posted on 2021-10-22, 19:35authored byStephen Lenzini, Koushik Debnath, Jagdish C. Joshi, Sing Wan Wong, Kriti Srivastava, Xue Geng, Ik Sung Cho, Angela Song, Raymond Bargi, James C. Lee, Gary C.H. Mo, Dolly Mehta, Jae-Won Shin
Extracellular
vesicles (EVs) are cell-secreted particles with broad
potential to treat tissue injuries by delivering cargo to program
target cells. However, improving the yield of functional EVs on a
per cell basis remains challenging due to an incomplete understanding
of how microenvironmental cues regulate EV secretion at the nanoscale.
We show that mesenchymal stromal cells (MSCs) seeded on engineered
hydrogels that mimic the elasticity of soft tissues with a lower integrin
ligand density secrete ∼10-fold more EVs per cell than MSCs
seeded on a rigid plastic substrate, without compromising their therapeutic
activity or cargo to resolve acute lung injury in mice. Mechanistically,
intracellular CD63+ multivesicular bodies (MVBs) transport
faster within MSCs on softer hydrogels, leading to an increased frequency
of MVB fusion with the plasma membrane to secrete more EVs. Actin-related
protein 2/3 complex but not myosin-II limits MVB transport and EV
secretion from MSCs on hydrogels. The results provide a rational basis
for biomaterial design to improve EV secretion while maintaining their
functionality.