Extracellular vesicles derived from neural EGFL-Like 1-modified mesenchymal stem cells improve acellular bone regeneration via the miR-25-5p-SMAD2 signaling axis.

Abstract

Stem cell based transplants effectively regenerate tissues; however, limitations such as immune rejection and teratoma formation prevent their application. Extracellular vesicles (EVs)-mediated acellular tissue regeneration is a promising alternative to stem cell based transplants. Although neural EGFL-like 1 (<i>Nell1</i>) is known to contribute to the osteogenic differentiation of bone marrow stem cells (BMSCs), it remains unknown whether EVs are involved in this process. Here, we present that EVs derived from <i>Nell1</i>-modified BMSCs (<i>Nell1</i>/EVs) have a stronger ability to promote BMSC osteogenesis owing to miR-25-5p downregulation. MiR-25-5p inhibits osteogenesis by targeting <i>Smad2</i> and suppressing the SMAD and extracellular signal-related kinase 1 and 2 (ERK1/2) pathway activation. In addition, we demonstrate that the 3D-<i>Nell1</i>/EV-hydrogel system is beneficial for bone regeneration <i>in vivo</i>, probably stemming from a slow, continuous release and high concentration of EVs in the bone defect area. Thus, our results have shown the potential of <i>Nell1</i>/EVs as a novel acellular bone regeneration strategy. Mechanistically, the identification of miR-25-5p-SMAD2 signaling axis expands the knowledge of <i>Nell1</i>/EVs induced osteogenesis.