The bone marrow mesenchymal stem cells derived migrasomes induced by Titania nanotubes surface serve as chemotaxis effect for osteogenesis

The regulatory role of migrasomes (Migs) has attracted growing attentions recently. However, most of the reports only focus on the influence of donor cells on Migs contents, regarding the substrate information. In the present study, the bone marrow mesenchymal stem cells (BMSCs) derived Migs were investigated on titania micropits/nanotubes (MNT) under different anodization voltages. The Migs formation was dependent on nanotubes dimensions, which was the most dominant on MNT5 (anodization under 5 V) surface and in line with ITGA5 expression level. The cargo analysis revealed significant enrichment of chemotaxis, in which the CXCL12 and CCL2 were the top enriched. Afterwards, the Migs could induce similar chemotaxis effect of CXCL12/CXCR4 axis in BMSCs and ECs and CCL2/CCR2 axis in macrophages. Further, the engulfment of Migs could induce significant enhancement of BMSCs osteogenic differentiation, ECs tube formation and macrophages M2 polarization. The in vivo ectopic bone formation model was subcutaneous implantation of biphasic calcium phosphate (BCP)/acylated methacrylate gelatin (GelMA) composite hydrogel with or without Migs. The scaffold could induce abundant cells recruitment 7 days post implantation and the CD90+ or CD31+ cell populations were significantly increased in the presence of Migs. After implantation for 2 and 4 weeks, the new bone growth within scaffold was significantly increased by Migs incorporation, both around BCP backbone and in the space area. In addition, the new bone area showed significant upregulation of CD163, CD31 and OSX. In conclusion, the titania nanotubes induced Migs from BMSCs could both recruit regenerative cells and directly promote osteogenesis, which may represent a new type of therapeutic EVs in bone tissue engineering. Titania nanotubes surface could induce migrasomes (Migs) formation in bone marrow mesenchymal stem cells (BMSCs) through upregulation of integrin alpha 5 subunit. The BMSCs derived Migs were enriched of various chemokines that enable enhanced chemotaxis effects in BMSCs, endothelial cells (ECs) and macrophages. Meanwhile, the Migs could also directly promote osteogenesis, angiogenesis and macrophages M2 polarization both in vitro and in vivo.