scholarly journals Sonic Hedgehog Induces Mesenchymal Stromal Cell Senescence-Associated Secretory Phenotype and Chondrocyte Apoptosis in Human Osteoarthritic Cartilage

2021 ◽  
Vol 9 ◽  
Author(s):  
Meng Feng ◽  
Wenguang Liu ◽  
Jing Ding ◽  
Yusheng Qiu ◽  
Qian Chen
Keyword(s):  
Gene Expression ◽  
Conditioned Medium ◽  
Sonic Hedgehog ◽  
Stromal Cells ◽  
Replicative Senescence ◽  
Critical Role ◽  
Chondrocyte Apoptosis ◽  
Low Grade ◽  
Osteoarthritic Cartilage ◽  
Inflammatory Microenvironment

Hedgehog (HH) signaling plays a critical role in osteoarthritis (OA) pathogenesis, but the molecular mechanism remains to be elucidated. We show here that Sonic Hedgehog (SHH) gene expression is initiated in human normal cartilage stromal cells (NCSC) and increased in OA cartilage mesenchymal stromal cells (OA-MSCs) during aging. Manifesting a reciprocal cellular distribution pattern, the SHH receptors PTCH1 and SMO and transcription factors GLI2 and GLI3 are expressed by chondrocytes (OAC) in OA cartilage. SHH autocrine treatment of osteoarthritis MSC stimulates proliferation, chondrogenesis, hypertrophy, and replicative senescence with elevated SASP gene expression including IL1B, IL6, CXCL1, and CXCL8. SHH paracrine treatment of OAC suppresses COL2A1, stimulates MMP13, and induces chondrocyte apoptosis. The OA-MSC conditioned medium recapitulates the stimulatory effects of SHH on OAC catabolism and apoptosis. SHH knock-down in OA-MSC not only inhibits catabolic and senescence marker expression in OA-MSC, but also abolishes the effect of the OA-MSC conditioned medium on OAC catabolism and apoptosis. We propose that SHH is a key mediator between OA-MSC and OA chondrocytes interaction in human OA cartilage via two mechanisms: (1) SHH mediates MSC growth and aging by activating not only its proliferation and chondrogenesis, but also low-grade inflammation and replicative senescence, and (2) SHH mediates OA-MSC-induced OAC catabolism and apoptosis by creating a pro-inflammatory microenvironment favoring tissue degeneration during OA pathogenesis.

scholarly journals Replicative senescence-associated gene expression changes in mesenchymal stromal cells are similar under different culture conditions

Haematologica ◽  
2010 ◽  
Vol 95 (6) ◽  
pp. 867-874 ◽  
Author(s):  
K. Schallmoser ◽  
C. Bartmann ◽  
E. Rohde ◽  
S. Bork ◽  
C. Guelly ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Replicative Senescence ◽  
Culture Conditions

Proinflammatory effects of arachidonic acid in a lipopolysaccharide-induced inflammatory microenvironment in 3T3-L1 adipocytes in vitro

2015 ◽  
Vol 40 (2) ◽  
pp. 142-154 ◽  
Author(s):  
Mary M. Cranmer-Byng ◽  
Danyelle M. Liddle ◽  
Anna A. De Boer ◽  
Jennifer M. Monk ◽  
Lindsay E. Robinson
Keyword(s):  
Gene Expression ◽  
Fatty Acids ◽  
Arachidonic Acid ◽  
Synergistic Effects ◽  
Nuclear Factor Κb ◽  
Stearidonic Acid ◽  
Low Grade ◽  
Monocyte Chemoattractant Protein 1 ◽  
Inflammatory Microenvironment

Long-chain n-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA), have known anti-inflammatory effects, including the modulation of adipose tissue-derived inflammatory mediators (i.e., adipokines) implicated in obesity-related pathologies, such as insulin resistance. Less is known about the effects of plant-derived n-3 PUFA, α-linolenic acid (ALA, 18:3n-3) and stearidonic acid (SDA 18:4n-3), or n-6 PUFA linoleic acid (LA, 18:2n-6) and arachidonic acid (AA, 20:4n-6), especially in combination with an inflammatory stimulus, such as lipopolysaccharide (LPS), at a dose intended to mimic obesity-associated low-grade inflammation. To study this, 3T3-L1 adipocytes were incubated with 100 μmol/L of various n-3 or n-6 PUFA with or without 10 ng/mL LPS for up to 24 h. AA in the presence of LPS synergistically increased (p < 0.05) pro-inflammatory monocyte chemoattractant protein-1 (MCP)-1 and interleukin (IL)-6 secretion and gene expression, as well as COX-2 and TLR2 gene expression at 6 and/or 24 h, suggesting their potential roles in the synergistic effects of AA and LPS. Plant-derived fatty acids ALA, SDA, and LA did not differentially affect adipokine gene expression or secretion, whereas LPS-induced pro-inflammatory IL-1β expression and MCP-1 secretion was decreased (p < 0.05) by EPA, DHA, and/or EPA+DHA (50 μmol/L each) compared with LPS alone. Only DHA increased (p < 0.05) gene expression of the n-3 PUFA receptor GPR120 and simultaneously decreased LPS-induced nuclear factor-κB activation compared with control. Our findings emphasize that specific fatty acids within the n-3 or n-6 PUFA class warrant consideration in the development of nutritional strategies to improve obesity-associated inflammation.

scholarly journals Individual response to mTOR inhibition in delaying replicative senescence of mesenchymal stromal cells

2018 ◽  
Author(s):  
Eliane Antonioli ◽  
Natália Torres ◽  
Mario Ferretti ◽  
Carla A. Piccinato ◽  
Andrea L. Sertie
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Molecular Mechanisms ◽  
Replicative Senescence ◽  
Expression Patterns ◽  
Critical Role ◽  
Mtor Signaling ◽  
Protein Accumulation ◽  
Individual Response ◽  
Mtor Inhibition

AbstractBackground aimsDelaying replicative senescence and extending lifespan of human mesenchymal stromal cells (MSCs) may enhance their potential for tissue engineering and cell based therapies. Accumulating evidence suggests that inhibitors of the mTOR signaling pathway, such as rapamycin, constitute promising pharmacological agents to retard senescence and extend stemness properties of various progenitor cell types. Here, we investigated whether the ability of rapamycin to postpone replicative senescence varies among bone marrow MSC samples (BM-MSCs) derived from different healthy donors, and explored the molecular mechanisms that drive rapamycin-mediated lifespan increment.MethodsBM-MSCs at early passages were serially passaged either in absence or continuous presence of rapamycin and the number of cell population doublings until growth arrest was measured. The inhibition of mTOR signaling was assessed by the phosphorylation status of the downstream target RPS6. The expression levels of several senescence and pluripotency markers at early and late/senescent passages were analyzed by RT-qPCR, flow cytometry and western blot.ResultsWe found that the lifespan extension in response to the continuous rapamycin treatment was highly variable among samples, but effective in most BM-MSCs. Despite all rapamycin-treated cells secreted significantly reduced levels of IL6, a major SASP cytokine, and expressed significantly higher levels of the pluripotency marker NANOG, the expression patterns of these markers were not correlated with the rapamycin-mediated increase in lifespan. Interestingly, rapamycin-mediated life-span extension was significantly associated only with repression of p16INK4A protein accumulation.ConclusionsTaken together, our results suggest that some, but not all, BM-MSC samples would benefit from using rapamycin to postpone replicative arrest and reinforce a critical role of p16INK4A protein downregulation in this process.

scholarly journals Loss of HuR Is Linked to Reduced Expression of Proliferative Genes during Replicative Senescence

2001 ◽  
Vol 21 (17) ◽  
pp. 5889-5898 ◽  
Author(s):  
Wengong Wang ◽  
Xiaoling Yang ◽  
Vincent J. Cristofalo ◽  
Nikki J. Holbrook ◽  
Myriam Gorospe
Keyword(s):  
Gene Expression ◽  
Rna Binding ◽  
Replicative Senescence ◽  
Binding Protein ◽  
Expression Patterns ◽  
Critical Role ◽  
Rna Binding Protein ◽  
Cellular Aging ◽  
Gene Expression Patterns ◽  
Senescent Phenotype

ABSTRACT Cellular aging is accompanied by alterations in gene expression patterns. Here, using two models of replicative senescence, we describe the influence of the RNA-binding protein HuR in regulating the expression of several genes whose expression decreases during senescence. We demonstrate that HuR levels, HuR binding to target mRNAs encoding proliferative genes, and the half-lives of such mRNAs are lower in senescent cells. Importantly, overexpression of HuR in senescent cells restored a “younger” phenotype, while a reduction in HuR expression accentuated the senescent phenotype. Our studies highlight a critical role for HuR during the process of replicative senescence.

scholarly journals Senescent Tissue-Resident Mesenchymal Stromal Cells Are an Internal Source of Inflammation in Human Osteoarthritic Cartilage

2021 ◽  
Vol 9 ◽  
Author(s):  
Wenguang Liu ◽  
Alexander S. Brodsky ◽  
Meng Feng ◽  
Yajun Liu ◽  
Jing Ding ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Transition Process ◽  
Sterile Inflammation ◽  
Internal Source ◽  
Osteoarthritic Cartilage ◽  
Human Cartilage

Human osteoarthritic cartilage contains not only chondrocytes (OACs), but also mesenchymal stromal cells (OA-MSCs), whose abundance increases during osteoarthritis (OA). However, it is not clear how OA-MSC contributes to OA pathogenesis. Here, we show that aging OA-MSC plays an important role in cell senescence, fibrosis, and inflammation in cartilage. Protein array analysis indicates that OA-MSC expresses pro-inflammatory senescence associated secretory phenotype (SASP) including IL-1β, IL-6, IL-8, and CXCL1, 5, and 6, which play key roles in OA pathogenesis. OAC is a main recipient of the inflammatory signals by expressing receptors of cytokines. RNAseq analysis indicates that the transition from normal cartilage stromal cells (NCSCs) to OA-MSC during aging results in activation of SASP gene expression. This cell transition process can be recapitulated by a serial passage of primary OAC in cell culture comprising (1) OAC dedifferentiation into NCSC-like cells, and (2) its subsequent senescence into pro-inflammatory OA-MSC. While OAC dedifferentiation is mediated by transcriptional repression of chondrogenic gene expression, OA-MSC senescence is mediated by transcriptional activation of SASP gene expression. We postulate that, through replication-driven OAC dedifferentiation and mesenchymal stromal cell (MSC) senescence, OA-MSC becomes an internal source of sterile inflammation in human cartilage joint.

A Review on Important Histone Acetyltransferase (HAT) Enzymes as Targets for Cancer Therapy

2019 ◽  
Vol 15 (2) ◽  
pp. 120-130
Author(s):  
Mohammad Ghanbari ◽  
Reza Safaralizadeh ◽  
Kiyanoush Mohammadi
Keyword(s):  
Gene Expression ◽  
Histone Acetyltransferase ◽  
Critical Role ◽  
Cancer Treatments ◽  
Control Of Gene Expression ◽  
Post Translational Modifications ◽  
Therapeutic Drugs ◽  
The Status ◽  
Acetyl Group ◽  
Increase Gene Expression

At the present time, cancer is one of the most lethal diseases worldwide. There are various factors involved in the development of cancer, including genetic factors, lifestyle, nutrition, and so on. Recent studies have shown that epigenetic factors have a critical role in the initiation and development of tumors. The histone post-translational modifications (PTMs) such as acetylation, methylation, phosphorylation, and other PTMs are important mechanisms that regulate the status of chromatin structure and this regulation leads to the control of gene expression. The histone acetylation is conducted by histone acetyltransferase enzymes (HATs), which are involved in transferring an acetyl group to conserved lysine amino acids of histones and consequently increase gene expression. On the basis of similarity in catalytic domains of HATs, these enzymes are divided into different groups such as families of GNAT, MYST, P300/CBP, SRC/P160, and so on. These enzymes have effective roles in apoptosis, signaling pathways, metastasis, cell cycle, DNA repair and other related mechanisms deregulated in cancer. Abnormal activation of HATs leads to uncontrolled amplification of cells and incidence of malignancy signs. This indicates that HAT might be an important target for effective cancer treatments, and hence there would be a need for further studies and designing of therapeutic drugs on this basis. In this study, we have reviewed the important roles of HATs in different human malignancies.

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