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The Best of the Best Poster and Young Investigator Oral Presentations
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Kamil Kranc, Md, Phd, University Of Edinburgh - Young Investigator Award Winner
Dustin R. Wakeman, Phd, Rush University Medical Center - Young Investigator Award Winner
Everyone I was Bernie siegel executive director of genetics Policy Institute of regenerative medicine foundation as the three-day extravaganza of the world stem cell summit winds down this is a very nice moment and actually the first time in the history this eleven world stem cell summit that we've had our poster honorees selected from our robust poster session actually have an opportunity to give oral presentations and for the three degrees from our poster session.
There's also a complimentary registration next year to the world stem cell summit which is going to be December 6 through the aid and Palm Beach Florida and in fact that is just been by executive privilege extended also to the honorees and the Young Investigator awards from alphabet press is why not why it's the right thing to do so that's true we're first going to honor the Young Investigator award winners today and I'm gonna call up Jan null 22 to welcome them and all of our poster winners get 10 minutes to present their science thanks so much Bernie so we are very pleased to welcome our third annual stencils Transnational Medicine young investigator award presented to Dustin wait for his study demonstrating an important step in evaluating cell types of methods that will be most effective for stem cell therapy in Parkinson'sdiseasequick.
So I want to thank you for the honor to speak today to get the society and for the award so this work we all started back in 2007 with this paper published in PNAS when I was 11 Snyder's group and basically what we showed here at this new buses are animals parkinsonian monkeys that were transplanted with fetal human neural stem cells and we showed as you can see we had functional improvement in these animals after they were transplanted and we actually look at these cells histologically can see the top right we found a bunch of these donors deride kids positive and so does this mean that Russia grafted now will be counted the cells and fortunately this was only about three to five percent of the total cells that were grafted it turns out about 95% of the main undifferentiated and so what they were doing was.
They were acting through secondary compensatory mechanisms to actually restore the endogenous narrows so we thought well how can we improve this so basically said well one way to do this is through neurotrophic factors so weoverexpressed lil derived neurotrophic factor in the stratum and this is the paper for which the award was given and we also can confidently then transplanted the same exact cells into the substantial nigra and you can see these graphs in the ability of panels had beautiful fighters in at the boots on and we had GDNF expression to even had it transported down to the niagaraunfortunately those GAPDH positive neurons over there are still only about three to five percent will be counted them.
So really what we knew now from this is one year post transplantation and we realize was that these fetal human neural stem cells really we're not going to be an ideal candidate for Parkinson's and why is it important his work seminal why do we put it in stem cells Transnational Medicine well to this day there are still overseas clinics that are providing these cells and saying that they have beneficial effects for Parkinson's disease in case of this is the problems we want to reach the clinical our clinical colleagues and want everybody to know that we have patience and ask these cells tell them unequivocally this is a bad idea so of course we didn't stop there I'm gonna fast forward now for about 10 years of my life and what am i doing now so we'really working with IPS.
So she stays and I have actually teamed up in partnered with cellular dynamics International which is now Fuji film company and so Thought this would be appropriate for today is this really is sort of marriage between basic science and companies and I think it's really important to stress that little vial over there and on the bottom right panel that's really important innovation for the field of transplantation so what CDIis good at doing as they make cells and in fact they're really good a crap reserving the cells and that's a really important innovation me think about going to the clinic so when dinosaurs and asked me how you can provide these cells what he wants to hear is you can call down to the incline your technicians an exe sees our souls and next minutes and will be ready for you and ideally you'll do that with little to no human manipulation and you have a product that has heavy QAQC and it's exactly what you can do is what I'm gonna tell you.
Now that I can take the cells from the time I grab that travel out of the liquid nitrogen into the second it's in the needle takes about 25minutes so we basically have these I sold open areas that CDI makes they're basically the exact same protocol that learns to use in fact they license IPad my job is the top part they're my job is to test themselves in both revenue and primate models of Parkinson's disease and of course the overall goal here is an IND package for the FDA.
So our model is quite simple we had a 68 dry season she said she doesn't mean the threat and it's very simple you inject a neurotoxin into the medial fore brain bundle those acts on that come from the substantial nigra neurons innervate the stratum ablated you can see that here in histology was a unilateral lesion on the right side you can see those errands done and be or completely wiped out and there their stride all efforts are going so what happens if we transmit these cells.
This is six months post transplantation into the sprague-dawley CSAimmunosuppressed rhett and you can see these beautiful human in CHEM positive neurons that innervate the stratum unilaterally and importantly here in the penalty on the top rate you see these human nuclei cells are stained with in the graph zone itself so bad distribution standpoint this is actually a good thing right we want them to stay where their acts it's a lot easier and easier for us to tell the FDA we know where they are so what do they do not and left panel what they're not doing they're not restoring those endogenoustarzan hydroxylase neurons that I should do before the monkey balls or not we're not rescuing read do anything with the induction system so what that tells uses that we see functional improvement in these animals.
It really is from graph drive innovation and so this bottom right hand was kind of hard to see I'm just gonna take that energy and then inverted case and now it's a little bit easier to see and so what I hope you can appreciate here in the top left is that we have animals are grafted we have extensive innovation in fact were iterated the entire stratum and compared to six hydroxy doping control right next to it you see that you don't have this is open your eyes and remember I just told you that there is no grand rounds are still missing in thesubstantia nigra so this really is graphed drive innovation now there are ways we can look at these animals functionally to see whether they're getting better perhaps the most simple tester to improve is something called amphetamine induced rotations.
Basically be given an injection of dan said I mean they start spinning and you cut the number of rotations per minute so you can see in the blue line here animals that have been grafted actually have a complete recovery in this rotational asymmetry of this is primarily a measure of dopaminerelease we also have a more stringent pharmacological test will be injectablemorphine and this is more of the surrogate for graph innovation so this actually would corroborate ourimmunohistochemical results and you can see again when animals have successful graphs and the blue line.
We actually have a significant functional improvement following grafting against the six months post transplantation so any stem cell therapy we talked about in the clinic the FDA's and most surprised most you know they are really interested and safety first and 62nd and 63rd and one of the things we have to do is show these cells are not proliferating and this is actually kind of shock to me.
I have not been able to find a single Kerr67 positive cell is not just a new six-month animal even it two weeks post transplantation and analyst I would probably fifty or sixty animals I have not found a single Kerr 67 passes and of course the lateral ventricle is shown there as a positive control over the indictments stem cells are so what exactly do these neurons quickly well they're extremely immature they have it the characteristic angler some of that we look for in a highly integrated in the brain itself and then we count the number of these cells that survive we put 450,000 cells and unilaterally in one injection site in about 20 to 25 percent of these cells actually survive of the surviving cells about 30 percent of them are actually.
The positive and this is actually in line with or better than any published data right now so they're writing the state up I know but so we should function in her own animal model now we wanted to see what would happen if we transplanted cells into the primate model of Parkinson's disease and that model is the MPTP mission monkey this is just a proof of concept experiment this is one month post transplantation and you can see that these are highly integrated into the host parenchyma and then be in one point out in Tennessee is that these cells are still somewhat bipolar and work their morphology so this template image surely that is in contrast to three months but transplantation we have very mature looking TH positive very large so they're highly integrated into the host parenchymal you can see antis is a cell disorder lies on the periphery it has an extremely mature morphology and you can see is how the arborist.
So those are healthy cells as many of you heard about allogeneic approaches to inhabit matching this is just be up a little of that we're also interested not telling us therapy sow hen you take a cell from a disease person in this case of Parkinson's disease patient you might hypothesize that there may be differences between a healthy individual and it is these individuals were right now actually collecting blood and making dopa mine neurons from sporadic Parkinson's disease patients and collaboration with Deborah hall and Russia so that I'll stop and I think the people that actually did this work very talented graduate student David Marion there on the left and Benjamin BenHillier on the right who really responsible for the majority the work.
I do showed you of course my mentor Jeff record over these pretty much given me created creative lead in the lab and then of course I couldn't have done this without the help both financially there's my disclosure at the bottom and the consultant in a research award recipient from cellular dynamics international they've they really understood the power of this project and they made sure that I've had ample funding and I will just say it as many investors are people that want to give me money I would be happy to increase the number of people on that disclosure and then finally of course EvanSchneider who was my graduate mentors and also gave me a lot of create a sort of ability in the lab to do pretty much whatever I wanted for a while which mayor may not have been a good idea.
Thank you very much introduced the stem cell thing investigator award winner so the symposium investigator award honors young scientist whose principal author of a significant research paper published in stem cells and read the stem cell senators support the efforts of these emerging researchers and encourage the development of these investigators who are making significant impact in this field is fostering the future of their clinical applications this year's Young Investigator award winner is doctor come up front and center for regenerative medicine University of Edinburgh United Kingdombut very grateful as a critical regulator of embryonic stem cellpluripotency in the past we have identified two very important factors in maintenance of somatic stem cells in particular haematopoietic stem cells and cancer stem cells differ.
We proposed that say 22 is a master regulator of multiple choices in different stem cell types this paper is published and a very welcome to have a look I would not be talking about it and the stock however I would talk about the role of hypoxia Singh and haematopoietic stem cell functions and they eventually give rise to more committed progenitors and embraced him much blood lineages's so much debate extensions I specialize in the bone marrow most acquires and then they so he knew andapoptosis and differentiated 20 black teenagers and it's important to say that the strict regulation of their balance between these cells fate decisions is a central market place's regulation of this balance is a key.
So for example in general towns and acute eyelid leukemia stem cells and progenitors a quiet enhanced cell renewal decreased apoptosis block and differentiation and that results in the generation of which are very difficult to eradicate using current therapies and they still haven't this is so depleted stem cells reside in specialized in the bone marrow and the bone marrow is known to be hypnotic so number hematopoiesis in the genesis orkut and hypnotic conditions themselves are indeed very hypnotic because there's particularly low in oxygen concentration.
They have a low metabolic activity and hypoxia signaling pathways have been implicated in stem cell maintenance hypoxia-induciblefactors I thought to be essential for stem cell maintenance and in fact Genesis and there are several publications showing that targets for you so in my lab in cellular responses mediated responses to oxygen a mediated by the prolyl hydroxylase system in no more than normal and anomalous concentrations of oxygen probably hydroxy leaders hydroxylated and that results in the gradation of however in hypnotic conditions such as bone marrow microenvironmenthydroxyl eases these are not active if 120 not hydroxylated anymore.
They are stabilized they are trans located to the nucleus where they trigger transcript activate transcription of genes so in my lab in a temporary addressing one key question how does hypoxia impact on stem cell function it's a very complex question and today I'll just focus on three questions listed here so dohematopoietic stem cells are required in his system to function and hypoxiapathways impact on Genesis and can be manipulated to actually took condition standard be transplanted so I took that generatetransplantationso but quite surprising so I don't and we can see this regulated on the 100th loss of both here two thousand different underscoring the interaction between everyone we could see a metabolic deregulation especially in energy metabolism where we had almost complete shutdown of glycolysis and increased Oxford and the crap cycle and we could see a pond edition of he took that until genes down regulated and prone genes up-regulated.
You are very welcome to have a look at our paper will be published on Monday I don't really have time to talk about it and I just finished with addressing how can we actually use this knowledge that we have gained two radically looking like stem cells so what we did was the opposite well we exacerbate leukemia what happens if you stabilize them so in this case we have used a genetic knockout for pricehydroxylated in those hips are stable at least I will show with these nato we have identified establishment I'd like to thank you very many scientists in the room is going to introduce next three poster sessions soI have to read very carefully.
'm going to mess this up so one of our honoreesis Anil Kumar postdoctoral research fellow Department of Chemistry at theUniversity of Georgia please come up and his poster conditioning of injury site using nanoparticles delivered Europe protestants for regenerative therapy of stroke my 10th grade biology teacher would be surprised thank you good afternoon everyone here and I'm looking at opposed Oakland Dr professorDepartment of Chemistry University of the idea so today I'm going to talk about the size of my focus for the progress of my decision in the topping instructed it'd be so first we think about the store you know the people had made a problem even in the knot in the USA in the Worldwide.
This will give them a problem there is no treatment there is no drug available for the stroke treatment if they don't post things mainly going to think about how we can get this done we have to think about whether your my uncles York impound yard run they have the capacity that it can rest of the blood lipid to the Bremen are not so on the basis of thinking and other designing and we think we can design and nobody good platform to Newton during the structure AP and to take the stock to pee in the large animal models and human to human applications.
So here we have designed our platforms that the locals into the ring and one involved the advantage of nanoparticle platform that it can target to the mitochondria upset and he otherwise cancer cells is the benchersany kind of sales it has the capacity that it can target to the microphone they are the same as something of the bad news evaluate the delivery system whether it higher penetration efficiency audit has the capacity to bend the blood brain barrier unarmed and after that we designed the in vivo model system and the pig model system for the stock preppy murder.
Really it had obligations are not on the basis of this research we are working in our life so first study with two extra mile post is a very common spring Marcos has been used in multiples and to find that below the supreme I'll go cinema nanoparticles system and people here because pleasures in nanoparticles with our deal assist our chemistry to the team study and we started the religious sturdy and this is self study thenanoparticles nanoparticles and we find that the nanoparticle doesn't have any effect but after loading the display it had some effect in that one so that's their problem on an abundant in the system.
So after the timing ofnanoparticle system than we think whether it had the penetration if you can see in the video as well as in vivo are not to risk to the bendable first have been busy because in the middle of Marion models that is to say two skeins of cells that is the endothelial cells and there's two sides sense that play a major role in the development of blood brain barrier so we use the TPS system that is a system can be available in the double-elimination models and we design they need in the period sales and operations and there's no side has a lower persons to make it a junk science for the in Vito blood brain barrier model.
We find that we remain below the nanoparticles into that system and we find that our targeted nanoparticles the North Eagles have a very good politician efficiency as compared to non-target in NY and it has been very well in the single cells endothelial cells and astrocytes cells after a study in the single-cell level then we moved to the to see the tight junctions because when this label barrier for beginner society and they took this as they found a very tight junctions so we stay in this tight junctions and we find that in the current process doesn't have any nanoparticles after treatment with the different value system with a different manner standing we have found that our American system had a very good penetration efficiency in the formation of Parkinson's so you find that our nanoparticles have a very good liberal backers to cross.
The blood brain barrier mara so invest in this study and it isn't whether this nanoparticles had an attorney for Cincy into the brain is on or not then we invite our nanoparticles into the impact through the intravenous injections in my phone in the mice and we find that this nanoparticles excited to bring reason and this man apart sorry this nanoparticles have the very good penetration efficiency in the brain region and elsewhere in the liver after that we take on this basis and we see the study of nanoparticles in the different type of brain tissues and we find that hardest nanoparticles linked to look like the brain reason.
So he'll be happy to stand this brain tissueBansal with the different antibody staining and you find that most of the nonsense oligodendrocytes a society in the TLC has had a very good penetration that nobody believed it since it can penetrate the cell level after reading this then we see the anti inflammatory response of our nanoparticles system and we find that when we enacted the LPS into the mice and we'll find out soon enough I'll sit level has increased and I'll then has to increase after treatment with the audio system with a sprained Marcus so this is the prime minister he had none in our system and the system we are going to emphasize and to a study noting with the different and little protective compound and no new protective compounds and antioxidant in 2009 ordered delivery system to apply this application for the stroke model system.
So this study have given very good design we can use this number plz stop all this talk therapy and recently we are working on this one so far this one I would like to thank all my group my professors and our collaborators from Dr Frank Dr Franklin this and our very real died in our lab city and for this 111 the funding agency that and I for the neurological disease stroke wanna thank you my next post robbery and went to a welcome to the podium Dr postdoctoral fellow research Galloway Forces Institute of regenerative medicine is title 3d bio printed by a mask for facial skin reconstruction my work is yet to be appointed by mass for facial skin reconstruction as you know the skin tissue the largest organ in the human body and then cast two different layers of the epidermis and dermis seized two specials teams days to decide facial skin tissue things that has a very complex quickly.
This is very hard to the region that these tissues even though there is a lot of us to commercialize the skin graft that such as the intake and demographic shift record is a ship type that is very hard to the supply the tunes that are Jerry officials to issue the issue is to overcome this limitation of a customized skin graft we really operate as our operating system for the skin tissue regeneration right side of the detailed pictures is tower by printing system and trust you can deliver still have still not supporting marriage as a friend and they can irritate the shaving in any size of the structures through the D study.
I did the two differentexperimentsskin tissue regeneration using to these structures that is very simple to the break by the IRS to design concept but after that i the conducted experiments that is the facial skin tissue regeneration using the 3d by a mask that is the real structure really expand my spirits died where ya the project the 2d structures experiments I designed the two structures like that actually structures has a report later and then what I mean polyurethanes players and the disappointing that these hydro gels sales in the second and third layer is the hydrogen read the curtain side and thefibroblast that these two layers of skin tissue and all these structures.
I confirm that he's there later actually mister you can see that with different layers the still with us these things layers using the hydro gel also to protect the cells can stay supplied by reading these hydro gels and then can cooperate and then they planned that these destructive structures to imply that these structures used to these mice and then made recreate that he's in the bath under the skin of mice and men like that then by tends to be more squares the signs of structures we imply that there's the real tor Batista's can use areas during the two weeks actually recognize that there is still room and you can see that in this group so you can see that the letter D studies just can't issue is also we conducted Esha standing using the temples.
As you can see that these to write the bottom the figures that he's 23 structures we sell and then studies to regenerate the layers of skin tissue those we can confirm that these were the desired has to function as well and they began used that these are the giant bird mask structures that these are supposed to be easy but this is just a scare and David just as they got the simulator was written by mask will be useddominica Leoni HDTVs and this case the comfort to add more though and they can retrieve of these tobaccos bus pass the king and then series of coal and by the way that these are real special structures like that so I think is pretty structures and then study the three biomass actually but there's no more though that these freedoms.
I'm a structure because the layer of mice this be helped create that these the face it goes to be the case that these the facial structures and the implant these toxins into the top 10 spoke at and then took away all the faces on them and then we create a room down there and they wanted these people I'm asked structures on their roster for the teamsters restructure its not just not my mask restructures patient structures to create these structures we use thence and then squeezed by being implanted these disclosures to the spot and then we can see that the controller based at the death of east across the room on theDSpace a skin and then we can find that these structures stills deputies yesterday generation doing the two weeks actually you can see that the rain by mass group that gets there first but the pink room that we can see that a try there is one problem that is this Kim K during the procedure and also make sure it was doing in biomass group they can stay as he did and it is saying.
These two regions can see that these yeah the bottom figures is to buy mass and then that these researchers can't issue a similar to the liver tissue like I just wrote that he studies actually can still print out that these are two different bills through the skin tissue and also created is a very complex issue using the rabbi princesses are doing the study and there were a lot of rising water check the times we used only mice and they used the larger animal models for the authority by masked thank you last but not least we have poster Travis Jackson Loch Dr all students graduate research assistant University of Texas Health Science Center at San Antonio one of our partners at the world stem cell summit.
Last year in San Antonio in the title of his poster rescuing the regenerative capacity of human bone marrow derived mesenchymal stem cells from the elderly ok so loud up there too so I am a graduate student health science center and Antonio under dr.Zhao dong Chan and this work all began with the very astute observation our lab that everyone gets old one everything people do and what we're trying to deal with is the problem that as we get old we also tend to have a lot of do generate of diseases and so our bodies failing to keep up with normal repair and maintenance and so we won't be able to treat these degenerative diseases which regenerative medicine but as our bodies get old and we're down to our stem cells and so we're trying to treat these conditions with therapies that are using stem cells that aren't necessarily up to the task anymore and so there's a really big incentive for trying to rescue the regenerative capacity of these stem cell populations from the elderly.
So we can treat these conditions with tautologous there so few years ago before I joined the lab my mentor publish this paper in a mouse model where he took young malesmesenchymal stem cells induced them to create a matrix and the culture dish and then remove those stem cells who is left with just a young matrix didn't put old mouse stem cells onto that matrix and they behave like young cells and he said this is great we fix aging and now we just need to in humans and it didn't work so hot in humans.
It was much more help kids story maybe 20 from the time we see great rescue and all the stem cells were just look great but the other80% the time we couldn't rescue these aging cell populations and so we set about to try to figure out why and look for markers that could indicate which populations were capable be rescued and which ones were just too far gone to be rescued and so we looked at just everything that we could and this is just a small sampling of markers we looked at we saw it young cells tend to elevated as I C A four and lower HLA DRand intracellular reactive oxygen species relative told cells but none of those really good enough and what was especially frustrating about this is that we can tell just by looking at them which ones are different anyone this looked at a lot of stem cells can tell the difference between old population and young population in these images are very typical young stem cells tend to be very small and the old stem cells tend to be more heterogeneous an appearance and a lot of cells that are very enlarged.
So what we're thinking is that in these old cell populations the young these populations dominated by cells are very useful phenotype and as we age we may still have some cells that still have a youthful phenotype but they're surrounded with a population that is dominated by an elderly phenotype cell but if we accept that idea that those cells that looked more like young cells behave like young so that we'd expect the young sells the elderly population to take over during culture so as we grow them in some cells are growing much faster they wouldn't wish they would eventually be the dominant population we're not seeing.
So what we concluded that those large cells are likely to enter prison cells and if you're creating a bunch of stuff that's hurting their neighbors and so we tested by looking at conditioned media from the aged and young embassies and so if we collect conditioned media from elderly donors and treat young stem cells with that conditioned media inhibits the proliferation of young stem cells this was enough evidence for us to conclude that it's possible that there are still some healthy stem cells within the elderly stem cell niche they're just being inhibited by really bad neighbors and if that's the case then we should be able to rescue them relatively easily by isolating them from their bad neighbors so they're protected from all the nasty stuff to spend now and we did this using flow optometry sorting based on that size I talked about as well as expression of stage-specific embryonic engine for and sweeter than 24 populations large small positive negative or SOC 84 and we see that in donors over the age of 65 roughly five to ten percent of their stem cells exhibit a small.
As I see if we're positive those cells however are highly enriched colony forming units and have much higher levels of ATP relative to other sub populations of elderly cells or the unnerved population so we feel great they were able to isolate a population of cells that much healthier elderly donors but we need to obtain a large number to meet both high quality and high quantity of stem cells in order forautologous therapies to be efficacious and so we expand them both in tissue culture plastic and that extra cellular matrix from young donors that talkedaboutand we see that the large cells could not be at all enhanced by culture on the extra cellular matrix and supports the idea that some populations could be just too far gone.
Whereas the small cells just went crazy when we put him on this environment so we see that we can put good cells onto environment where they can thrive and they will but bad cells are going to continue to be bad cells you're just the quantification of that data showing that small positive population proliferated a much greater rate relative to the other unsorted cells and other populations from elderly donors and after culturing ECM that county forming capacity on par with young cells additionally their ability to differentiate down a suicide and it's like when you chose was on par with young cells and exaggerated by culture on ECM when you combine their ability to form colonies with the greater number of cells in total we see that after one week and culture.
We had a fourteen fold increase in the total number of stem cells in small posit population differences and see if you opt in eighty populations on par with young cells lastly their Linotype after culturing ECM is exaggerated is more similar to young cells they tend to exhibit higher associate for lower reactive oxygen species and Lower Trestles an exit 56 puree buttocks cells so it seems like we're able to get a healthy sub population of cells an elderly donors and were able to expand them an environment where they canthrivewere able to get really large number of healthy cells military donors so we have had a vision that we could have an eight-year-old donor come into a clinic will we be able to get his head regimes population of cells we could isolate from that only the healthiest cells that he haves at five to ten percent put them onto environment simulates.
A young bitch so they can thrive expand a large number of is healthy cells were elderly donor and then use them for tautologous cell their base their fees so that an eight-year-old donor go into a clinic and have tautologous cell based therapies with sells it looks like they're still1808 that take any questions or want to congratulate all the presenters today and I feel that this by having our poster honorees presented this meeting I think it's taken to another level and we will try to expand this is part of our summit every year going forward so now we're going to take a break at about4:15 please join me back in this room the closing session I'm going to have a few remarks on patient advocacy and were going to have our town hall meeting to all of you who are staying to the bitter end which we certainly appreciate open forum and then we'll go and have some refreshments outside and celebrate another year another years apart from hard work look forward to 2016 all right thank you take a break season.