Cell-Matrix Interactions Regulate Functional Extracellular Vesicle Secretion from Mesenchymal Stromal Cells

Stephen 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

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)17439-17452
Number of pages14
JournalACS nano
Volume15
Issue number11
DOIs
Publication statusPublished - Nov 23 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Materials Science
  • General Engineering
  • General Physics and Astronomy

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