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Tumor necrosis factor-α-activated mesenchymal stem cells promote endothelial progenitor cell homing and angiogenesis
Open accessAbstract
Mesenchymal stem cells (MSCs) accelerate regeneration of ischemic or injured tissues by stimulation of angiogenesis through a paracrine mechanism. Tumor necrosis factor-α (TNF-α)-activated MSCs secrete pro-angiogenic cytokines, including IL-6 and IL-8. In the present study, using an ischemic hindlimb animal model, we explored the role of IL-6 and IL-8 in the paracrine stimulation of angiogenesis and tissue regeneration by TNF-α-activated MSCs. Intramuscular injection of conditioned medium derived from TNF-α-treated MSCs (TNF-α CM) into the ischemic hindlimb resulted in attenuated severe limb loss and stimulated blood perfusion and angiogenesis in the ischemic limb. Immunodepletion of IL-6 and IL-8 resulted in attenuated TNF-α CM-stimulated tissue repair, blood perfusion, and angiogenesis. In addition, TNF-α CM induced migration of human cord blood-derived endothelial progenitor cells (EPCs) through IL-6- and IL-8-dependent mechanisms in vitro. Intramuscular injection of TNF-α CM into the ischemic limb led to augmented homing of tail vein-injected EPCs into the ischemic limb in vivo and immunodepletion of IL-6 or IL-8 from TNF-α CM attenuated TNF-α CM-stimulated homing of EPCs. In addition, intramuscular injection of recombinant IL-6 and IL-8 proteins resulted in increased homing of intravenously transplanted EPCs into the ischemic limb and improved blood perfusion in vivo. These results suggest that TNF-α CM stimulates angiogenesis and tissue repair through an increase in homing of EPCs through paracrine mechanisms involving IL-6 and IL-8.
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“Additionally, several cytokines produced by inflammatory cells have angiogenic effects, including TNF, IL-6, and IL-8 (57, 58).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [57]
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“Pretreatment conditioning by exposure to exogenous cytokines [4–10], hypoxia [11–13], or through three-dimensional (3D) spheroid culture [14–16] enhances the anti-inflammatory phenotype of MSCs. Three-dimensional culture of human MSCs upregulates caspase-dependent IL-1 signaling during…”
Zomer, H. D., Lima, V. J. D. S., Bion, M. C., Brito, K. N. L., Rode, M. P., Stimamiglio, M. A., Jeremias, T. D. S., & Trentin, A. G. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03630-y · Cited by 14
Cheng, H. S., Pérez‐Cremades, D., Zhuang, R., Jamaiyar, A., Wu, W. W., Chen, J., Tzani, A. I., Stone, L., Plutzky, J., RYAN, T. E., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.163041 · Cited by 13
“Intramuscular injection of IL-8 increased neovascularization after hindlimb ischemia in mice by improving homing of tail vein-injected endothelial progenitor cells (46).”
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“In the proliferative phase, TNF-α controls the angiogenesis and formation of the tissue granulation; this is composed of cells and a network of blood vessels responsible for reestablishing regional circulation [17, 18].”
BackgroundAn Outstanding Role of Adipose Tissue in Canine Stem Cell Therapy
Prišlin, M., Vlahović, D., Kostešić, P., Ljolje, I., Brnić, D., Turk, N., Lojkić, I., Kunić, V., Karadjole, T., & Krešić, N. (2022) · Animals · doi:10.3390/ani12091088 · Cited by 13
“In the liver, the mRNA expression levels of pro-inflammatory cytokines, such as IL-1, IL-6, IL-8, and IFNγ decreased significantly, but anti-inflammatory cytokines such as IL-4 and IL-10, HGF and VEGFA, were significantly increased after the first ASCs injection.”
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Borges, F. T., Convento, M. B., & Schor, N. (2018) · Stem Cells and Cloning Advances and Applications · doi:10.2147/sccaa.s147804 · Cited by 12
“Conditioning of MSC with tumor necrosis factor α (TNF-α), an inflammatory cytokine produced by macrophages, stimulated an MSC angiogenic effect through VEGF production, proliferation, and differentiation into osteocytes.(58,59) Proteins can also be carried by EVs released by MSC, which keep them protected from microen…”
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“Additionally, IL-6 and IL-8 are reported to increase endothelial progenitor cell homing to areas of ischemia [21].”
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“enhance MSC-mediated angiogenesis [27, 41, 50] whereas IL-10, IFN-γ, IL-α, and IL-1β were shown to stimulate the immunomodulatory properties of MSCs [28, 30, 31].”
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“TNF-α activated MSCs promote endothelial progenitor cell homing and angiogenesis.(78) Inflammation affects immunomodulation and inflammation modulation of MSCs.”
BackgroundRevolutionizing orofacial pain management: the promising potential of stem cell therapy
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Hypoxia in Mesenchymal Stem Cell
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Hypoxia and interleukin-1-primed mesenchymal stem/stromal cells as novel therapy for stroke
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“This cytokine also enhanced homing following intramuscular administration of the activated MSC and promoted tissue repair through the release of pro-angiogenic cytokines [113].”
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Mesodermal Derivatives of Pluripotent Stem Cells Route to Scarless Healing
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Metadata
- Authors
- Kwon, Y. W., Heo, S. C., Jeong, G. O., Yoon, J. W., Mo, W. M., Lee, M. J., Jang, I.-H., Kwon, S. M., Lee, J. S., & Kim, J. H.
- Affiliations
- Pusan National University (KR)
- Pusan National University Yangsan Hospital (KR)
- Corresponding author
- Kim, Jae Ho
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 1832
- Issue
- 12
- Pages
- 2136-2144
- ISSN
- 0925-4439 (ISSN-L)
- OpenAlex
- W1968254493
- Cited by
- 137
- References
- 42
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 11 · 2023: 12 · 2022: 13 · 2021: 13 · 2020: 17 · 2019: 11 · 2018: 11 · 2017: 11 · 2016: 16 · 2015: 11 · 2014: 3
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Research Foundation of Korea
- Ministry of Education, Science and Technology (2010-0020274, 2012M3A9C7050093, 2012M3A9C7050184)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Keywords
- mesenchymal stem cells, TNF-α, endothelial progenitor cells, angiogenesis, EPC homing, interleukin-6, interleukin-8, paracrine signaling, hindlimb ischemia, tissue regeneration, blood perfusion, conditioned medium, immunodepletion
- MeSH terms
- Animals, Cell Movement, Cells, Cultured, Fluorescent Antibody Technique, Hindlimb, Humans, Ischemia, Mice, Nude, Necrosis, Stem Cells, Tumor Necrosis Factor-alpha, Wound Healing, Blotting, Western, Interleukin-6, Interleukin-8, Culture Media, Conditioned, Adipocytes, Neovascularization, Physiologic, Cell Proliferation, Mice, Mesenchymal Stem Cells, Human Umbilical Vein Endothelial Cells
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