Establishment of NF-κB sensing and interleukin-4 secreting mesenchymal stromal cells as an “on-demand” drug delivery system to modulate inflammation

Lin, Tzuhua; Pajarinen, Jukka; Nabeshima, Akira; Lu, Laura; Nathan, Karthik; Yao, Zhenyu; Goodman, Stuart B.

doi:10.1016/j.jcyt.2017.06.008

Cited by 45 publications

(83 citation statements)

References 55 publications

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“…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). A similar phenomenon of intermitted stimulus leading to dissimilar and nonstereotypical responses in innate immunity has been reported in studies conducted with macrophages exposed to PAMPs such as b-glucans and LPS and has been named "innate immune memory" or "trained immunity" (14)(15)(16).…”

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confidence: 99%

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

et al. 2018

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Mesenchymal stem cell (MSC)‐mediated immunomodulation affects both innate and adaptive immune systems. These responses to environmental cues, such as pathogen‐associated molecular patterns, damage‐associated molecular patterns, or proinflammatory cytokines, are crucial for resolution of inflammation, as well as successful tissue healing and regeneration. We observed that intermittent, repeated exposure of MSCs to LPS induced stronger NF‐κB activation than singular stimulation. A similar phenomenon, named innate immune memory or trained immunity, has been reported with macrophages. However, the potential regulation of “immune memory” in nonclassic immune cells, such as MSCs, has not been reported. In the current study, we chose IFN‐γ plus TNF‐α restimulation‐induced iNOS expression as a model of MSC activation, because IFN‐γ and TNF‐α play crucial roles in MSC‐mediated immunomodulation. The iNOS expression was enhanced in LPS‐trained MSCs, 3 d after a washout period following primary stimulation. LPS‐trained MSCs enhanced the anti‐inflammatory (arginase 1 and CD206) marker expression, but decreased the proinflammatory marker (TNF‐α, IL‐lβ, iNOS, and IL‐6) expression using an MSC‐macrophage coculture model. In contrast, LPS‐trained MSCs demonstrated a defective regulation on CD4 T‐cell proliferation. Mechanistic studies suggested that histone methylation and the JNK pathway are involved in LPS‐trained immunomodulation in MSCs. Our results demonstrate differential immunomodulatory effects of trained MSCs on macrophages and T cells. These immunomodulatory consequences are critical, because they will have a major impact on current MSC‐based cell therapies.—Lin, T., Pajarinen, J., Kohno, Y., Huang, J.‐F., Maruyama, M., Romero‐Lopez, M., Nathan, K., Yao, Z., Goodman, S. B. Trained murine mesenchymal stem cells have anti‐inflammatory effect on macrophages, but defective regulation on T‐cell proliferation. FASEB J. 33,4203–4211 (2019). http://www.fasebj.org

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confidence: 99%

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

et al. 2018

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“…This simple procedure avoids the potential risk of genetic modification‐mediated cell transformation. In addition, the induction of osteogenesis in the preconditioned MSCs was found in vitro, which was not observed with IL4 secreting MSCs …”

Section: Discussionmentioning

confidence: 82%

“…In addition, the induction of osteogenesis in the preconditioned MSCs was found in vitro, 13 which was not observed with IL4 secreting MSCs. 14 In conclusion, NFκB-IL4 MSC has shown an "on-demand" immunomodulatory ability to mitigate the proinflammatory response and subsequent tissue damage. The therapeutic potential of NFκB-IL4 MSCs in periprosthetic osteolysis or other chronic inflammatory diseases will be further examined in translational in vivo models.…”

Section: Discussionmentioning

confidence: 92%

“…Expression of Arg 1 and CD206 in macrophages co‐cultured with the preconditioned MSCs was increased. In addition, we generated genetically modified MSCs that produce IL4 only in response to inflammatory stimulation and NFκB activation, thus creating an “on‐demand” targeted drug delivery system . These novel strategies have a potential to mitigate chronic inflammatory diseases including periprosthetic osteolysis.…”

Section: Introductionmentioning

confidence: 99%

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NFκB sensing IL‐4 secreting mesenchymal stem cells mitigate the proinflammatory response of macrophages exposed to polyethylene wear particles

Lin

Kohno

Huang

et al. 2018

J Biomedical Materials Res

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Total joint replacement is a highly effective treatment for patients with end-stage arthritis. Proinflammatory macrophages (M1) mediate wear particle-associated inflammation and bone loss. Anti-inflammatory macrophages (M2) help resolve tissue damage and favor bone regeneration. Mesenchymal stem cell (MSC)-based therapy mitigates the M1 dominated inflammatory reaction and favorably modulates the bone remodeling process. In the current study, the immunomodulating ability of (1) unmodified MSCs, (2) MSCs preconditioned by NFκB stimulating ligands [lipopolysaccharide (LPS) plus TNFα], and (3) genetically modified MSCs that secrete IL-4 as a response to NFκB activation (NFκB-IL4) was compared in a macrophage/MSC co-culture system. Sterile or LPS-contaminated ultra-high molecular weight polyethylene particles were used to induce the proinflammatory responses in the macrophages. Contaminated particles induced M1 marker expression (TNFα, IL1β, and iNOS), while NFκB-IL4 MSCs modulated the macrophages from an M1 phenotype into a more favorable M2 phenotype (Arginase 1/Arg 1 and CD206 high). The IL4 secretion by NFκB-IL4 MSCs was significantly induced by the contaminated particles. The induction of Arg 1 and CD206 in macrophages via the preconditioned or naïve MSCs was negligible when compared with NFκB-IL4 MSC. Our findings indicated that NFκB-IL4 MSCs have the "on-demand" immunomodulatory ability to mitigate wear particle-associated inflammation with minimal adverse effects. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2744-2752, 2018.

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“…Modulation of M1 to M2 phenotype at an appropriate time optimized bone regeneration in vitro [3]. However, during the acute (as opposed to the chronic) inflammatory period of bone healing which lasts several days, IL-4 was shown to inhibit osteogenesis by MSCs [4,5]. A novel strategy of GM MSCs therapy to optimize bone regeneration and remodeling is continuous production of IL-4 by GM-MSCs together with a second growth factor to counteract the initial potential adverse effects of IL-4 during the first few days of inflammation.…”

Section: Introductionmentioning

confidence: 99%

PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration

Zhang

Utsunomiya

et al. 2020

Preprint

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Background Mesenchymal stem cell (MSC)-based therapy has the potential for immunomodulation and enhancement of tissue regeneration. Genetically modified (GM) MSCs that over-express specific cytokines, growth factors or chemokines have shown great promise in pre-clinical studies. In this regard, the anti-inflammatory cytokine Interleukin (IL)-4 converts pro-inflammatory M1 macrophages into an anti-inflammatory M2 phenotype; M2 macrophages could potentially enhance osteogenesis by MSC lineage cells. However, IL-4 inhibits osteogenesis during the acute inflammatory period. Platelet-derived growth factor (PDGF)-BB has been shown to enhance osteogenesis of MSCs with a dose-dependent effect. Methods In this study, we generated a lentiviral vector that produces PDGF-BB under a weak promoter (phosphoglycerate kinase, PGK) and lentiviral vector producing IL-4 under a strong promoter (cytomegalovirus, CMV). We infected the MSCs with the PDGF-BB and IL-4-producing lentiviral vectors separately or in combination to investigate protein expression, cell proliferation and viability as well as the capability for osteogenesis. Results Co-overexpression of PDGF-BB and IL-4 was observed in the co-infected MSCs and shown to enhance cell proliferation and viability, and osteogenesis compared to IL-4 overexpressing MSCs alone. Conclusions Thus, overexpression of both PDGF-BB and IL-4 may be a potential strategy to facilitate osteogenesis in scenarios of both acute and chronic inflammation.

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Establishment of NF-κB sensing and interleukin-4 secreting mesenchymal stromal cells as an “on-demand” drug delivery system to modulate inflammation

Cited by 45 publications

References 55 publications

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

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

NFκB sensing IL‐4 secreting mesenchymal stem cells mitigate the proinflammatory response of macrophages exposed to polyethylene wear particles

PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration

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