Apigenin and rutaecarpine target cellular senescence to prevent aging-bone phenotype in human mesenchymal skeletal stem cells

In order to provide a sufficient number of cells for clinical use, mesenchymal stem cells (MSCs) must be cultured for long-term expansion, which inevitably triggers cellular senescence. Although the small size of MSCs is known as a critical determinant of their fate, the main regulators of stem cell senescence and the underlying signaling have not been addressed. Umbilical cord blood-derived MSCs (UCB-MSCs) were obtained using size-isolation methods and then cultured with control or small cells to investigate the major factors that modulate MSC senescence. Cytokine array data suggested that the secretion of interukin-8 (IL-8) or growth-regulated oncogene-alpha (GROa) by senescent cells was markedly inhibited during incubation of small cells along with suppression of cognate receptor (C-X-C motif chemokine receptor2, CXCR2) via blockade of the autocrine/paracrine positive loop. Moreover, signaling via toll-like receptor 2 (TLR2) and TLR5, both pattern recognition receptors, drove cellular senescence of MSCs, but was inhibited in small cells. The activation of TLRs (2 and 5) through ligand treatment induced a senescent phenotype in small cells. Collectively, our data suggest that small cell from UCB-MSCs exhibit delayed cellular senescence by inhibiting the process of TLR signaling-mediated senescence-associated secretory phenotype (SASP) activation.

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Hydrogen alleviates cellular senescence via regulation of ROS/p53/p21 pathway in bone marrow-derived mesenchymal stem cells in vivo

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2018.07.020 ◽

2018 ◽

Vol 106 ◽

pp. 1126-1134 ◽

Cited By ~ 3

Author(s):

Wenbo Zhang ◽

Chao Huang ◽

Aijun Sun ◽

Liang Qiao ◽

Xi Zhang ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Cellular Senescence

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Suppression of Transforming Growth Factor-β Signaling Delays Cellular Senescence and Preserves the Function of Endothelial Cells Derived from Human Pluripotent Stem Cells

Stem Cells Translational Medicine ◽

10.5966/sctm.2016-0089 ◽

2016 ◽

Vol 6 (2) ◽

pp. 589-600 ◽

Cited By ~ 10

Author(s):

Hao Bai ◽

Yongxing Gao ◽

Dixie L. Hoyle ◽

Tao Cheng ◽

Zack Z. Wang

Keyword(s):

Stem Cells ◽

Endothelial Cells ◽

Growth Factor ◽

Cellular Senescence ◽

Pluripotent Stem Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Human Pluripotent Stem Cells

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MicroRNA-487a-3p Regulates the Senescence of Mesenchymal Stem Cells by Targeting Silencing Information Regulator-Associated Enzyme 1 (SIRT1)

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2021.2711 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1576-1581

Author(s):

Yiwei Shen ◽

Xue Li ◽

Xiaoke Wu ◽

Yi Li ◽

Yiwei Shen ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cellular Senescence ◽

Control Group ◽

Human Mscs ◽

Galactosidase Activity ◽

Activity Staining ◽

Plasmid Transfection ◽

Related Proteins ◽

The Relationship

SIRT1 is known to be closely associated with cellular senescence, while the relationship between miR-487a-3p and SIRT1 and their role in mesenchymal stem cells (MSCs) remains unclear. MiRDB analysis showed SIRT1 is a target of miR-487a-3p. Here we investigated whether miR-487a-3p modulates senescence of mesenchymal stem cells by targeting SIRT1. The human MSCs (hMSCs) were divided into control group (NC group), miR-487a-3p Mimics group, pCMV-SIRT+miR-487a-3p Mimics group followed by analysis of miR-487a-3p expression by qPCR and protein level of SIRT1, P21 and P53 by western blot. Dual luciferin report assay verified the binding of miR-487a-3p to SIRT1 mRNA and β-galactosidase activity staining detected hMSCs senescence. miR-487a-3p level was significantly elevated after miR-487a-3p Mimics treatment (P <0.01) without difference between miR-487a-3p Mimics group and pCMV-SIRT1 group+miR-487a-3pMimics (P >0.05). miR-487a-3p mimics significantly decreased SIRT1 level (P < 0.01), which was reversed by pCMVSIRT1 plasmid transfection (P <0.05). Moreover, miR-487a-3p could bind SIRT1 mRNA 3′-UTR region. Further more, miR-487a-3p Mimics induced cellular senescence as displayed by increased β-galactosidase activity (P <0.01) and increased level of senescence-related proteins P21 and P53 (P < 0.01), which were all reversed by overexpression of SIRT1 (P < 0.05). In conclusion, miR-487a-3p reduced SIRT1 expression, thus promoting hMSCs senescence, while overexpression of SIRT1 could counteract the senescence of hMSCs induced by miR-487a-3p.

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Pigment epithelium-derived factor delays cellular senescence of human mesenchymal stem cells in vitro by reducing oxidative stress

Cell Biology International ◽

10.1002/cbin.10041 ◽

2013 ◽

Vol 37 (4) ◽

pp. 305-313 ◽

Cited By ~ 6

Author(s):

Yukun Cao ◽

Ting Yang ◽

Chunhu Gu ◽

Dinghua Yi

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cellular Senescence ◽

Pigment Epithelium ◽

Human Mesenchymal Stem Cells ◽

Pigment Epithelium Derived Factor

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TWIST1 controls cellular senescence and energy metabolism in mesenchymal stem cells

10.22203/ecm.v042a25 ◽

2021 ◽

Vol 42 ◽

pp. 401-414

Author(s):

C Voskamp ◽

◽

LA Anderson ◽

WJLM Koevoet ◽

S Barnhoorn ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cellular Senescence ◽

Extracellular Acidification ◽

Cell Lineages ◽

Knowing That ◽

Control Mscs ◽

Multiple Cell ◽

Cellular Bioenergetics ◽

Secretory Phenotype

Mesenchymal stem cells (MSCs) are promising cells for regenerative medicine therapies because they can differentiate towards multiple cell lineages. However, the occurrence of cellular senescence and the acquiring of the senescence-associated secretory phenotype (SASP) limit their clinical use. Since the transcription factor TWIST1 influences expansion of MSCs, its role in regulating cellular senescence was investigated. The present study demonstrated that silencing of TWIST1 in MSCs increased the occurrence of senescence, characterised by a SASP profile different from irradiation-induced senescent MSCs. Knowing that senescence alters cellular metabolism, cellular bioenergetics was monitored by using the Seahorse XF apparatus. Both TWIST1-silencing-induced and irradiation-induced senescent MSCs had a higher oxygen consumption rate compared to control MSCs, while TWIST1-silencing-induced senescent MSCs had a low extracellular acidification rate compared to irradiation-induced senescent MSCs. Overall, data indicated how TWIST1 regulation influenced senescence in MSCs and that TWIST1 silencing-induced senescence was characterised by a specific SASP profile and metabolic state.

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Rejuvenation of mesenchymal stem cells by extracellular vesicles inhibits the elevation of reactive oxygen species

Scientific Reports ◽

10.1038/s41598-020-74444-8 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Vuong Cat Khanh ◽

Toshiharu Yamashita ◽

Kinuko Ohneda ◽

Chiho Tokunaga ◽

Hideyuki Kato ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Extracellular Vesicles ◽

Cellular Senescence ◽

Skin Flap ◽

Reactive Oxygen ◽

Oxygen Species

Abstract Aging induces numerous cellular disorders, such as the elevation of reactive oxygen species (ROS), in a number type of cells, including mesenchymal stem cells (MSCs). However, the correlation of ROS and impaired healing abilities as well as whether or not the inhibition of elevating ROS results in the rejuvenation of elderly MSCs is unclear. The rejuvenation of aged MSCs has thus recently received attention in the field of regenerative medicine. Specifically, extracellular vesicles (EVs) act as a novel tool for stem cell rejuvenation due to their gene transfer ability with systemic effects and safety. In the present study, we examined the roles of aging-associated ROS in the function and rejuvenation of elderly MSCs by infant EVs. The data clearly showed that elderly MSCs exhibited the downregulation of superoxide dismutase (SOD)1 and SOD3, which resulted in the elevation of ROS and downregulation of the MEK/ERK pathways, which are involved in the impairment of the MSCs’ ability to decrease necrotic area in the skin flap model. Furthermore, treatment with the antioxidant Edaravone or co-overexpression of SOD1 and SOD3 rescued elderly MSCs from the elevation of ROS and cellular senescence, thereby improving their functions. Of note, infant MSC-derived EVs rejuvenated elderly MSCs by inhibiting ROS production and the acceleration of cellular senescence and promoting the proliferation and in vivo functions in both type 1 and type 2 diabetic mice.

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