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| Author | Cell source | Study type | Cell management | Involvement of Mφ polarization in MSC osteogenic induction | Proposed mechanisms |
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| Gong L 2016 | C57BL/6 mice—BMSCs; C57BL/6 mice—Mφs | In vitro | Coculture of BMSCs and polarized Mφs (M1 induced by LPS and M2 induced by IL-4) with the osteogenic medium | M2 Mφs enhance osteoblast differentiation of MSCs | Proregenerative cytokines (TGF-β, VEGF, and IGF-1) produced by M2 Mφs facilitate MSC osteogenesis |
| Chen Z 2017 | SD rats—BMSCs; RAW 264.7—Mφs | In vitro | CM from nanopore structure/Mφs is applied to stimulate BMSCs under the osteogenic induction medium | Osteogenesis of BMSCs is enhanced by the stimulation of the nanostructure/Mφ CM | Osteogenic pathways (Wnt and BMP) of BMSCs are regulated by different nanopore-induced inflammatory environments |
| Zhang Y 2017 | Human—ADSCs; THP-1—Mφs | In vitro | Direct and indirect coculture of ADSCs and polarized Mφs during osteogenic differentiation (M1 induced by IFN-γ & LPS and M2 induced by IL-4 & IL-13) | M2 Mφs have beneficial effects on ADSC mineralization by promoting their proliferation and osteogenic differentiation | M2 Mφs enhance osteogenic differentiation of MSCs in a manner dependent on OSM and BMP2 signaling pathways |
| Tang H 2017 | Human—ADSCs; THP-1—Mφs | In vitro | 3D spheroid cocultures of M2 Mφs and ADSCs are conducted under osteogenic differentiation conditions | The osteogenic differentiation of ADSCs was inhibited by M2 Mφs | N-cadherin-mediated cell-cell interactions between M2 Mφs and ADMSCs result in inhibited osteogenesis |
| He XT 2018 | C57BL/6 mice—BMSCs; RAW 264.7—Mφs | In vitro | BMSCs incubated with different CMs generated by unpolarized Mφs (M0) or polarized Mφs (M1 and M2) supplemented with osteoinductive media | CM from M2 Mφs exhibits the potential to foster osteogenic differentiation of BMSCs | / |
| Wang J 2018 | C57BL/6 mice—BMSCs; C57BL/6 mice—Mφs | In vitro | BMSCs undergo osteogenic differentiation with NT/Mφ CM | NT-30 induces more M2 Mφs while enhancing BMSC osteogenesis while NT-100 induces M1 Mφ polarization | / |
| Ma QL 2018 | Human—BMSCs; human—Mφs | In vitro & in vivo | In vitro: osteogenic differentiation of BMSCs on different Ti surfaces in CM from Mφs
In vivo: three types of Ti implants inserted in the distal femur | In vitro: the NT surfaces and corresponding CM types together promote osteogenic gene expression in BMSCs, and osteoclast formation is likely promoted by factors (sRANKL, OPG, and M-CSF) secreted by BMSCs cultured in NT20-CM but suppressed in NT5-CM
In vivo: the NT5 and NT20 surfaces lead to enhanced bone formation after 12 weeks postimplantation | NF-κB and BMP pathways activated by the polarized macrophages are involved in both osteogenesis and osteoclastogenesis |
| Jin SS 2019 | Human—BMSCs; THP-1—Mφs | In vitro & in vivo | In vitro: BMSCs are cultured with supernatants of Mφs seeded on scaffolds
In vivo: deplete the Mφs by clodronate liposomes and implant HIMC as a bone graft in rat mandible defect models | In vitro: M2 Mφ polarization induced by HIMC interacts with BMSCs to promote osteogenic differentiation and mineralization
In vivo: the ectopic bone formation stimulated by tricalcium phosphate is blocked by Mφ depletion | HIMC intrinsically promotes M2 Mφ polarization with IL-4 secretion, further enhancing BMSC osteogenesis |
| Sadowska JM 2019 | Human—BMSCs, human—SaOS-2; RAW 264.7—Mφs | In vitro | LPS-stimulated Mφs first cultured on the CaPs and CaP-Mφ-conditioned extracts are incubated with the bone-forming cells (BMSCs and SaOS-2) for osteogenic stimulation | The microenvironment created after culturing Mφs on CDHA showed more potent osteogenic effects, fostering osteogenic differentiation of both BMSCs and SaOS-2 cells | / |
| Tang H 2019 | Human—ADSCs; THP-1—Mφs | In vitro | Mφs (M1, M2) and ADSC coculture on PLGA/PCL scaffolds with osteogenic induction components | Both macrophage subtypes inhibit the osteogenic differentiation of ADMSCs on 3D PLGA/PCL scaffolds | Mφs inhibit osteogenic-related pathways (BMP & OSM signaling) during ADSC differentiation |
| Yang C 2019 | Wistar rats—BMSCs; RAW 264.7—Mφs | In vitro & in vivo | In vitro: BMSCs undergo osteogenesis under the CM collected from Mφs stimulated by Ti+LiCl
In vivo: the air pouch models are injected with Ti+LiCl | In vitro: LiCl promotes M2 polarization, and the better osteogenic differentiation driven by Ti+LiCl-stimulated CM was also observed
In vivo: the LiCl group has fewer infiltrating cells, and thinner fibrous layers further induce higher levels of anti-inflammatory cytokines from M2 | LiCl attenuated wear Ti particle-induced inflammation via the suppression of ERK and p38 phosphorylation |
| Zhu K 2019 | C57BL/6 mice—BMSCs; RAW 264.7—Mφs | In vitro & in vivo | In vitro: crocin-pretreated Mφs indirectly cocultured with BMSCs
In vivo: the air pouch model is treated with Ti particles+crocin | In vitro: crocin-pretreated Mφs provide an immunomodulatory microenvironment that further promotes osteogenic differentiation
In vivo: crocin inhibits Ti particle-induced inflammation and induces M2 polarization | M2 polarization promoted by crocin via the inhibition of p38 and c-Jun N-terminal kinase |
| Lin T 2019 | Balb/c mice—BMSCs; Balb/c mice—Mφs | In vitro | Coculture of BMSCs (preconditioned or genetically modified IL-4-secreting BMSCs) and Mφs directly under the osteogenic medium, including LPS-contaminated polyethylene particles | Both IL-4-secreting BMSCs and preconditioned BMSCs enhance osteogenesis during coculture but at different stages (preconditioned MSCs on day 3 and IL-4-secreting MSCs on day 7) | Enhanced osteogenesis at a later stage associated with the M1-to-M2 Mφ transition |
| Wang C 2019 | NZW rabbits—BMSCs; RAW 264.7—Mφs | In vitro | Osteogenic differentiation of BMSCs with the supernatants of CS- and Sr-CS-pretreated Mφs | Extracts from Mφs cultured in Sr-CS promote Mφ polarization and enhance BMSC osteogenesis | / |
| Wendler S 2019 | C57BL/6 mice—BMSCs; C57BL/6 mice—Mφs | In vitro & in vivo | In vitro: osteogenic differentiation of BMSCs treated with the CM from bone marrow cells and iloprost
In vivo: implantation of a biphasic fibrin scaffold with iloprost into the bone defect | Iloprost decreases the proinflammatory phase and enhances the anti-inflammatory phase to improve bone healing
In vivo: postsurgery of receiving iloprost shows an improved fracture healing outcome of the mice | Iloprost signaling leads to an increase of anti-inflammatory agent cAMP to suppress M1 |
| Wu RX 2019 | SD rats—BMSCs; SD rats—Mφs | In vivo | Rat periodontal defects are implanted with ECM particles and gels | Gel-type bone ECM has a greater tendency toward M2 polarization showing a better healing tendency | / |
| Gao A 2020 | Human—BMSCs; THP-1—Mφs | In vitro & in vivo | In vitro: BMSCs undergo osteogenic differentiation with Mφ CM collected from the PEEK culture system (rinsing in pH 1.8)
In vivo: PEEK (rinsing in pH 1.8) is implanted in the bone defect on the rat femur | In vitro: Mφs in contact with PEEK expressing the M2 phenotype create a more favorable microenvironment for osteogenic differentiation of BMSCs
In vivo: the quality and quantity of newly formed bone surrounding the pH 1.8 implants better than the PEEK and O2 groups | PI3K-Akt signaling, TLR signaling, NLR signaling, and TNF-α signaling all are the mechanisms that alleviate the acute inflammatory response and indirectly enhance osteogenesis |
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