Stimulating Extracellular Vesicles Production from Engineered Tissues by Mechanical Forces

Extracellular vesicles (EVs) have
emerged as a promising strategy
to promote tissue regeneration. However, overcoming the low EV production
yield remains a big challenge in translating EV-based therapies to
the clinical practice. Current EV production relies heavily on 2D
cell culture, which is not only less physiologically relevant to cells
but also requires substantial medium and space. In this study, we
engineered tissues seeded with stem cells from dental pulp or adipose
tissues, or skeletal muscle cells, and significantly enhanced the
EV production yield by applying mechanical stimuli, including flow
and stretching, in bioreactors. Further mechanistic investigation
revealed that this process was mediated by yes-associated protein
(YAP) mechanosensitivity. EVs from mechanically stimulated dental
pulp stem cells on 3D scaffolds displayed superior capability in inducing
axonal sprouting than the 2D counterparts. Our results demonstrate
the promise of this strategy to boost EV production and optimize their
functional performance toward clinical translation.