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Cited by 120Mesenchymal stem cell researchTelomeres, Telomerase, and SenescenceTGF-β signaling in diseases

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TGF-β1 induces senescence of bone marrow mesenchymal stem cells via increase of mitochondrial ROS production

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Wu, Junfang, Niu, Jie, Li, Xiaopeng, Wang, Xianwei, Guo, Zhikun, Zhang, Fenxi·2014·BMC Developmental Biology
DOI 10.1186/1471-213x-14-21PMC PMC4031602
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Abstract

BACKGROUND: Bone marrow derived mesenchymal stem cells (bmMSCs) are multipotent cells that can differentiate into diverse cell types, including cardiomyocytes. BmMSC-based transplantation is capable of repairing acute and chronic myocardial infarction. Prior to the transplantation, MSCs are usually induced in vitro by biological reagents and chemicals for directional differentiation. Transforming growth factor beta (TGF-β) is one of the most commonly used biological reagents for induction of cardiomyocyte differentiation of bmMSCs. Previous studies have shown that TGF-β induces senescence in several cell types. However, whether TGF-β affects senescence of bmMSCs has not been elucidated. The goal of this study was to investigate the effect of TGF-β1 on senescence of bmMSCs and the underlying mechanisms. RESULTS: We found that TGF-β1 increased activity of senescence-associated-galactosidase (SA-Gal) and production of mitochondrial reactive oxygen species (mtROS) in bmMSCs in a dose-dependent manner. TGF-β1 also significantly decreased expression of superoxide dismutase 2 (SOD2) and Id1, and increased expression of 4-Hydroxynonenal (4-HNE) subunits and p16 in bmMSCs in a dose-dependent manner. Pre-treatment with mtROS inhibitor acetyl-L-carnitine (ALCAR, 0.1 mM) significantly inhibited TGF-β1-induced mtROS production and SA-Gal activity. CONCLUSION: TGF-β1 can induce senescence of bmMSCs, which at least partially depends on mtROS production.

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Figures

Figure 1 Identification of bone marrow mesenchymal stem cells (bmMSCs). Immunofluorescence assay shows that bmMSCs positively express MSC markers CD44 and CD90. Immunochemistry staining shows that alkaline phosphatase (ALP) is positively expressed in bmMSCs following 3 weeks of osteogenic differntiation culture. Oil Red O staining displays that lipid droplets are accumulated in a part of bmMSCs following 3 weeks of adipogenic differentiation culture.
Figure 1 Identification of bone marrow mesenchymal stem cells (bmMSCs). Immunofluorescence assay shows that bmMSCs positively express MSC markers CD44 and CD90. Immunochemistry staining shows that alkaline phosphatase (ALP) is positively expressed in bmMSCs following 3 weeks of osteogenic differntiation culture. Oil Red O staining displays that lipid droplets are accumulated in a part of bmMSCs following 3 weeks of adipogenic differentiation culture.CC BY · PubMed Central
Figure 2 Dose–response of β-galactosidase activity in bone marrow mesenchymal stem cells (bmMSCs) after exposure to 0, 1, 5 and 10 ng/mL recombinant mouse transforming growth factor β1 (TGF-β1) for 24 hours. Bar graphs represent mean ± SD (4 independent experiments/group). *P < 0.05 vs. control.
Figure 2 Dose–response of β-galactosidase activity in bone marrow mesenchymal stem cells (bmMSCs) after exposure to 0, 1, 5 and 10 ng/mL recombinant mouse transforming growth factor β1 (TGF-β1) for 24 hours. Bar graphs represent mean ± SD (4 independent experiments/group). *P < 0.05 vs. control.CC BY · PubMed Central
Figure 3 Time-response of β-galactosidase activity in bone marrow mesenchymal stem cells (bmMSCs) after exposure to 5 ng/mL recombinant mouse transforming growth factor β1 (TGF-β1) for 0–24 hours. Bar graphs represent mean ± SD (4 independent experiments/group). *P < 0.05 vs. control.
Figure 3 Time-response of β-galactosidase activity in bone marrow mesenchymal stem cells (bmMSCs) after exposure to 5 ng/mL recombinant mouse transforming growth factor β1 (TGF-β1) for 0–24 hours. Bar graphs represent mean ± SD (4 independent experiments/group). *P < 0.05 vs. control.CC BY · PubMed Central
Figure 4 Western-blot assay shows expression of aging marker proteins 4-Hydroxynonenal (4-HNE), p16 and Id1 in bmMSCs after exposure to 0, 1, 5 and 10 ng/mL TGF-β1 for 24 hours. A. 4-HNE expression; B. P16 expression; C. Id1 expression. Bar graphs represent mean ± SD (4 independent experiments/group). *P < 0.05 vs. control.
Figure 4 Western-blot assay shows expression of aging marker proteins 4-Hydroxynonenal (4-HNE), p16 and Id1 in bmMSCs after exposure to 0, 1, 5 and 10 ng/mL TGF-β1 for 24 hours. A. 4-HNE expression; B. P16 expression; C. Id1 expression. Bar graphs represent mean ± SD (4 independent experiments/group). *P < 0.05 vs. control.CC BY · PubMed Central
Figure 5 Mitochondrial reactive oxygen species (mtROS) production in bone marrow mesenchymal stem cells (bmMSCs) after exposure to 0, 1, 5 and 10 ng/mL TGF-β1 for 24 hours. A. MitoSOX™ Red Indicator staining shows mtROS in bmMSCs after exposure to 0, 1, 5 and 10 ng/mL TGF-β1 for 24 hours. B. Quantification of fluorescence density of mtROS. C. Western blot assay shows expression of superoxide dismutase 2 (SOD2) in bmMSCs after exposure to 0, 1, 5 and 10 ng/mL TGF-β1 for 24 hours. Bar graphs represent mean ± SD (4 independent experiments/group). *P < 0.05 vs. control.
Figure 5 Mitochondrial reactive oxygen species (mtROS) production in bone marrow mesenchymal stem cells (bmMSCs) after exposure to 0, 1, 5 and 10 ng/mL TGF-β1 for 24 hours. A. MitoSOX™ Red Indicator staining shows mtROS in bmMSCs after exposure to 0, 1, 5 and 10 ng/mL TGF-β1 for 24 hours. B. Quantification of fluorescence density of mtROS. C. Western blot assay shows expression of superoxide dismutase 2 (SOD2) in bmMSCs after exposure to 0, 1, 5 and 10 ng/mL TGF-β1 for 24 hours. Bar graphs represent mean ± SD (4 independent experiments/group). *P < 0.05 vs. control.CC BY · PubMed Central
Figure 6 Mitochodrial ROS (mtROS) specific inhibitor acetyl-L-carnitine (ALCAR) inhibits TGF-β1-induced mtROS generation and bmMSC senescence. Bar graphs represent mean ± SD (4 independent experiments/group). *P < 0.05 vs. treatments with 5 ng/mL TGF-β1.
Figure 6 Mitochodrial ROS (mtROS) specific inhibitor acetyl-L-carnitine (ALCAR) inhibits TGF-β1-induced mtROS generation and bmMSC senescence. Bar graphs represent mean ± SD (4 independent experiments/group). *P < 0.05 vs. treatments with 5 ng/mL TGF-β1.CC BY · PubMed Central
Figure 7 Expression of aging markers 4-Hydroxynonenal (4-HNE), p16 and Id1 in bmMSCs as the cells were exposed to acetyl-L-carnitine (ALCAR, 0.1 mM) and TGF-β1 (5 ng/mL) simultaneously. A. 4-HNE expression; B. P16 expression; C. Id1 expression. Bar graphs represent mean ± SD (4 independent experiments/group). *P < 0.05 vs. treatments with 5 ng/mL TGF-β1.
Figure 7 Expression of aging markers 4-Hydroxynonenal (4-HNE), p16 and Id1 in bmMSCs as the cells were exposed to acetyl-L-carnitine (ALCAR, 0.1 mM) and TGF-β1 (5 ng/mL) simultaneously. A. 4-HNE expression; B. P16 expression; C. Id1 expression. Bar graphs represent mean ± SD (4 independent experiments/group). *P < 0.05 vs. treatments with 5 ng/mL TGF-β1.CC BY · PubMed Central

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Research works printed but not linked: 1

  1. Lü Y, Wang HP, Liu B, Wu ZG, Huo YL, Gao CW: TGF-β1 induced bone marrow mesenchymal stem cells differentiate in cardiomyocyte-like cells. Acta Antomica Sinica. 2013, 44: 49-54.

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Metadata

Authors
Wu, J., Niu, J., Li, X., Wang, X., Guo, Z., & Zhang, F.
Affiliations
Henan Medical University (CN)
Corresponding author
Zhang, Fenxi
ORCID
Venue
BMC Developmental Biology
Publisher
Springer Science and Business Media LLC
Published
2014-05-18
Volume
14
Issue
1
Pages
21-21
ISSN
1471-213X (ISSN-L)
DOI
10.1186/1471-213x-14-21
PMC
PMC4031602
OpenAlex
W2080878133
Cited by
120
References
38
Citations by year
2026: 5 · 2025: 7 · 2024: 8 · 2023: 10 · 2022: 13 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 15 · 2017: 14 · 2016: 11 · 2015: 14
FWCI
6.51
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • BMC Developmental Biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (81370428)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
TGF-β1, bone marrow mesenchymal stem cells, cellular senescence, mitochondrial reactive oxygen species, manganese superoxide dismutase, Id1, 4-hydroxynonenal, p16, acetyl-L-carnitine, cardiomyocyte differentiation, myocardial infarction
MeSH terms
Superoxide Dismutase 2, Acetylcarnitine, Aldehydes, Animals, Bone Marrow Cells, Cells, Cultured, Dose-Response Relationship, Drug, Galactosidases, Mice, Inbred C57BL, Microscopy, Fluorescence, Mitochondria, Osteogenesis, Superoxide Dismutase, Vitamin B Complex, Blotting, Western, Cellular Senescence, Reactive Oxygen Species, Cyclin-Dependent Kinase Inhibitor p16, Adipogenesis, Mice, Inhibitor of Differentiation Protein 1, Transforming Growth Factor beta1, Mesenchymal Stem Cells

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