Non-cell-autonomous effects of vector-expressed regulatory RNAs in mammalian heart cells (original) (raw)

Gene Therapy volume 16, pages 1163–1168 (2009)Cite this article

Abstract

In mammalian cells, small regulatory RNA molecules are able to modulate gene expression in a cell-autonomous manner. In contrast, this mechanism of gene regulation can occur systemically in plants and nematodes. The existence of similar cell-to-cell transmission in mammalian cells has been explored, but generalizibilty and mechanistic insights have remained elusive. Here, we show that small regulatory RNA molecules are capable of a non-cell-autonomous effect between primary cardiac myocytes through a gap-junction-dependent mechanism. Co-culture experiments showed that both Dicer-processed small-interfering RNAs (siRNAs) and Drosha-processed microRNAs (miRNAs) were capable of target gene knockdown and physiological effects in a non-cell-autonomous manner. Target gene siRNA molecules were detected in recipient cells, indicating transfer of the primary effector molecule. All of these effects were abrogated by dominant-negative molecular suppression of gap junction function. Our results show that both siRNAs and miRNAs are capable of a non-cell-autonomous effect between mammalian cells through gap junctions. The recognition of this biological process raises the novel therapeutic prospect of a bystander effect after gene transfer to tissues bearing gap junctions and for cell engineering with a view to creating regulatory RNA donor cells that exert their influence throughout a syncytium.

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Authors and Affiliations

  1. Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
    E Kizana, E Cingolani & E Marbán
  2. Department of Cardiology, Westmead Hospital and The University of Sydney, Sydney, New South Wales, Australia
    E Kizana

Authors

  1. E Kizana
  2. E Cingolani
  3. E Marbán

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Correspondence toE Marbán.

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Kizana, E., Cingolani, E. & Marbán, E. Non-cell-autonomous effects of vector-expressed regulatory RNAs in mammalian heart cells.Gene Ther 16, 1163–1168 (2009). https://doi.org/10.1038/gt.2009.64

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