# Mechanical Cues and Lineage Commitment Govern the Angiogenic Potential of Mesenchymal Cell‐Derived Extracellular Vesicles

## TL;DR

This paper shows that mechanically stimulated osteocyte-derived extracellular vesicles can boost blood vessel growth, offering a new approach for better bone repair.

## Contribution

The study demonstrates that mechanical cues and cell differentiation stage modulate EV angiogenic potential, with osteocyte-derived EVs being most effective.

## Key findings

- Mechanically stimulated osteocyte-derived EVs enhance endothelial cell migration and tube formation.
- These EVs promote CD31 expression and induce robust neovascularization in a pre-clinical model.

## Abstract

Bone regeneration requires a finely tuned interplay between osteogenesis and angiogenesis. While current treatments, such as auto/allografts, provide support, they often fail to promote adequate vascularization necessary for complete repair. Extracellular vesicles (EVs), as mediators of intercellular communication, have emerged as promising acellular nanotechnologies for tissue regeneration due to their bioactive cargo and low immunogenicity. Mechanical stimulation, a known enhancer of bone cell function, can modulate EV cargo and potentially improve regenerative efficacy. In this study, we investigated how mechanical stimulation and the stage of mesenchymal lineage commitment influence the angiogenic potential of secretomes and EVs derived from mesenchymal stromal/stem cells, osteoblasts, and osteocytes. Our findings reveal that both cell mechanical stimulation and their differentiation stage significantly modulate the angiogenic properties of the resulting EVs. Among the tested conditions, mechanically‐stimulated osteocyte‐derived EVs demonstrate superior angiogenesis, promoting endothelial cell migration, tube formation, and CD31 expression. These effects were further validated in a pre‐clinical ex ovo chick chorioallantoic membrane assay, where robust neovascularization was observed. This work highlights the critical role of both mechanical cues and cell differentiation stage in regulating the angiogenic capacity of EVs and proposes mechanically activated osteocyte‐derived EVs as a novel pro‐angiogenic nanotherapeutic for bone repair.

Bone healing relies on coordinated osteogenic and angiogenic processes, yet current grafts seldom achieve sufficient vascularization. Emerging evidence shows that mechanically stimulated cells release extracellular vesicles with enhanced regenerative potential. This study reveals how mechanical cues and differentiation stage shape EV‑driven angiogenesis, highlighting osteocyte‑derived EVs as particularly potent and suggesting a promising nanotherapeutic avenue for improved bone repair.