Cell-cell transfer of mRNA and its role in mammalian cell physiology

HER2 mRNA (red) visualized by single-molecule FISH in SKBR3 cells
HER2 mRNA (red) visualized by single-molecule FISH in SKBR3 cells

Cells receive sensory input from neighboring cells that allows them to rapidly respond to changes in their surrounding environment. This can occur via secreted signaling molecules that bind to cell surface receptors and elicit downstream signaling events that lead to changes in cell physiology. While much information is known about cell-cell communication via signaling molecules, much less is known about whether cells transfer information via the exchange of RNA. Despite this paucity of knowledge, most extracellular fluids contain RNA molecules, mainly within secreted nanovesicles, although free ribonucleoprotein complexes have also been identified. Most of the extracellular RNA is composed of small RNAs (e.g. miRNA, tRNA and mRNA fragments). Thus, the horizontal transfer of RNA may be yet another means for cells to exchange information and, perhaps, constitutes part of the mechanism by which cells like neurons can reach meters in length and still respond rapidly to injury or changes in synaptic signaling (i.e. via cell-cell transfer of RNAs between myelinating cells and axons).
We are examined whether cultured cells, such as mouse fibroblasts or cancer cell-lines, can transfer mRNAs between themselves and, thereby, possibly affect the cellular physiology of neighboring cells. In collaboration with the group of Rob Singer (Einstein Medical College) and Arjun Raj (University of Pennsylvania), we have shown that donor cells can transfer mRNA to naïve acceptor cells [Haimovich et al 2017]. By using single molecule fluorescence in situ hybridization [Haimovich & Gerst 2018]  and single molecule live imaging procedures we can show that mRNA molecules undergo horizontal cell transfer. Surprisingly, this is mediate by a contact dependent mechanism by tunneling (membrane) nanotubes, and not by extracellular mRNA transfer. Furthermore, we found that the transferred mRNA is packaged in a protein "shell" of yet unknown composition [Haimovich & Gerst 2019]. 

We believe that this phenomenon will prove to be a common mechanism for cells to respond to and affect local changes in their local environment. We are currently working to identify the entire "transferrome" using a protocol we developed in the lab [Dasgupta & Gerst, 2020], the molecular mechnism that mediates and regulates nanotubular mRNA transfer, and the physiological consequences of this process.