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The journal of gene medicine2018; 20(5); e3021; doi: 10.1002/jgm.3021

Cytokine-induced interleukin-1 receptor antagonist protein expression in genetically engineered equine mesenchymal stem cells for osteoarthritis treatment.

Abstract: A combination of tissue engineering methods employing mesenchymal stem cells (MSCs) together with gene transfer takes advantage of innovative strategies and highlights a new approach for targeting osteoarthritis (OA) and other cartilage defects. Furthermore, the development of systems allowing tunable transgene expression as regulated by natural disease-induced substances is highly desirable. Bone marrow-derived equine MSCs were transduced with a lentiviral vector expressing interleukin-1 receptor antagonist (IL-1Ra) gene under the control of an inducible nuclear factor-kappa B-responsive promoter and IL-1Ra production upon pro-inflammatory cytokine stimulation [tumor necrosis factor (TNF)α, interleukin (IL)-1β] was analysed. To assess the biological activity of the IL-1Ra protein that was produced and the therapeutic effect of IL-1Ra-expressing MSCs (MSC/IL-1Ra), cytokine-based two- and three-dimensional in vitro models of osteoarthritis using equine chondrocytes were established and quantitative real-time polymerase chain reaction (PCR) analysis was used to measure the gene expression of aggrecan, collagen IIA1, interleukin-1β, interleukin-6, interleukin-8, matrix metalloproteinase-1 and matrix metalloproteinase-13. A dose-dependent increase in IL-1Ra expression was found in MSC/IL-1Ra cells upon TNFα administration, whereas stimulation using IL-1β did not lead to IL-1Ra production above the basal level observed in nonstimulated cells as a result of the existing feedback loop. Repeated cycles of induction allowed on/off modulation of transgene expression. In vitro analyses revealed that IL-1Ra protein present in the conditioned medium from MSC/IL-1Ra cells blocks OA onset in cytokine-treated equine chondrocytes and co-cultivation of MSC/IL-1Ra cells with osteoarthritic spheroids alleviates the severity of the osteoarthritic changes. Thus, pro-inflammatory cytokine induced IL-1Ra protein expression from genetically modified MSCs might represent a promising strategy for osteoarthritis treatment.
© 2018 The Authors. The Journal of Gene Medicine published by John Wiley & Sons, Ltd.
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Publication Date: 2018-04-22 PubMed ID: 29608232PubMed Central: PMC6001542DOI: 10.1002/jgm.3021Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research article explores the use of genetically engineered equine mesenchymal stem cells (MSCs) with modified expression of interleukin-1 receptor antagonist (IL-1Ra) protein to alleviate osteoarthritis. The study noted an innovative approach where the IL-1Ra gene production is influenced by disease-induced factors, showing promising results in blocking the onset of osteoarthritis and reducing its severity.

Methodology

  • The researchers genetically modified Mesenchymal Stem Cells (MSCs) derived from horse bone marrow to express the interleukin-1 receptor antagonist (IL-1Ra) gene. This gene was regulated by an inducible nuclear factor-kappa B-responsive promoter – a type of “switch” that can turn the gene on or off.
  • The genetically engineered MSCs (MSC/IL-1Ra) were exposed to pro-inflammatory cytokines, which are molecular messengers involved in cell-to-cell communication during immune responses. In this case, the cytokines used were tumor necrosis factor (TNF)α, and interleukin (IL)-1β. Their impact on IL-1Ra production was analyzed.
  • The biological activity of the IL-1Ra protein produced, and the therapeutic effect of MSC/IL-1Ra, were assessed using two- and three-dimensional in vitro (outside of a living organism) models of equine osteoarthritis.
  • Using quantitative real-time polymerase chain reaction (PCR) analysis, the researchers measured the gene expression of several significant components associated with bone and cartilage health, as well as inflammatory responses in the body. These include aggrecan, collagen IIA1, interleukin-1β, interleukin-6, interleukin-8, matrix metalloproteinase-1, and matrix metalloproteinase-13.

Findings

  • Following exposure to TNFα, there was a dose-dependent increase in IL-1Ra expression from the MSC/IL-1Ra cells. However, exposure to IL-1β did not cause increased IL-1Ra production beyond the baseline level found in non-stimulated cells. The latter is likely due to the existing feedback loop within the system.
  • The lab tests showed that the IL-1Ra protein was able to block the onset of osteoarthritis in the equine chondrocytes (cartilage cells) that were treated with cytokines. Furthermore, when MSV/IL-1Ra cells were co-cultured with osteoarthritic spheroids (3D clusters of cells), the severity of osteoarthritic changes was reduced.

Implications

The results of this research indicate that pro-inflammatory cytokine-induced IL-1Ra protein expression in genetically modified MSCs could be a promising approach for treating osteoarthritis. This potentially represents a new and innovative strategy for managing this common and debilitating condition, using the body’s own cellular mechanisms to mitigate the disease. Further research will be necessary to confirm and expand upon these promising findings.

Cite This Article

APA
Gabner S, Ertl R, Velde K, Renner M, Jenner F, Egerbacher M, Hlavaty J. (2018). Cytokine-induced interleukin-1 receptor antagonist protein expression in genetically engineered equine mesenchymal stem cells for osteoarthritis treatment. J Gene Med, 20(5), e3021. https://doi.org/10.1002/jgm.3021

Publication

The journal of gene medicine
ISSN: 1521-2254
NlmUniqueID: 9815764
Country: England
Language: English
Volume: 20
Issue: 5
Pages: e3021
PII: e3021

Researcher Affiliations

Gabner, Simone
  • Institute of Pathology and Forensic Veterinary Medicine, Working Group Histology and Embryology, University of Veterinary Medicine Vienna, Vienna, Austria.
Ertl, Reinhard
  • VetCORE, Facility for Research, University of Veterinary Medicine, Vienna, Austria.
Velde, Karsten
  • Equine University Hospital, University of Veterinary Medicine Vienna, Vienna, Austria.
Renner, Matthias
  • Division of Medical Biotechnology, Paul-Ehrlich-Institut, Langen, Germany.
Jenner, Florien
  • Equine University Hospital, University of Veterinary Medicine Vienna, Vienna, Austria.
Egerbacher, Monika
  • Institute of Pathology and Forensic Veterinary Medicine, Working Group Histology and Embryology, University of Veterinary Medicine Vienna, Vienna, Austria.
Hlavaty, Juraj
  • Institute of Pathology and Forensic Veterinary Medicine, Working Group Histology and Embryology, University of Veterinary Medicine Vienna, Vienna, Austria.

MeSH Terms

  • Animals
  • Cells, Cultured
  • Chondrocytes / cytology
  • Chondrocytes / metabolism
  • Cytokines / pharmacology
  • Gene Expression / drug effects
  • Genetic Engineering / methods
  • Genetic Therapy / methods
  • Horse Diseases / genetics
  • Horse Diseases / pathology
  • Horse Diseases / therapy
  • Horses
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / genetics
  • Interleukin 1 Receptor Antagonist Protein / metabolism
  • Lentivirus / genetics
  • Male
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism
  • Osteoarthritis / genetics
  • Osteoarthritis / pathology
  • Osteoarthritis / therapy
  • Tumor Necrosis Factor-alpha / pharmacology

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