Tuesday, May 12, 2009

Microvesicles and MicroRNA: An Important Discovery


My last post touched on microRNA, but this post's subject is a recent discovery involving something I've never mentioned: microvesicles. The paper is Transfer of MicroRNAs by Embryonic Stem Cell Microvesicles by Alex Yuan, Erica L. Farber, Ana Lia Rapoport, Desiree Tejada, Roman Deniskin, Novrouz B. Akhmedov, Debora B. Farber. Among the important points this paper offers is that RNA, both messenger RNA (mRNA) and microRNA, can be carried between cells by carriers called microvesicles.

I can do no better than blockquote from the abstract:
Microvesicles are plasma membrane-derived vesicles released into the extracellular environment by a variety of cell types. Originally characterized from platelets, microvesicles are a normal constituent of human plasma, where they play an important role in maintaining hematostasis. Microvesicles have been shown to transfer proteins and RNA from cell to cell and they are also believed to play a role in intercellular communication. We characterized the RNA and protein content of embryonic stem cell microvesicles and show that they can be engineered to carry exogenously expressed mRNA and protein such as green fluorescent protein (GFP). We demonstrate that these engineered microvesicles dock and fuse with other embryonic stem cells, transferring their GFP. Additionally, we show that embryonic stem cells microvesicles contain abundant microRNA and that they can transfer a subset of microRNAs to mouse embryonic fibroblasts in vitro. [...O]ur findings open up the intriguing possibility that stem cells can alter the expression of genes in neighboring cells by transferring microRNAs contained in microvesicles. Embryonic stem cell microvesicles may be useful therapeutic tools for transferring mRNA, microRNAs, protein, and siRNA to cells and may be important mediators of signaling within stem cell niches.

Although a few earlier papers have mentioned the ability of microvesicles to carry microRNA between cells (see Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication by Hadi Valadi, Karin Ekström, Apostolos Bossios, Margareta Sjöstrand, James J. Lee, and Jan O. Lötvall; and Detection of microRNA Expression in Human Peripheral Blood Microvesicles by Melissa Piper Hunter, Noura Ismail1, Xiaoli Zhang, Baltazar D. Aguda, Eun Joo Lee, Lianbo Yu, Tao Xiao, Jeffrey Schafer, Mei-Ling Ting Lee, Thomas D. Schmittgen, S. Patrick Nana-Sinkam, David Jarjoura, and Clay B. Marsh), nobody appears to have demonstrated this process between early stem cells. Thus, this paper offers the important hope that early (ie totipotent) stem cells may be manipulated by artificial microvesicles containing appropriate RNA and enzymes (or other proteins).

It also confirms the fact that both types of RNA can be carried between cells, and verifies the ability of cells to select which microRNAs are transfered into the microvesicles, at least to some extent. This has very important implications for cell-to-cell communication.

I've discussed how the cell (potentially) uses its enzymes and DNA activation as a very powerful analog computer, with a rough correspondence in power between one enzyme or expressible gene and one transistor, but I haven't discussed the communication between/among these "smart" cells (except a bit regarding neurons).

The best known method of communicating between cells involves the secretion of signal molecules: neurotransmitters, neurohormones, and hormones. Briefly, neurotransmitters work across the synaptic cleft, neurohormones work in small regions close to where they are emitted by nerve cells in response to an action potential, and hormones circulate within the bloodstream and work body-wide. All these fit into one class out of several known for cell-to-cell communication.

Other methods include gap junctions, cell-to-cell adhesion contacts mediated by special molecules, and tunneling nanotubules. Starting with the last, these nanotubules actually "establish tubular conduits between cells that provide for the exchange of both cell-surface molecules and cytoplasmic content." Very little seems to be known about them yet. Cell-to-cell adhesion has been studied extensively, and it uses specifically evolved proteins and glycoproteins that react to their co-evolved partners and little else. Finally, gap junctions, like nanotubules, permit actual cytoplasmic exchange, but generally seems to be limited to very small molecules: a few signaling molecules and the general ionic environment.

Microvesicles operate like a sort of long-distance nanotubule, capable of carrying large molecules like mRNA, but not limited to the distance a nanotubule can tunnel, or the need to avoid to much relative motion. They can enter the bloodstream, or potentially be confined to smaller intercellular regions. At present we know almost nothing regarding the "intelligence" of their docking logic: which microvesicles from which donor cells can "dock with" and release their cargo to which target cells. Nevertheless, given the extensive variety of surface-adhesion proteins that have so far been discovered in cell-to-cell adhesion, as well as the complexity of vesicle signaling within the cytoplasm, it can't be ruled out (without much further research) that a similar level of complexity exists regarding these "outside" vesicles.

Microvesicles and nanotubules fill similar roles of "general package delivery" between cells, as they can potentially carry just about any molecule that isn't too large between cells. Nanotubules presumably require some sort of "evolved in" recognition system similar (or perhaps identical) to those in adhesion. They perform their work between cells close enough to "reach out" to one another, but the necessary exclusiveness is there (or so we can assume), except in pathological situations. Similarly, microvesicles almost certainly have an "evolved in" system of "docking" recognition to avoid the general delivery of cytoplasmic extracts to any cell within reach.

Unlike nanotubules, microvesicles can, and will, extend themselves as far as the liquid medium they inhabit, spreading out in a manner similar to diffusing molecules through Brownian motion. Of course, if it's a large volume, a large number of donor cells will be necessary to produce enough to be sure of reaching every target cell.

For communicating cells, let's try an analogy:1 signal molecules, whether cell-adhesion or diffused in the surrounding medium, are rather like signalling flags between old-time sailing vessels. They are limited to a pre-defined code. Tunneling nanotubules and microvesicles are more like sending a mailbag full of letters, either directly from one ship to another (after they've maneuvered together using flags as signals), or via a rowboat or pinnace, which uses flags as signals to identify the ship it's trying to reach. (I've left out gap junctions, as they don't have a precise analogy, but perhaps we can consider them as a long speaking tube stretched between ships: it can carry anything said in the appropriate medium, but nothing else.)

For purposes of manipulating the body, these microvesicles will likely offer an extremely valuable way of delivering our own medical "mailbag", with custom messages, taking advantage of the body's own system of "flag messages" to target the desired cells.

Even to early stem cells.

Altogether a very important discovery.

Yuan, A., Farber, E., Rapoport, A., Tejada, D., Deniskin, R., Akhmedov, N., & Farber, D. (2009). Transfer of MicroRNAs by Embryonic Stem Cell Microvesicles PLoS ONE, 4 (3) DOI: 10.1371/journal.pone.0004722

Links: (I only have a couple this time, I've left out any already called out in the text.

Exosomal transfer of proteins and RNAs at synapses in the nervous system

Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells

1. This is my own analogy, as far as I know it hasn't been used before. Feel free to use it, credit would be nice but not required.

1 comment:

  1. MicroRNAs (miRNA) are small non-coding RNAs that regulate translation of mRNA and protein, 17- to 27-nucleotide RNA molecules that regulate gene expression by posttranscriptional silencing of target mRNAs. Microvesicles, also known as exosomes or microparticles, circulate in the peripheral blood and can stimulate cellular signaling. Microvesicles have been shown to transfer proteins and RNA from cell to cell and they are also believed to play a role in intercellular communication. Thanks a lot!