Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis

Abstract

BackgroundMesenchymal 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.MethodsIn 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.ResultsPreconditioned 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0730-z) contains supplementary material, which is available to authorized users.

Hormetic approaches to the treatment of Parkinson's disease: Perspectives and possibilities

“…Moreover, hormetic bi‐phasic dose‐responses may be involved in the process of macrophage reprogramming and polarization that is produced by chemicals, as well as ionizing radiation (Genard, Lucas & Michiels, ; Walton, ; Wu et al, ). Other studies have shown that preconditioning‐induced protection responses are associated with increased M2 polarization across multiple organs/cell types (e.g., bone, Young et al, ; spinal cord, Hayakawa et al, ; mesenchymal stem cells, Lin et al, , Mountziaris, Tzouanas, & Mikos, ; Kidney, Hato et al, ) reflecting the generality of the adaptive strategy. These findings suggest that hormetic mechanisms may play a role in mediating M1 or M2 macrophagic cell (e.g., microglial) phenotypes that respectively mediate pro and/or anti‐inflammatory functions that are likely operative in pathologic and adaptive processes.…”

Trained murine mesenchymal stem cells have anti‐inflammatory effect on macrophages, but defective regulation on T‐cell proliferation

“…Mouse MSCs were treated with 20 mg/ml LPS for 24 h or otherwise as indicated below. The dose of LPS was determined based on a previous study (10). The trained MSCs were washed by PBS and incubated with fresh medium without LPS for 3 d before the secondary stimulations (Fig.…”

“…Recent studies indicate that proinflammatory stimulation may have prolonged effects on the function of MSCs. MSCs preconditioned by transient exposure to inflammatory cytokines alone or combined with PAMP enhanced immunomodulation and tissue regeneration (10)(11)(12). We recently observed that when MSCs were exposed to LPS repeatedly, NF-kB activation was significantly increased compared with single LPS exposure (13).…”

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“…The biological responses of MSCs to inflammatory stimulation could further enhance the immunomodulatory and tissue regenerative abilities of MSC‐based therapy . Indeed, by simulating the proinflammatory environment, we found that MSCs preconditioned with TNFα and LPS synergistically enhanced osteogenic capacity . Expression of Arg 1 and CD206 in macrophages co‐cultured with the preconditioned MSCs was increased.…”

“…Due to these properties, MSC‐based therapy has been applied in more than 400 clinical trials including bone regeneration and chronic inflammatory diseases . The biological responses of MSCs to inflammatory stimulation could further enhance the immunomodulatory and tissue regenerative abilities of MSC‐based therapy . Indeed, by simulating the proinflammatory environment, we found that MSCs preconditioned with TNFα and LPS synergistically enhanced osteogenic capacity .…”