Extracellular Vesicles from Neural Stem Cells Transfer IFN-γ via Ifngr1 to Activate Stat1 Signaling in Target Cells.

Chiara Cossetti; Nunzio Iraci; Tim R Mercer; Tommaso Leonardi; Emanuele Alpi; Denise Drago; Clara Alfaro-Cervello; Harpreet K Saini; Matthew P Davis; Julia Schaeffer; Beatriz Vega; Matilde Stefanini; CongJian Zhao; Werner Muller; Jose Manuel Garcia-Verdugo; Suresh Mathivanan; Angela Bachi; Anton J Enright; John S Mattick; Stefano Pluchino

doi:10.1016/j.molcel.2014.08.020

Extracellular Vesicles from Neural Stem Cells Transfer IFN-γ via Ifngr1 to Activate Stat1 Signaling in Target Cells.

Chiara Cossetti, Nunzio Iraci, Tim R Mercer, Tommaso Leonardi, Emanuele Alpi, Denise Drago, Clara Alfaro-Cervello, Harpreet K Saini, Matthew P Davis, Julia Schaeffer, Beatriz Vega, Matilde Stefanini, CongJian Zhao, Werner Muller, Jose Manuel Garcia-Verdugo, Suresh Mathivanan, Angela Bachi, Anton J Enright, John S Mattick, Stefano Pluchino

Research output: Contribution to journal › Article › peer-review

Abstract

The idea that stem cell therapies work only via cell replacement is challenged by the observation of consistent intercellular molecule exchange between the graft and the host. Here we defined a mechanism of cellular signaling by which neural stem/precursor cells (NPCs) communicate with the microenvironment via extracellular vesicles (EVs), and we elucidated its molecular signature and function. We observed cytokine-regulated pathways that sort proteins and mRNAs into EVs. We described induction of interferon gamma (IFN-γ) pathway in NPCs exposed to proinflammatory cytokines that is mirrored in EVs. We showed that IFN-γ bound to EVs through Ifngr1 activates Stat1 in target cells. Finally, we demonstrated that endogenous Stat1 and Ifngr1 in target cells are indispensable to sustain the activation of Stat1 signaling by EV-associated IFN-γ/Ifngr1 complexes. Our study identifies a mechanism of cellular signaling regulated by EV-associated IFN-γ/Ifngr1 complexes, which grafted stem cells may use to communicate with the host immune system.

Original language	English
Pages (from-to)	193-204
Journal	Molecular Cell
Volume	56
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2014.08.020
Publication status	Published - 18 Sept 2014

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Cossetti, C., Iraci, N., Mercer, T. R., Leonardi, T., Alpi, E., Drago, D., Alfaro-Cervello, C., Saini, H. K., Davis, M. P., Schaeffer, J., Vega, B., Stefanini, M., Zhao, C., Muller, W., Garcia-Verdugo, J. M., Mathivanan, S., Bachi, A., Enright, A. J., Mattick, J. S., & Pluchino, S. (2014). Extracellular Vesicles from Neural Stem Cells Transfer IFN-γ via Ifngr1 to Activate Stat1 Signaling in Target Cells. Molecular Cell, 56(2), 193-204. https://doi.org/10.1016/j.molcel.2014.08.020

@article{b6b05ec6d3ef4a2c9b47d010098ad148,

title = "Extracellular Vesicles from Neural Stem Cells Transfer IFN-γ via Ifngr1 to Activate Stat1 Signaling in Target Cells.",

abstract = "The idea that stem cell therapies work only via cell replacement is challenged by the observation of consistent intercellular molecule exchange between the graft and the host. Here we defined a mechanism of cellular signaling by which neural stem/precursor cells (NPCs) communicate with the microenvironment via extracellular vesicles (EVs), and we elucidated its molecular signature and function. We observed cytokine-regulated pathways that sort proteins and mRNAs into EVs. We described induction of interferon gamma (IFN-γ) pathway in NPCs exposed to proinflammatory cytokines that is mirrored in EVs. We showed that IFN-γ bound to EVs through Ifngr1 activates Stat1 in target cells. Finally, we demonstrated that endogenous Stat1 and Ifngr1 in target cells are indispensable to sustain the activation of Stat1 signaling by EV-associated IFN-γ/Ifngr1 complexes. Our study identifies a mechanism of cellular signaling regulated by EV-associated IFN-γ/Ifngr1 complexes, which grafted stem cells may use to communicate with the host immune system.",

author = "Chiara Cossetti and Nunzio Iraci and Mercer, {Tim R} and Tommaso Leonardi and Emanuele Alpi and Denise Drago and Clara Alfaro-Cervello and Saini, {Harpreet K} and Davis, {Matthew P} and Julia Schaeffer and Beatriz Vega and Matilde Stefanini and CongJian Zhao and Werner Muller and Garcia-Verdugo, {Jose Manuel} and Suresh Mathivanan and Angela Bachi and Enright, {Anton J} and Mattick, {John S} and Stefano Pluchino",

year = "2014",

month = sep,

day = "18",

doi = "10.1016/j.molcel.2014.08.020",

language = "English",

volume = "56",

pages = "193--204",

journal = "Molecular Cell",

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Cossetti, C, Iraci, N, Mercer, TR, Leonardi, T, Alpi, E, Drago, D, Alfaro-Cervello, C, Saini, HK, Davis, MP, Schaeffer, J, Vega, B, Stefanini, M, Zhao, C, Muller, W, Garcia-Verdugo, JM, Mathivanan, S, Bachi, A, Enright, AJ, Mattick, JS & Pluchino, S 2014, 'Extracellular Vesicles from Neural Stem Cells Transfer IFN-γ via Ifngr1 to Activate Stat1 Signaling in Target Cells.', Molecular Cell, vol. 56, no. 2, pp. 193-204. https://doi.org/10.1016/j.molcel.2014.08.020

TY - JOUR

T1 - Extracellular Vesicles from Neural Stem Cells Transfer IFN-γ via Ifngr1 to Activate Stat1 Signaling in Target Cells.

AU - Cossetti, Chiara

AU - Iraci, Nunzio

AU - Mercer, Tim R

AU - Leonardi, Tommaso

AU - Alpi, Emanuele

AU - Drago, Denise

AU - Alfaro-Cervello, Clara

AU - Saini, Harpreet K

AU - Davis, Matthew P

AU - Schaeffer, Julia

AU - Vega, Beatriz

AU - Stefanini, Matilde

AU - Zhao, CongJian

AU - Muller, Werner

AU - Garcia-Verdugo, Jose Manuel

AU - Mathivanan, Suresh

AU - Bachi, Angela

AU - Enright, Anton J

AU - Mattick, John S

AU - Pluchino, Stefano

PY - 2014/9/18

Y1 - 2014/9/18

N2 - The idea that stem cell therapies work only via cell replacement is challenged by the observation of consistent intercellular molecule exchange between the graft and the host. Here we defined a mechanism of cellular signaling by which neural stem/precursor cells (NPCs) communicate with the microenvironment via extracellular vesicles (EVs), and we elucidated its molecular signature and function. We observed cytokine-regulated pathways that sort proteins and mRNAs into EVs. We described induction of interferon gamma (IFN-γ) pathway in NPCs exposed to proinflammatory cytokines that is mirrored in EVs. We showed that IFN-γ bound to EVs through Ifngr1 activates Stat1 in target cells. Finally, we demonstrated that endogenous Stat1 and Ifngr1 in target cells are indispensable to sustain the activation of Stat1 signaling by EV-associated IFN-γ/Ifngr1 complexes. Our study identifies a mechanism of cellular signaling regulated by EV-associated IFN-γ/Ifngr1 complexes, which grafted stem cells may use to communicate with the host immune system.

AB - The idea that stem cell therapies work only via cell replacement is challenged by the observation of consistent intercellular molecule exchange between the graft and the host. Here we defined a mechanism of cellular signaling by which neural stem/precursor cells (NPCs) communicate with the microenvironment via extracellular vesicles (EVs), and we elucidated its molecular signature and function. We observed cytokine-regulated pathways that sort proteins and mRNAs into EVs. We described induction of interferon gamma (IFN-γ) pathway in NPCs exposed to proinflammatory cytokines that is mirrored in EVs. We showed that IFN-γ bound to EVs through Ifngr1 activates Stat1 in target cells. Finally, we demonstrated that endogenous Stat1 and Ifngr1 in target cells are indispensable to sustain the activation of Stat1 signaling by EV-associated IFN-γ/Ifngr1 complexes. Our study identifies a mechanism of cellular signaling regulated by EV-associated IFN-γ/Ifngr1 complexes, which grafted stem cells may use to communicate with the host immune system.

U2 - 10.1016/j.molcel.2014.08.020

DO - 10.1016/j.molcel.2014.08.020

M3 - Article

C2 - 25242146

SN - 1097-4164

VL - 56

SP - 193

EP - 204

JO - Molecular Cell

JF - Molecular Cell

IS - 2

ER -

Extracellular Vesicles from Neural Stem Cells Transfer IFN-γ via Ifngr1 to Activate Stat1 Signaling in Target Cells.

Abstract

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