Apoptotic Extracellular Vesicles Induced Endothelial Cell-Mediated Autologous Stem Cell Recruitment Dominates Allogeneic Stem Cell Therapeutic Mechanism for Bone Repair

Although
stem cell therapy is proved to be a promising strategy
for bone repair and regeneration, transplanted allogeneic stem cells
generally suffer from unfavorable apoptosis instead of differentiation
into osteocytes. How the apoptotic stem cells promote bone regeneration
still needs to be uncovered. In this work, we found that apoptotic
extracellular vesicles released by allogeneic stem cells are critical
mediators for promoting bone regeneration. Based on the results of in vivo experiments, a mechanism of apoptotic stem cells
determined autologous stem cell recruitment and enhance osteogenesis
was proposed. The nanoscaled apoptotic extracellular vesicles released
from transplanted stem cells were endocytosed by vascular endothelial
cells and preferentially distribute at endoplasmic reticular region.
The oxidized phosphatidylcholine enriched in the vesicles activated
the endoplasmic reticulum stress and triggered the reflective elevation
of adhesion molecules, which induced the recruitment of autologous
stem cells located in the blood vessels, transported them into the
defect region, and promoted osteogenesis and bone repair. These findings
not only reveal the mechanism of stem cell therapy of bone defects
but also provide a cue for investigation of the biological process
of stem cell therapy for other diseases and develop stem cell therapeutic
strategies.