Exosomes surf on filopodia to enter cells at endocytic hot spots, traffic within endosomes, and are targeted to the ER.
Exosomes are nanovesicles released by virtually all cells, which act as intercellular messengers by transfer of protein, lipid, and RNA cargo. Their quantitative efficiency, routes of cell uptake, and subcellular fate within recipient cells remain elusive. We quantitatively characterize exosome cell uptake, which saturates with dose and time and reaches near 100% transduction efficiency at picomolar concentrations. Highly reminiscent of pathogenic bacteria and viruses, exosomes are recruited as single vesicles to the cell body by surfing on filopodia as well as filopodia grabbing and pulling motions to reach endocytic hot spots at the filopodial base. After internalization, exosomes shuttle within endocytic vesicles to scan the endoplasmic reticulum before being sorted into the lysosome as their final intracellular destination. Our data quantify and explain the efficiency of exosome internalization by recipient cells, establish a new parallel between exosome and virus host cell interaction, and suggest unanticipated routes of subcellular cargo delivery.
Novartis Institutes for Biomedical Research, CH-4000 Basel, Switzerland wolf.heusermann@unibas.ch nicole.meisner-kober@novartis.com.
Wolf
W
Heusermann
Novartis Institutes for Biomedical Research, CH-4000 Basel, Switzerland Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, England, UK.
Justin
J
Hean
Novartis Institutes for Biomedical Research, CH-4000 Basel, Switzerland.
Dominic
D
Trojer
Novartis Institutes for Biomedical Research, CH-4000 Basel, Switzerland.
Emmanuelle
E
Steib
Novartis Institutes for Biomedical Research, CH-4000 Basel, Switzerland.
Stefan
S
von Bueren
Friedrich-Miescher Institute for Biomedical Research, CH-4000 Basel, Switzerland.
Alexandra
A
Graff-Meyer
Friedrich-Miescher Institute for Biomedical Research, CH-4000 Basel, Switzerland.
Christel
C
Genoud
Department of Biomedicine, University of Basel, CH-4058 Basel, Switzerland.
Katrin
K
Martin
Novartis Institutes for Biomedical Research, CH-4000 Basel, Switzerland.
Nicolas
N
Pizzato
Novartis Institutes for Biomedical Research, CH-4000 Basel, Switzerland.
Johannes
J
Voshol
Novartis Institutes for Biomedical Research, Cambridge, MA 02139.
David V
DV
Morrissey
Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, England, UK Department of Laboratory Medicine, Karolinska Institutet, SE-141 86 Huddinge, Sweden.
Samir E L
SE
Andaloussi
Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, England, UK.
Matthew J
MJ
Wood
Novartis Institutes for Biomedical Research, CH-4000 Basel, Switzerland wolf.heusermann@unibas.ch nicole.meisner-kober@novartis.com.
Nicole C
NC
Meisner-Kober
D001692:Biological Transport; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D055354:Exosomes / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D057809:HEK293 Cells; D006801:Humans; D008855:Microscopy, Electron, Scanning; D011554:Pseudopodia / Q000502:physiology* / Q000648:ultrastructure