Abstract Background: Disorders of bone metabolism caused by hyperlipidemia is not conducive to osseointegration of implants. Autophagy, an evolutionarily conserved, lysosomal-mediated degradation process, is indispensable for bone homeostasis, its effects on hyperlipidemia-induced osteoporosis remain to be elucidated. The objective of this study was to determine whether autophagy affects bone metabolism and implant osseointegration through regulating the function of bone marrow mesenchymal stem cells (BMMSCs) in rats with hyperlipidemia and to confirm signaling pathway involved in the regulation of autophagy. Methods: Hyperlipidemia models were established through a long-term high-carbohydrate, high-fat diet in 6-week-old male Sprague-Dawley rats. The impact of hyperlipidemia on bone metabolism and early osseointegration of implants was explored by the methods including serum biochemical detection, micro-computed tomography and bone morphology detection. Biological properties and autophagy levels of BMMSCs were also determined. Further, we determined if autophagy was involved in bone metabolism changes resulting from high-fat diet by focusing on the lineage differentiation of BMMSCs. The signaling pathway involved in the regulation of autophagy was also explored.Results: The high-carbohydrate, high-fat diet (HCHF) was given to the rats for seven months aggravated bone loss in the cancellous bone and reduced osseointegration of implants. BMMSCs from hyperlipidemia rats exhibited decreased osteogenesis, increased adipogenesis and decreased autophagic activity compared with regular diet (RD) BMMSCs. Rapamycin treatment restored the impaired osteogenic differentiation and inhibited the adipogenic differentiation of HCHF-BMMSCs through the activation of autophagy. Further, AMPK/mTOR signaling pathways was related to the impairment of autophagy of HCHF-BMMSCs. Conclusions: Our data indicate that long-term high-carbohydrate, high-fat diet-induced hyperlipidemia hampers the differentiation balance of bone marrow mesenchymal stem cells by suppressing autophagy via the AMPK/ mTOR pathway, which ultimately led to aggravated bone loss in the cancellous bone and reduced osseointegration of implants in rat models.

Abstract 353: Chronic Polarization of Low-grade Inflammatory Monocytes During the Pathogenesis of Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Liwu Li ◽  
Shuo Geng
Keyword(s):  
High Fat Diet ◽  
Immunohistochemical Staining ◽  
Molecular Mechanisms ◽  
Molecular Switches ◽  
Low Grade ◽  
High Fat ◽  
Inflammatory Monocytes ◽  
Severe Atherosclerosis ◽  
Low Grade Inflammation ◽  
Deficient Mice

Background: Chronic inflammation mediated by low-grade inflammatory monocytes may serve as a key culprit for atherosclerosis. However, the cellular and molecular mechanisms responsible for the low-grade inflammatory polarization of monocytes are not well understood. We hypothesize that the selective clearance of homeostatic molecular switches may pre-dispose innate monocytes for the establishment of non-resolving low-grade inflammation. Methods and Results: By comparing high-fat-diet (HFD) fed ApoE deficient mice chronically challenged with either PBS or a subclinical dose endotoxin, we observed that subclinical endotoxin potently induced the establishment of low-grade inflammation, as manifested in elevated levels of systemic inflammatory mediators, accumulation of low-grade inflammatory circulating monocytes and neutrophils, as well as lipids. Immunohistochemical staining of liver and aorta tissues revealed significantly elevated steatosis and atherosclerosis in ApoE deficient mice chronically challenged with subclinical dose of endotoxin. At the mechanistic level, the polarization of low-grade inflammatory monocytes were due to the down-regulation and removal of key homeostatic molecules such as IRAK-M and Tollip. ApoE and IRAK-M double deficient mice had enhanced inflammatory polarization of innate monocytes, and developed severe atherosclerosis. Conclusions: Our data suggest that the clearance of homeostatic suppressors such as IRAK-M and Tollip may cause the memory establishment of low-grade inflammatory monocytes that are conducive for the chronic pathogenesis of atherosclerosis. Key words: Low-grade inflammation, monocyte polarization, innate memory, atherosclerosis

scholarly journals Melatonin Reverses the Loss of Stemness Induced by TNF-α in Human Bone Marrow Mesenchymal Stem Cells through Upregulation of YAP Expression

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Xudong Wang ◽  
Tongzhou Liang ◽  
Jincheng Qiu ◽  
Xianjian Qiu ◽  
Bo Gao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Molecular Mechanisms ◽  
Inflammatory Factor ◽  
Cell Transplant ◽  
Alizarin Red ◽  
Marrow Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro culture results in loss of MSC stemness. The inflammation that occurs at stem cell transplant sites (such as that resulting from TNF-α) is a contributing factor for stem cell treatment failure. Currently, there is little evidence regarding the protective role of melatonin with regard to the negative effects of TNF-α on the stemness of MSCs. In this study, we report a melatonin-based method to reduce the inflammatory effects on the stemness of bone marrow mesenchymal stem cells (BMMSCs). The results of colony formation assays, Alizarin red staining, western blotting, and reverse transcription-polymerase chain reactions suggest that melatonin can reverse the inflammatory damage caused by TNF-α treatment in the third, seventh, and tenth generations of primary BMMSCs (vs. control and the TNF-α-treated group). Meanwhile, a detailed analysis of the molecular mechanisms showed that the melatonin receptor and YAP signaling pathway are closely related to the role that melatonin plays in negative inflammatory effects against BMMSCs. In addition, in vivo experiments showed that melatonin could reverse the damage caused by TNF-α on bone regeneration by BMMSCs in nude mice. Overall, our results suggest that melatonin can reverse the loss of stemness caused by inflammatory factor TNF-α in BMMSCs. Our results also provide a practical strategy for the application of BMMSCs in tissue engineering and cell therapy.

scholarly journals MicroRNA-346-5p Regulates Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells by Inhibiting Transmembrane Protein 9

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Yicai Zhang ◽  
Yi Sun ◽  
Jinlong Liu ◽  
Yu Han ◽  
Jinglong Yan
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Osteogenic Differentiation ◽  
Protein Level ◽  
Molecular Mechanisms ◽  
Transmembrane Protein ◽  
Luciferase Reporter ◽  
Alizarin Red ◽  
Protein Levels

The molecular mechanisms how bone marrow-derived mesenchymal stem cells (BMSCs) differentiate into osteoblast need to be investigated. MicroRNAs (miRNAs) contribute to the osteogenic differentiation of BMSCs. However, the effect of miR-346-5p on osteogenic differentiation of BMSCs is not clear. This study is aimed at elucidating the underlying mechanism by which miR-346-5p regulates osteogenic differentiation of human BMSCs. Results of alkaline phosphatase (ALP) and Alizarin Red S (ARS) staining indicated that upregulation of miR-346-5p suppressed osteogenic differentiation of BMSCs, whereas downregulation of miR-346-5p enhanced this process. The protein levels of the osteoblastic markers Osterix and Runt-related transcription factor 2 (Runx2) were decreased in cells treated with miR-346-5p mimic at day 7 and day 14 after being differentiated. By contrast, downregulation of miR-346-5p elevated the protein levels of Osterix and Runx2. Moreover, a dual-luciferase reporter assay revealed that Transmembrane Protein 9 (TMEM9) was a target of miR-346-5p. In addition, the Western Blot results demonstrated that the TMEM9 protein level was significantly reduced by the miR-346-5p mimic whereas downregulation of miR-346-5p improved the protein level of TMEM9. These results together demonstrated that miR-346-5p served a key role in BMSC osteogenic differentiation of through targeting TMEM9, which may provide a novel target for clinical treatments of bone injury.

MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 4055-4063 ◽  
Author(s):  
Christian Ries ◽  
Virginia Egea ◽  
Marisa Karow ◽  
Helmut Kolb ◽  
Marianne Jochum ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Migration ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Human Mesenchymal Stem Cells ◽  
Basement Membranes ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Matrix Metalloproteinase 2

Abstract Human mesenchymal stem cells (hMSCs) represent promising tools in various clinical applications, including the regeneration of injured tissues by endogenous or transplanted hMSCs. The molecular mechanisms, however, that control hMSC mobilization and homing which require invasion through extracellular matrix (ECM) barriers are almost unknown. We have analyzed bone marrow–derivedhMSCs and detected strong expression and synthesis of matrix metalloproteinase 2 (MMP-2), membrane type 1 MMP (MT1-MMP), tissue inhibitor of metalloproteinase 1 (TIMP-1), and TIMP-2. The ability of hMSCs to traverse reconstituted human basement membranes was effectively blocked in the presence of synthetic MMP inhibitors. Detailed studies by RNA interference revealed that gene knock-down of MMP-2, MT1-MMP, or TIMP-2 substantially impaired hMSC invasion, whereas silencing of TIMP-1 enhanced cell migration, indicating opposing roles of both TIMPs in this process. Moreover, the inflammatory cytokines TGF-β1, IL-1β, and TNF-α up-regulated MMP-2, MT1-MMP, and/or MMP-9 production in these cells, resulting in a strong stimulation of chemotactic migration through ECM, whereas the chemokine SDF-1α exhibited minor effects on MMP/TIMP expression and cell invasion. Thus, induction of specific MMP activity in hMSCs by inflammatory cytokines promotes directed cell migration across reconstituted basement membranes in vitro providing a potential mechanism in hMSC recruitment and extravasation into injured tissues in vivo.

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