Abstract
BackgroundMesenchymal stem cell (MSC)-based therapy has the potential for immunomodulation and enhancement of tissue regeneration. Genetically modified 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 mitigate chronic inflammation and enhance osteogenesis by MSC lineage cells. However, exposure to IL-4 prematurely inhibits osteogenesis of MSCs in vitro; furthermore, IL-4 overexpressing MSCs inhibit osteogenesis in vivo during the acute inflammatory period. Platelet-derived growth factor (PDGF)-BB has been shown to enhance osteogenesis of MSCs with a dose-dependent effect.MethodsIn 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 MSCs with PDGF-BB and IL-4-producing lentiviral vectors separately or in combination to investigate cell proliferation and viability, protein expression, and the capability for osteogenesis.ResultsPDGF-BB and IL-4 co-overexpression was observed in the co-infected MSCs and shown to enhance cell proliferation and viability, and osteogenesis compared to IL-4 overexpressing MSCs alone.ConclusionsOverexpression of PDGF-BB together with IL-4 mitigates the inhibitory effect of IL-4 on osteogenesis by IL-4 overexpressing MSCS. PDGF-BB and IL-4 overexpressing MSCs may be a potential strategy to facilitate osteogenesis in scenarios of both acute and chronic inflammation.
Highlights
Mesenchymal stem cell (MSC)-based therapy has the potential for immunomodulation and enhancement of tissue regeneration
Platelet-derived growth factor-BB (PDGF-BB) and IL-4 co-overexpression is successfully generated in co-infected MSC group MSCs were successfully infected by empty vector or single and combined use of lentiviral vectors expressing IL-4 and Platelet-derived growth factor (PDGF)-BB
Infected cells showed fluorescence (GFP/Red fluorescence protein (RFP)) positivity (Fig. 2a, b). 84.2% of BALB/c MSCs and 79.4% of C57BL/6 MSCs in MSCs-IL-4-PDGF group were co-infected by both IL4 and PDGF-BB lentiviral vectors (Fig. 2b)
Summary
Mesenchymal stem cell (MSC)-based therapy has the potential for immunomodulation and enhancement of tissue regeneration. Modified 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 mitigate chronic inflammation and enhance osteogenesis by MSC lineage cells. Specific properties of MSCs, such as the capability for differentiation and potential for immunomodulation, need further refinement to optimize MSC-based therapy [2]. A novel strategy of genetically modified MSC therapy to optimize bone regeneration and remodeling is continuous production of IL-4 by genetically modified MSCs together with a second growth factor to counteract the initial potential adverse effects of IL-4 during the first few days of acute inflammation
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