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ESCRT-independent pathway Early endosome Endosome MVB ESCRT-dependent pathway Tetraspanin Exosome Membrane surface marker Endosome membrane Golgi apparatus MESENCHYMAL STROMAL CELL Endocytosis Exosomes 1. Membrane proteins accumulate into microdomains on late endosomes or at PM domains, then cluster via the ESCRT-0/ESCRT-I or ceramide/tetraspanin pathways. 2. Exosome cargo is sequestered from the cytoplasm to the endosome surface. 3. Inward budding of the endosomal membrane is directed by either ESCRT-II/ESCRT-III binding or 4 MVBs are delivered to the plasma membrane and dock and SNARE proteins. 5 The MVB fuses with the plasma membrane, releasing the exosomes into the extracellular space. Membrane proteins and export-tagged molecules cluster at microdomain sites. 1 2+ dependent enzymes) triggers a physical restructuring of the PM to promote outward bud release via shedding. 2 Microvesicle ESCRT-I ESCRT-II Ub Ub ESCRT-0 ESCRT-I Ub RNA Proteins ESCRT-III 1 2 3 Ceramide ESCRT-I Ub Ub ESCRT-0 ESCRT-I Ub Exosomes bind to surface receptors on the PM of the recipient cell. 1 Exosomes release their contents via direct membrane fusion or and subsequent fusion with endosomal membranes. 2 RECIPIENT CELL Document # 10000005955 Version 00 | For Internal Use Only Material # 27162 Gorgun, C. et al. cells. Curr. Protoc. Stem Cell Biol. 48, e76 (2019). Busato, A. et al. Curr. Protoc. Cell Biol. 75, 3.44.1-3.44.15 (2017). Curr. Protoc. Immunol. 115, 14.42.1-14.42.21 (2016). Curr. Protoc. Cell Biol. 30, 3.22.1-3.22.29 (2006). MesenCult™-ACF Plus Culture Kit proteins CD9, CD63 or CD81, or pan-tetraspanin expression. Visit . References Cytotherapy 17, 1514–1523 (2015). 2. Banas, A. et al. Hepatology 46, 219–228 (2007). 3. Dong, Q. et al. Methods Mol. Biol. 1922, 91–101 (2019). Stem Cells Int 2016, 6901286 (2016). 5. Zou, L. et al. Sci Rep 3, 2243 (2013). et al. Stem Cells 37, 572–581 (2019). et al. 497, 305–312 (2018). Physiology 34, 169–177 (2019). Nat. Rev. Mol. Cell Biol. 19, 213–228 (2018). Nat Cell Biol 21, 9–17 (2019). PROTEOMICS 19, 1800397 (2019). et al. Stem Cell Research & Therapy 6, 127 (2015). et al. Cells 8, 22 (2019). J Biotechnol 241, 136–146 (2017). 15. Wang, X. et al. 5, 13721 (2015). et al. The FASEB Journal 32, 6038–6050 (2018). mRNA: miRNA: Cytokines: 11,12 13 • miR-146a: 14 • miR-223: 15 • miR-147: 16 et al. Biogenesis, Release, and Uptake of Extracellular Vesicles Mesenchymal Stromal Cell- erived Exosomes: Biogenesis and Cargoes M 1 8–10 9,10 are recipient cells.

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Page 1: Mesenchymal Stromal Cell- erived Exosomes: Biogenesis and ... · . o u v U Z Z } 'dW U 2+ dependent enzymes) triggers a physical restructuring of the PM to promote outward bud ( }

ESCRT-independentpathway

Earlyendosome

Endosome

MVB

ESCRT-dependentpathway

Tetraspanin

Exosome

Membranesurface marker

Endosome membrane

Golgiapparatus

MESENCHYMALSTROMAL CELL

Endocytosis

Exosomes

1. Membrane proteins accumulate intomicrodomains on late endosomes orat PM domains, then cluster via theESCRT-0/ESCRT-I orceramide/tetraspanin pathways.

2. Exosome cargo issequestered from thecytoplasm to theendosome surface.

3. Inward budding of the endosomal membrane isdirected by either ESCRT-II/ESCRT-III binding or

MVBs are delivered to the plasma membrane and dock

and SNARE proteins.

The MVB fuses with the plasma membrane, releasing the exosomes into the extracellular space.

Membrane proteins and export-tagged molecules cluster at microdomain sites.

2+ dependent enzymes) triggers a physical restructuring of the PM to promote outward bud

release via shedding.

Microvesicle

ESCRT-I

ESCRT-II

Ub UbESCRT-0

ESCRT-I

RNA

Proteins ESCRT-III

1 2 3

Ceramide

ESCRT-IUb Ub

ESCRT-0

ESCRT-I

Exosomes bind to surface receptors on the PM of the recipient cell.

Exosomes release their contents via direct membrane fusion or

and subsequent fusion with endosomal membranes.

RECIPIENT CELL

Document # 10000005955 Version 00 | For Internal Use Only Material # 27162

Gorgun, C. et al.

cells. Curr. Protoc. Stem Cell Biol. 48, e76 (2019).

Busato, A. et al.Curr. Protoc. Cell Biol. 75, 3.44.1-3.44.15 (2017).

Curr. Protoc. Immunol. 115, 14.42.1-14.42.21 (2016).

Curr. Protoc. Cell Biol. 30, 3.22.1-3.22.29 (2006).

MesenCult™-ACF Plus Culture Kit

proteins CD9, CD63 or CD81, or pan-tetraspanin expression.

Visit

References

Cytotherapy 17, 1514–1523 (2015).2. Banas, A. et al.

Hepatology 46, 219–228 (2007).3. Dong, Q. et al.

Methods Mol. Biol. 1922, 91–101 (2019).

Stem Cells Int 2016, 6901286 (2016).5. Zou, L. et al.

Sci Rep 3, 2243 (2013).et al.

Stem Cells37, 572–581 (2019).

et al.

497, 305–312 (2018).

Physiology 34, 169–177 (2019).

Nat. Rev.Mol. Cell Biol. 19, 213–228 (2018).

Nat Cell Biol 21, 9–17 (2019).

PROTEOMICS 19, 1800397 (2019).et al.

Stem Cell Research & Therapy 6, 127 (2015).et al.

Cells 8, 22 (2019).

J Biotechnol 241, 136–146(2017).

15. Wang, X. et al. 5, 13721 (2015).

et al.The FASEB Journal 32, 6038–6050 (2018).

mRNA:

miRNA:

Cytokines:

11,12

• miR-146a:

• miR-223:

• miR-147:

16et al.

Biogenesis, Release, and Uptake of Extracellular Vesicles

Mesenchymal Stromal Cell- erived Exosomes: Biogenesis and CargoesM

8–10

9,10 are

recipient cells.

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