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

doi:10.1021/acsnano.1c03231

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 journal › Article › peer-review

6 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 language	English
Pages (from-to)	17439-17452
Number of pages	14
Journal	ACS nano
Volume	15
Issue number	11
DOIs	https://doi.org/10.1021/acsnano.1c03231
Publication status	Published - Nov 23 2021
Externally published	Yes

All Science Journal Classification (ASJC) codes

Materials Science(all)
Engineering(all)
Physics and Astronomy(all)

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10.1021/acsnano.1c03231

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@article{14d132dd1a6a46238f1f793fa22e7924,

title = "Cell-Matrix Interactions Regulate Functional Extracellular Vesicle Secretion from Mesenchymal Stromal Cells",

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.",

author = "Stephen Lenzini and Koushik Debnath and Joshi, {Jagdish C.} and Wong, {Sing Wan} and Kriti Srivastava and Xue Geng and Cho, {Ik Sung} and Angela Song and Raymond Bargi and Lee, {James C.} and Mo, {Gary C.H.} and Dolly Mehta and Shin, {Jae Won}",

note = "Funding Information: We acknowledge P. Toth from the Fluorescence Imaging Core, B. Ganesh from the Flow Cytometry Core, and F. Seiler from the Electron Microscopy Core at the University of Illinois at Chicago, as well as the Analytical bioNanoTechnology Core (ANTEC) at Northwestern University for their help and support. We thank S. Rayees and M.Z. Akhter from the laboratory of D. Mehta (UIC) for technical advice on a mouse model of acute lung injury. This work made use of instruments in the Fluorescence Imaging Core (Research Resources Center, UIC). This work was supported by National Institutes of Health Grant R01-HL141255 (J.-W.S.), R01-GM141147 (J.-W.S.), R00-HL125884 (J.-W.S.), R01-HL084153 (D.M.), R01-AG044404 (J.C.L.), T32-HL07829 (S.L.), and American Heart Association Grant 19PRE34380087 (S.L.). Publisher Copyright: {\textcopyright} ",

year = "2021",

month = nov,

day = "23",

doi = "10.1021/acsnano.1c03231",

language = "English",

volume = "15",

pages = "17439--17452",

journal = "ACS Nano",

issn = "1936-0851",

publisher = "American Chemical Society",

number = "11",

}

TY - JOUR

T1 - Cell-Matrix Interactions Regulate Functional Extracellular Vesicle Secretion from Mesenchymal Stromal Cells

AU - Lenzini, Stephen

AU - Debnath, Koushik

AU - Joshi, Jagdish C.

AU - Wong, Sing Wan

AU - Srivastava, Kriti

AU - Geng, Xue

AU - Cho, Ik Sung

AU - Song, Angela

AU - Bargi, Raymond

AU - Lee, James C.

AU - Mo, Gary C.H.

AU - Mehta, Dolly

AU - Shin, Jae Won

N1 - Funding Information: We acknowledge P. Toth from the Fluorescence Imaging Core, B. Ganesh from the Flow Cytometry Core, and F. Seiler from the Electron Microscopy Core at the University of Illinois at Chicago, as well as the Analytical bioNanoTechnology Core (ANTEC) at Northwestern University for their help and support. We thank S. Rayees and M.Z. Akhter from the laboratory of D. Mehta (UIC) for technical advice on a mouse model of acute lung injury. This work made use of instruments in the Fluorescence Imaging Core (Research Resources Center, UIC). This work was supported by National Institutes of Health Grant R01-HL141255 (J.-W.S.), R01-GM141147 (J.-W.S.), R00-HL125884 (J.-W.S.), R01-HL084153 (D.M.), R01-AG044404 (J.C.L.), T32-HL07829 (S.L.), and American Heart Association Grant 19PRE34380087 (S.L.). Publisher Copyright: ©

PY - 2021/11/23

Y1 - 2021/11/23

N2 - 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.

AB - 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.

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U2 - 10.1021/acsnano.1c03231

DO - 10.1021/acsnano.1c03231

M3 - Article

C2 - 34677951

AN - SCOPUS:85118952303

SN - 1936-0851

VL - 15

SP - 17439

EP - 17452

JO - ACS Nano

JF - ACS Nano

IS - 11

ER -

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

Abstract

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