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Macrophage-Mediated Bone Formation of Scaffolds Modified with MSC-derived Extracellular Matrix Depends on Migration Inhibitory Factor Signaling Pathway

ABSTRACT: Recently the role of macrophages on osteogenesis of mesenchymal stem cells (MSCs) is brought to focus. On the other hand, the cross-talk between macrophages and MSCs confirms that the paracrine molecules derived from macrophages are also carefully regulated by MSCs. Human umbilical cord mesenchymal stem cells (hucMSCs) could reduce secretions of inflammatory factors from macrophages for improving injury healing. hucMSC-derived extracellular matrix (hucMSC-ECM) exhibit nature similar to hucMSCs. It has been demonstrated that hucMSC-ECM possess considerable effects on reducing inflammatory response of macrophages, while the role of hucMSC-ECM on the expression of macrophage-derived paracrine osteogenic molecules is unclear. Here, we presented the decalcified bone scaffolds modified by hucMSC-derived extracellular matrix (DBM-ECM) maintaining multiple soluble cytokines including macrophage migration inhibitory factor (MIF). Compared with DBM, the DBM-ECM scaffolds induced bone formation in a macrophage-depending manner by an improved heterotopic ossification in SCID mice with or without macrophage depletion. Macrophage cocultured with the DBM-ECM expressed four osteoinductive cytokines (BMP2, FGF2, TGFβ3 and OSM), which were screen out by RNA sequencing, qPCR and western blot. The conditioned medium from macrophages cocultured with the DBM-ECM improved osteogenic differentiation of hBMSCs and activated CD74/CD44 signal transduction including phosphorylation of P38 and dephosphorylation of c-jun. Furthermore, the inhibitory effects of the DBM-ECM scaffolds with knockdown of MIF on osteogenesis in vitro and in vivo revealed that macrophage-mediated osteogenesis depends on MIF/CD74/ P38 signal transduction. This study indicates the coordinated crosstalk of macrophages and MSCs play a key role on bone regeneration induced by the DBM-ECM, with the emphasis on the constructing macrophage-derived osteoimmunological microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE174477 | GEO | 2021/10/13

REPOSITORIES: GEO

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Project description:Background: The therapeutic and protective efects of human umbilical cord mesenchymal stem cells-exosomes (hucMSC-Exs) on traumatic pancreatitis (TP) remain unknown. Here, we established a rat model of TP and evaluated and compared the therapeutic efects of hucMSC-Exs. Methods: HucMSC-Exs were obtained by ultracentrifugation and identifed using transmission electron microscopy and western blot analysis. TP rats were treated by tail vein injection of hUC-MSCs and hucMSC-Exs. Their homing in rats was observed by performing fuorescence microscopy. Rat pancreatic tissue was subjected to high-throughput sequence to determine transcriptome expression levels. The degree of pancreatic tissue damage was assessed by HE staining, the expression levels of amylase, lipase, and infammatory cytokines were detected by ELISA, apoptosis was detected by TUNEL assay, and the expression levels of various apoptosis-related proteins were detected by western-blot. The expression levels of apoptosis-related molecular markers were detected by RT-qPCR. Results: The colonization of exosomes was observed in pancreatic tissue. Compared to TP group, the histopathological score of pancreas was signifcantly decreased in the TP+hucMSC-Exs group (P<0.05). Compared to TP group, the activity of serum amylase and lipase was signifcantly decreased (P<0.05). The expression levels of IL-6 and TNF-α were signifcantly decreased, while those of IL-10 and TGF-β were signifcantly increased (P<0.05). The apoptosis index of the TP group was signifcantly increased (P<0.05), whereas that of the TP+hucMSC-Exs groups was signifcantly decreased (P<0.05). Compared to TP group, the expression levels of Bax, Bcl-2, and Caspase-3 were signifcantly decreased in the TP+hUC-MSCs group and TP+hucMSC-Exs group (P<0.05). Conclusion: HucMSC-Exs can colonize injured pancreatic tissue, inhibit the apoptosis of acinar cells, and control the systemic infammatory response to facilitate the repair of pancreatic tissue.

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Macrophage-Mediated Bone Formation of Scaffolds Modified with MSC-derived Extracellular Matrix Depends on Migration Inhibitory Factor Signaling Pathway

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