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Original article
Hepatic cell-to-cell transmission of small silencing RNA can extend the therapeutic reach of RNA interference (RNAi)
  1. Qiuwei Pan1,
  2. Vedashree Ramakrishnaiah2,
  3. Scot Henry2,3,
  4. Suomi Fouraschen2,
  5. Petra E de Ruiter2,
  6. Jaap Kwekkeboom1,
  7. Hugo W Tilanus2,
  8. Harry L A Janssen1,
  9. Luc J W van der Laan2
  1. 1Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
  2. 2Department of Surgery, Laboratory of Experimental Transplantation and Intestinal Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
  3. 3Department of Surgery, Columbia University Medical Center, Columbia University, New York, USA
  1. Correspondence to Dr Luc J W van der Laan, Laboratory of Experimental Transplantation and Intestinal Surgery (LETIS), Department of Surgery, Erasmus MC-University Medical Center, Room L458, 's Gravendijkwal 230, Rotterdam 3015 CE, The Netherlands; l.vanderlaan{at}erasmusmc.nl

Abstract

Background/aims RNA interference (RNAi), a sequence-specific gene silencing technology triggered by small interfering RNA (siRNA), represents promising new avenues for treatment of various liver diseases including hepatitis C virus (HCV) infection. In plants and invertebrates, RNAi provides an important mechanism of cellular defence against viral pathogens and is dependent on the spread of siRNA to neighbouring cells. A study was undertaken to investigate whether vector-delivered RNAi can transfer between hepatic cells in vitro and in mice, and whether this exchange could extend the therapeutic effect of RNAi against HCV infection.

Methods Transmission of RNAi was investigated in culture by assessing silencing of HCV replication and expression of viral entry receptor CD81 using a human hepatic cell line and primary B lymphocytes transduced with siRNA-expressing vectors. In vivo transmission between hepatic cells was investigated in NOD/SCID mice. Involvement of exosomes was demonstrated by purification, uptake and mass spectrometric analysis.

Results Human and mouse liver cells, as well as primary human B cells, were found to have the ability to exchange small RNAs, including cellular endogenous microRNA and delivered siRNA targeting HCV or CD81. The transmission of RNAi was largely independent of cell contact and partially mediated by exosomes. Evidence of RNAi transmission in vivo was observed in NOD/SCID mice engrafted with human hepatoma cells producing CD81 siRNA, causing suppression of CD81 expression in mouse hepatocytes.

Conclusion Both human and mouse hepatic cells exchange small silencing RNAs, partially mediated by shuttling of exosomes. Transmission of siRNA potentially extends the therapeutic reach of RNAi-based therapies against HCV as well as other liver diseases.

  • RNA interference
  • siRNA
  • microRNA
  • HCV
  • transfer
  • liver transplantation
  • hepatitis
  • hepatic veno-occlusive disease
  • budd chiari syndrome
  • venocclusive disease
  • hepatitis A
  • hepatitis B
  • hepatitis C
  • hepatitis D

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Footnotes

  • Funding Financial support was provided by the Erasmus MC Translational Research Fund and the Liver Research Foundation (SLO) Rotterdam.

  • Competing interest None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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