Endosomal signalling via exosome surface TGFβ-1

Ganesh Vilas Shelke; Yanan Yin; Su Chul Jang; Cecilia Lässer; Stefan Wennmalm; Hans Jürgen Hoffmann; Li Li; Yong Song Gho; Jonas Andreas Nilsson; Jan Lötvall

doi:10.1080/20013078.2019.1650458

Endosomal signalling via exosome surface TGFβ-1

J Extracell Vesicles. 2019 Sep 20;8(1):1650458. doi: 10.1080/20013078.2019.1650458. eCollection 2019.

Authors

Ganesh Vilas Shelke^{1

2}, Yanan Yin^{1

3}, Su Chul Jang¹, Cecilia Lässer¹, Stefan Wennmalm⁴, Hans Jürgen Hoffmann^{5

6}, Li Li⁷, Yong Song Gho⁸, Jonas Andreas Nilsson², Jan Lötvall¹

Affiliations

¹ Krefting Research Centre, Institute of Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
² Department of Surgery, Institute of Clinical Sciences, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
³ Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
⁴ Royal Institute of Technology-KTH, Department of Applied Physics, Experimental Biomolecular Physics Group, SciLife Laboratory, Solna, Sweden.
⁵ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
⁶ Department of respiratory and Allergy, Aarhus University Hospital, Aarhus, Denmark.
⁷ Department of Laboratory Medicine, Shanghai First People's Hospital, Shanghai JiaoTong University, Shanghai, China.
⁸ Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.

Abstract

Extracellular vesicles such as exosomes convey biological messages between cells, either by surface-to-surface interaction or by shuttling of bioactive molecules to a recipient cell's cytoplasm. Here we show that exosomes released by mast cells harbour both active and latent transforming growth factor β-1 (TGFβ-1) on their surfaces. The latent form of TGFβ-1 is associated with the exosomes via heparinase-II and pH-sensitive elements. These vesicles traffic to the endocytic compartment of recipient human mesenchymal stem cells (MSCs) within 60 min of exposure. Further, the exosomes-associated TGFβ-1 is retained within the endosomal compartments at the time of signalling, which results in prolonged cellular signalling compared to free-TGFβ-1. These exosomes induce a migratory phenotype in primary MSCs involving SMAD-dependent pathways. Our results show that mast cell-derived exosomes are decorated with latent TGFβ-1 and are retained in recipient MSC endosomes, influencing recipient cell migratory phenotype. We conclude that exosomes can convey signalling within endosomes by delivering bioactive surface ligands to this intracellular compartment.

Keywords: Mast cells; cellular localization; endosomal signalling; exosomes; extracellular vesicles; mesenchymal stem cells; proteoglycan; tumour growth factor beta-1.

Grants and funding

This work was supported by the intramural funding from the VBG group Herman Krefting Foundation for Allergy and Asthma Research; Swedish Cancer Foundation [CAN2014/844]; Swedish Research Council [2016-02854]; and the Swedish Heart-Lung Foundation [2015-0588]. GS was supported by European Academy of Allergy and Clinical Immunology [Long term fellowship-2012]; Assar Gabrielssons Foundation [FB16-104]; Stiftelserna Wilhelm and Martina Lundgrens [2017-1842]; Sahlgrenska Academy; and Sahlgrenska University Hospital.