Intercellular mRNA trafficking via membrane nanotube-like extensions in mammalian cells

Gal Haimovich, Christopher M. Ecker, Margaret C. Dunagin, Elliott Eggan, Arjun Raj, Jeffrey E. Gerst, Robert H. Singer

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

RNAs have been shown to undergo transfer between mammalian cells, although the mechanism behind this phenomenon and its overall importance to cell physiology is not well understood. Numerous publications have suggested that RNAs (microRNAs and incomplete mRNAs) undergo transfer via extracellular vesicles (e.g., exosomes). However, in contrast to a diffusion-based transfer mechanism, we find that full-length mRNAs undergo direct cell–cell transfer via cytoplasmic extensions characteristic of membrane nanotubes (mNTs), which connect donor and acceptor cells. By employing a simple coculture experimental model and using single-molecule imaging, we provide quantitative data showing that mRNAs are transferred between cells in contact. Examples of mRNAs that undergo transfer include those encoding GFP, mouse β-actin, and human Cyclin D1, BRCA1, MT2A, and HER2. We show that intercellular mRNA transfer occurs in all coculture models tested (e.g., between primary cells, immortalized cells, and in cocultures of immortalized human and murine cells). Rapid mRNA transfer is dependent upon actin but is independent of de novo protein synthesis and is modulated by stress conditions and gene-expression levels. Hence, this work supports the hypothesis that full-length mRNAs undergo transfer between cells through a refined structural connection. Importantly, unlike the transfer of miRNA or RNA fragments, this process of communication transfers genetic information that could potentially alter the acceptor cell proteome. This phenomenon may prove important for the proper development and functioning of tissues as well as for host–parasite or symbiotic interactions.

Original languageEnglish (US)
Pages (from-to)E9873-E9882
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number46
DOIs
StatePublished - Nov 14 2017

Fingerprint

Nanotubes
Messenger RNA
Membranes
Coculture Techniques
RNA
MicroRNAs
Actins
Exosomes
Cell Physiological Phenomena
Proteome
Publications
Theoretical Models
Communication
Gene Expression

Keywords

  • Membrane nanotubes
  • MS2
  • smFISH
  • β-actin mRNA

ASJC Scopus subject areas

  • General

Cite this

Intercellular mRNA trafficking via membrane nanotube-like extensions in mammalian cells. / Haimovich, Gal; Ecker, Christopher M.; Dunagin, Margaret C.; Eggan, Elliott; Raj, Arjun; Gerst, Jeffrey E.; Singer, Robert H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 46, 14.11.2017, p. E9873-E9882.

Research output: Contribution to journalArticle

Haimovich, Gal ; Ecker, Christopher M. ; Dunagin, Margaret C. ; Eggan, Elliott ; Raj, Arjun ; Gerst, Jeffrey E. ; Singer, Robert H. / Intercellular mRNA trafficking via membrane nanotube-like extensions in mammalian cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 46. pp. E9873-E9882.
@article{86e1cad8df4548039eaa8de150111c30,
title = "Intercellular mRNA trafficking via membrane nanotube-like extensions in mammalian cells",
abstract = "RNAs have been shown to undergo transfer between mammalian cells, although the mechanism behind this phenomenon and its overall importance to cell physiology is not well understood. Numerous publications have suggested that RNAs (microRNAs and incomplete mRNAs) undergo transfer via extracellular vesicles (e.g., exosomes). However, in contrast to a diffusion-based transfer mechanism, we find that full-length mRNAs undergo direct cell–cell transfer via cytoplasmic extensions characteristic of membrane nanotubes (mNTs), which connect donor and acceptor cells. By employing a simple coculture experimental model and using single-molecule imaging, we provide quantitative data showing that mRNAs are transferred between cells in contact. Examples of mRNAs that undergo transfer include those encoding GFP, mouse β-actin, and human Cyclin D1, BRCA1, MT2A, and HER2. We show that intercellular mRNA transfer occurs in all coculture models tested (e.g., between primary cells, immortalized cells, and in cocultures of immortalized human and murine cells). Rapid mRNA transfer is dependent upon actin but is independent of de novo protein synthesis and is modulated by stress conditions and gene-expression levels. Hence, this work supports the hypothesis that full-length mRNAs undergo transfer between cells through a refined structural connection. Importantly, unlike the transfer of miRNA or RNA fragments, this process of communication transfers genetic information that could potentially alter the acceptor cell proteome. This phenomenon may prove important for the proper development and functioning of tissues as well as for host–parasite or symbiotic interactions.",
keywords = "Membrane nanotubes, MS2, smFISH, β-actin mRNA",
author = "Gal Haimovich and Ecker, {Christopher M.} and Dunagin, {Margaret C.} and Elliott Eggan and Arjun Raj and Gerst, {Jeffrey E.} and Singer, {Robert H.}",
year = "2017",
month = "11",
day = "14",
doi = "10.1073/pnas.1706365114",
language = "English (US)",
volume = "114",
pages = "E9873--E9882",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "46",

}

TY - JOUR

T1 - Intercellular mRNA trafficking via membrane nanotube-like extensions in mammalian cells

AU - Haimovich, Gal

AU - Ecker, Christopher M.

AU - Dunagin, Margaret C.

AU - Eggan, Elliott

AU - Raj, Arjun

AU - Gerst, Jeffrey E.

AU - Singer, Robert H.

PY - 2017/11/14

Y1 - 2017/11/14

N2 - RNAs have been shown to undergo transfer between mammalian cells, although the mechanism behind this phenomenon and its overall importance to cell physiology is not well understood. Numerous publications have suggested that RNAs (microRNAs and incomplete mRNAs) undergo transfer via extracellular vesicles (e.g., exosomes). However, in contrast to a diffusion-based transfer mechanism, we find that full-length mRNAs undergo direct cell–cell transfer via cytoplasmic extensions characteristic of membrane nanotubes (mNTs), which connect donor and acceptor cells. By employing a simple coculture experimental model and using single-molecule imaging, we provide quantitative data showing that mRNAs are transferred between cells in contact. Examples of mRNAs that undergo transfer include those encoding GFP, mouse β-actin, and human Cyclin D1, BRCA1, MT2A, and HER2. We show that intercellular mRNA transfer occurs in all coculture models tested (e.g., between primary cells, immortalized cells, and in cocultures of immortalized human and murine cells). Rapid mRNA transfer is dependent upon actin but is independent of de novo protein synthesis and is modulated by stress conditions and gene-expression levels. Hence, this work supports the hypothesis that full-length mRNAs undergo transfer between cells through a refined structural connection. Importantly, unlike the transfer of miRNA or RNA fragments, this process of communication transfers genetic information that could potentially alter the acceptor cell proteome. This phenomenon may prove important for the proper development and functioning of tissues as well as for host–parasite or symbiotic interactions.

AB - RNAs have been shown to undergo transfer between mammalian cells, although the mechanism behind this phenomenon and its overall importance to cell physiology is not well understood. Numerous publications have suggested that RNAs (microRNAs and incomplete mRNAs) undergo transfer via extracellular vesicles (e.g., exosomes). However, in contrast to a diffusion-based transfer mechanism, we find that full-length mRNAs undergo direct cell–cell transfer via cytoplasmic extensions characteristic of membrane nanotubes (mNTs), which connect donor and acceptor cells. By employing a simple coculture experimental model and using single-molecule imaging, we provide quantitative data showing that mRNAs are transferred between cells in contact. Examples of mRNAs that undergo transfer include those encoding GFP, mouse β-actin, and human Cyclin D1, BRCA1, MT2A, and HER2. We show that intercellular mRNA transfer occurs in all coculture models tested (e.g., between primary cells, immortalized cells, and in cocultures of immortalized human and murine cells). Rapid mRNA transfer is dependent upon actin but is independent of de novo protein synthesis and is modulated by stress conditions and gene-expression levels. Hence, this work supports the hypothesis that full-length mRNAs undergo transfer between cells through a refined structural connection. Importantly, unlike the transfer of miRNA or RNA fragments, this process of communication transfers genetic information that could potentially alter the acceptor cell proteome. This phenomenon may prove important for the proper development and functioning of tissues as well as for host–parasite or symbiotic interactions.

KW - Membrane nanotubes

KW - MS2

KW - smFISH

KW - β-actin mRNA

UR - http://www.scopus.com/inward/record.url?scp=85033698896&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85033698896&partnerID=8YFLogxK

U2 - 10.1073/pnas.1706365114

DO - 10.1073/pnas.1706365114

M3 - Article

C2 - 29078295

AN - SCOPUS:85033698896

VL - 114

SP - E9873-E9882

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 46

ER -