Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis
Abstract Background Mesenchymal stem cells (MSCs) are capable of immunomodulation and tissue regeneration, highlighting their potential translational application for treating inflammatory bone disorders. MSC-mediated immunomodulation is regulated by proinflammatory cytokines and pathogen-associated...
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doaj-bdb9c4a9a385448699e152d9a02873a12020-11-24T23:28:52ZengBMCStem Cell Research & Therapy1757-65122017-12-01811910.1186/s13287-017-0730-zPreconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesisTzuhua Lin0Jukka Pajarinen1Akira Nabeshima2Laura Lu3Karthik Nathan4Eemeli Jämsen5Zhenyu Yao6Stuart B. Goodman7Department of Orthopaedic Surgery, Stanford University School of MedicineDepartment of Orthopaedic Surgery, Stanford University School of MedicineDepartment of Orthopaedic Surgery, Stanford University School of MedicineDepartment of Orthopaedic Surgery, Stanford University School of MedicineDepartment of Orthopaedic Surgery, Stanford University School of MedicineDepartment of Orthopaedic Surgery, Stanford University School of MedicineDepartment of Orthopaedic Surgery, Stanford University School of MedicineDepartment of Orthopaedic Surgery, Stanford University School of MedicineAbstract Background Mesenchymal stem cells (MSCs) are capable of immunomodulation and tissue regeneration, highlighting their potential translational application for treating inflammatory bone disorders. MSC-mediated immunomodulation is regulated by proinflammatory cytokines and pathogen-associated molecular patterns such as lipopolysaccharide (LPS). Previous studies showed that MSCs exposed to interferon gamma (IFN-γ) and the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) synergistically suppressed T-cell activation. Methods In the current study, we developed a novel preconditioning strategy for MSCs using LPS plus TNF-α to optimize the immunomodulating ability of MSCs on macrophage polarization. Results Preconditioned MSCs enhanced anti-inflammatory M2 macrophage marker expression (Arginase 1 and CD206) and decreased inflammatory M1 macrophage marker (TNF-α/IL-1Ra) expression using an in-vitro coculture model. Immunomodulation of MSCs on macrophages was significantly increased compared to the combination of IFN-γ plus TNF-α or single treatment controls. Increased osteogenic differentiation including alkaline phosphate activity and matrix mineralization was only observed in the LPS plus TNF-α preconditioned MSCs. Mechanistic studies showed that increased prostaglandin E2 (PGE2) production was associated with enhanced Arginase 1 expression. Selective cyclooxygenase-2 inhibition by Celecoxib decreased PGE2 production and Arginase 1 expression in cocultured macrophages. Conclusions The novel preconditioned MSCs have increased immunomodulation and bone regeneration potential and could be applied to the treatment of inflammatory bone disorders including periprosthetic osteolysis, fracture healing/nonunions, and osteonecrosis.http://link.springer.com/article/10.1186/s13287-017-0730-zMesenchymal stem cellsImmunomodulationMacrophage polarizationOsteogenesisProstaglandin E2 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tzuhua Lin Jukka Pajarinen Akira Nabeshima Laura Lu Karthik Nathan Eemeli Jämsen Zhenyu Yao Stuart B. Goodman |
spellingShingle |
Tzuhua Lin Jukka Pajarinen Akira Nabeshima Laura Lu Karthik Nathan Eemeli Jämsen Zhenyu Yao Stuart B. Goodman Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis Stem Cell Research & Therapy Mesenchymal stem cells Immunomodulation Macrophage polarization Osteogenesis Prostaglandin E2 |
author_facet |
Tzuhua Lin Jukka Pajarinen Akira Nabeshima Laura Lu Karthik Nathan Eemeli Jämsen Zhenyu Yao Stuart B. Goodman |
author_sort |
Tzuhua Lin |
title |
Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis |
title_short |
Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis |
title_full |
Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis |
title_fullStr |
Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis |
title_full_unstemmed |
Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis |
title_sort |
preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis |
publisher |
BMC |
series |
Stem Cell Research & Therapy |
issn |
1757-6512 |
publishDate |
2017-12-01 |
description |
Abstract Background Mesenchymal stem cells (MSCs) are capable of immunomodulation and tissue regeneration, highlighting their potential translational application for treating inflammatory bone disorders. MSC-mediated immunomodulation is regulated by proinflammatory cytokines and pathogen-associated molecular patterns such as lipopolysaccharide (LPS). Previous studies showed that MSCs exposed to interferon gamma (IFN-γ) and the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) synergistically suppressed T-cell activation. Methods In the current study, we developed a novel preconditioning strategy for MSCs using LPS plus TNF-α to optimize the immunomodulating ability of MSCs on macrophage polarization. Results Preconditioned MSCs enhanced anti-inflammatory M2 macrophage marker expression (Arginase 1 and CD206) and decreased inflammatory M1 macrophage marker (TNF-α/IL-1Ra) expression using an in-vitro coculture model. Immunomodulation of MSCs on macrophages was significantly increased compared to the combination of IFN-γ plus TNF-α or single treatment controls. Increased osteogenic differentiation including alkaline phosphate activity and matrix mineralization was only observed in the LPS plus TNF-α preconditioned MSCs. Mechanistic studies showed that increased prostaglandin E2 (PGE2) production was associated with enhanced Arginase 1 expression. Selective cyclooxygenase-2 inhibition by Celecoxib decreased PGE2 production and Arginase 1 expression in cocultured macrophages. Conclusions The novel preconditioned MSCs have increased immunomodulation and bone regeneration potential and could be applied to the treatment of inflammatory bone disorders including periprosthetic osteolysis, fracture healing/nonunions, and osteonecrosis. |
topic |
Mesenchymal stem cells Immunomodulation Macrophage polarization Osteogenesis Prostaglandin E2 |
url |
http://link.springer.com/article/10.1186/s13287-017-0730-z |
work_keys_str_mv |
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