Exosomes derived from grapes communicate with intestinal stem cells

Posted by Kasra

I worked on exosomes for some time, so I have written about them and other secreted vesicles every now and then. I still try to follow up the research in the field and get excited with the new findings, methods and applications. Here is exciting work by by Ju et al.  where they study the interaction between grape (yes the fruit) exosomes with mouse intestinal cells.

They purified exosome-like vesicles from grapes that they bought from grocery stores. Given to mice, the exosomes appeared to be absorbed by intestinal stem cells present in the intestinal crypts. Interestingly, the authors show that picking up these vesicles induce the Wnt/β-Catenin pathway. Generally, activation of this pathway promotes proliferation of stem cells. Ju et al. show grape exosomes induce proliferation of stem cells by putting stem cells together with the vesicles ex vivo and looking at crypt formation in organoids. Finally, to provide a health-related application for their vesicles, the authors show that grape exosomes protect mice and delay death in a murine colitis model. This can be because the vesicles induce proliferation of the stem cells and thus enhance tissue regeneration to revert the damage caused by colitis.

Formation of crypts from a single intestinal stem cell ex vivo is quickened when exposed to grape exosomes. From Ju et al. Molecular Therpay 2013

Formation of crypts from a single intestinal stem cell ex vivo is quickened when exposed to grape exosomes. From Ju et al. 11 June 2013;doi: 0.1038/mt.2013.64

This study contains so many buzz-words, I could think of terrible ways by which it can be mis-interpretted by media: grapes heal gut disease, nano-particles in fruit protect against gut disease, … As the authors say in the first paragraphs of the paper, this study is a proof of concept and there is still a lot more to learn. Thankfully, they show enough evidence to tickle other scientists to look at application of plant-derived exosomes and exosome-like vesicles as means for drug delivery and therapy. For one thing, plants-derived products are available in higher abundance compared to their animal-derived counterparts and can be cheaper to purify in commercial quantities.  Also, humans have been exposed to them (maybe not in such high concentrations) for millions of years, so they are no strangers to the gut cells.

Ju S, Mu J, Dokland T, Zhuang X, Wang Q, Jiang H, Xiang X, Deng ZB, Wang B, Zhang L, Roth M, Welti R, Mobley J, Jun Y, Miller D, & Zhang HG (2013). Grape Exosome-like Nanoparticles Induce Intestinal Stem Cells and Protect Mice From DSS-Induced Colitis. Molecular therapy : the journal of the American Society of Gene Therapy PMID: 23752315


Bacteriophages may protect us against pathogens

Posted by Kasra

Given the extremely large amount of bacteria in our gastrointestinal track, it is not surprising to think that the gut would be also swarming with pathogens of bacteria, that is bacteriophages as well. In their recent work published in PNAS, Barr et al. take a look at what impact these particles could have on the population of bacteria in mucosal surfaces and what could it mean for us. Their work actually turns out very interesting results.

Mucosal surfaces are the body’s points of contact  with the outside. Being highly populated with bacteria, they can be suitable points of infection as well. That is why they are heavily guarded with various immune barriers and mechanisms, both innate and adaptive. Barr et al. point to a possible mechanism of protection against infection which not innate nor adaptive. They start by comparing the amounts of bacteria and bacteriophages in different mucosal and non-mucosal surfaces in various mucus producing animals. They interestingly observe that the bacteriophage to bacteria ratio in mucosal sites is way larger than those in adjacent non-mucosal sites (from average about 40fold to average about 3fold). They verify this in both invertebrates and vertebrates and thus suggest that this could be a phenomenon in all mucus-producing metazoans.

Next, they point to a previous recent study by Minot et al. who had found immunoglobulin (Ig)-like domains in the total analyzed genome of human gut viruses (or so called human gut virome).  These domains that usually act as in recognition and binding (as an antibody would do); they show that the bacteriophages actually bind to mucus through these proteins.  Barr et al. also show that presence of bacteriophages on a mucosal surface significantly reduces Escherichia coli invasion in vitro.


Model for how presence of bacteriophage on the mucosal surface can help in protection against bacterial infection. From Barr et al. PNAS 2013 PMID: 23690590

This is an incredible system where the benefit of the bacteriophages and their hosts actually match. It is not clear at this point whether the animal body would have to do something other than producing mucus to keep the bacteriophages where they are or that it is just enjoying this protection more or less free of charge.

Barr JJ, Auro R, Furlan M, Whiteson KL, Erb ML, Pogliano J, Stotland A, Wolkowicz R, Cutting AS, Doran KS, Salamon P, Youle M, & Rohwer F (2013). Bacteriophage adhering to mucus provide a non-host-derived immunity. Proceedings of the National Academy of Sciences of the United States of America PMID: 23690590

Minot S, Grunberg S, Wu GD, Lewis JD, & Bushman FD (2012). Hypervariable loci in the human gut virome. Proceedings of the National Academy of Sciences of the United States of America, 109 (10), 3962-6 PMID: 22355105


Science is boring

Posted by Kasra:

I often think of how Richard Feynman so simply and truly describes the beauty or extra-beauty that science brings to everything around us. I believe what Feynman says is more or less obvious to scientists or people somehow involved in science. We enjoy asking questions and seeking answers that naturally lead to more questions. Then why is it that we can’t convey this feeling to more people? Why the general consensus is that “Science is boring?” Is it because it solves riddles and demystifies magic? Or is it because of the overused and misused jargon? Or mazybe it is because it replaces a preferred presumption with hard truth? With all the discoveries and advancements and technologies surrounding us, why would some people still think science is boring? Maybe science communication should not be just writing about cool stuff that happen in science, but also discussing why we find them cool and fascinating. Feynman elegantly describes the way a scientist would look at nature.

I tried to read only little bit about the interaction of pollinators and flowering plants and was overwhelmed with its complexity. At least one way that I find science fascinating is how it explains the complexity of nature by enhancing its details. It reveals and explains hidden patterns and interactions, at the end making it even more complex that it originally was, nevertheless more beautiful. Here is just a glimpse of this beauty, ultraviolet vision of butterflies and nectar guides of flowers.

Apoptosis, not so quiet after all

Posted by Kasra

Apoptosis has been conventionally regarded as a quiet and non-inflammatory event, compared to necrosis which results in release of alarmins and other danger signals inducing inflammation and immune cell recruitment. However, a recent report by Cullen et al. published in Molecular Cell suggests otherwise. They suggest that at least in one form of apoptosis, pro-inflammatory mediators are released by the apoptotic cells and can act as ‘find-me’ signals to the phagocytes to find and clear them.

Fas receptor or CD95 is among the famous apoptosis receptors. It is a member of the TNF receptor family and it induces apoptosis through Caspase-8 activation. Interestingly, Cullen et al. show that different cell types produce pro-inflammatory chemikones such as MCP-1, CXCL1 and MIP-2 when they go through apoptosis via Fas-pathway. They show that this chemokine release is NF-kappa-B mediated and independent of Caspase-8 activation. It is possible be that somewhere during the evolution, the apoptotic pathway cross-linked with the pro-inflammatory signaling pathway and found benefit in it. Accordingly, Cullen et al. show that the Fas-induced pro-inflammatory cytokine/chemokine production still occurs  even if the apoptotic pathway is inhibited showing that these pathways are separate.

Next the authors show that the supernatant from the apoptotic cells can induce migration of macrophages and neutrophils. They also pinpoint the responsible chemokine by depleting them one-by-one. They show that MCP-1 induces macrophage migration and IL-8 recruits neutrophils.

At this point it cannot be said really how inflammatory these apoptotic cells would be in vivo. There are parts of the body where apoptosis occurs constantly,  so this could potentially lead to an unwanted constant inflammation in those areas. Therefore, either different cells would have different levels of apoptotic-proinflammatory chemokine release, or local mechanisms would compensate and counteract the inflammation. More studies will help us understand how apoptotic cells can send their ‘find-me’ signals without causing too much turbulence in their tissue.

Schematic diagram of model proposed by Cullen et al. From

From Cullen et al. Molecular cell, 49 (6), 1034-48

Cullen SP, Henry CM, Kearney CJ, Logue SE, Feoktistova M, Tynan GA, Lavelle EC, Leverkus M, & Martin SJ (2013). Fas/CD95-induced chemokines can serve as “find-me” signals for apoptotic cells. Molecular cell, 49 (6), 1034-48 PMID: 23434371