Channel: VJDementia clear
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| 1 | VJDementia | iPSC-derived 3D organoid models to explore Alzheimer’s disease | 894 | 8 | 46.3 | 2:32 | I think that it's a great enhancement for science, the possibility to use IPS-based models. So there are a lot of advantages mainly due to the fact that we can use patient-driving IPS, but we can also make genetic through CRISPR-Cas9 and using isogenic IPS that express only the mutation that we need in order to dissect the impact of that mutation on a particular phenotype instead of having a background influence on that. It could be hard, so I mean, it's strange to think that something like neurodegenerative disease could be studied using neurodevelopmental models because starting from IPS, even though we can arrive through three months or four months or five months development, they were still developmental model and not degenerative models. But it has been demonstrated that this type of mutations mainly also on towel, for instance, we have also did on that. They already impact on the neuronal size, neuronal formation, neuronal morphology and also in the synaptic activity. So we can see from the beginning in the organized model in the cell lines derived from IPS, things that maybe will have a strong impact in the huddle-tod and not in the development. And another thing is that moving from 2D to 3D system, this is a very nice example of how much increasing the degree of freedom is improving our ability to find things because thanks to the extra cellular matrix in 3D, is it possible to find the bitarmyloid aggregates that you cannot see in 2D culture? So I think that organoids can offer a very nice model to study both neurodevelopmental but also neurodegenerative diseases. | ↗ | ||
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| 2 | VJDementia | Potential of iPSC models in Alzheimer's disease research | 278 | 4 | 45.4 | 0:52 | I'm really excited to work on a human-based model for Alzheimer's research, because although animal models have been extremely useful throughout the years to elucidate lots of mechanisms, we are also at a stage where clinical trials are kept failing and lots of people are thinking there might just be big enough differences between human genetics and mass genetics that we should be trying to work with human systems. And it's also a really good opportunity to try and screen lots of molecule first before we even need to do, for example, the animal models or the clinical trials. | ↗ | ||
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| 3 | VJDementia | iPSC models of neurodegenerative disease | 419 | 2 | 42.6 | 3:27 | One of the big challenges that we have faced as a field quite broadly is the difficulty in making accurate in vitro models that captured the disease process. And there are a number of reasons that that's been challenging, but potentially the biggest one is the fact that the human brain is really inaccessible to us during life. So up until the availability of IPS cells, we didn't really have a method by which we could have unlimited human neurons to grow in lab. And so in that regard, the availability of IPS has been really transformative. And so what we, what I'm saying IPS without finding it induced, who repotence themselves. Obviously, the big advantage of this is we can make specific, patient specific models, because we generate the stem cells from a sample of skin, which is easily accessible to us and non-invasive. And so in our lab, what we do is collaborate with our clinicians who are just in the building across the square. And when they see a person with either a genotypone or phenotype of interest, they ask them for a skin sample, which we can then use to make their stem cells. The next step is making the relevant cell type from both stem cells. And there are two real ways that we do that. So we can make cortical neurons as a 2D culture. And so these are cells which kind of grow in a single monolayer on plastic. We do this by a process called dual-smanned inhibition. So we're using small molecules that kind of essentially inhibit signaling pathways. And the consequence of that is the cells undergo something that very closely mimics cortical differentiation during human development. So these cells are really useful to work with. They've kind of given us a lot of insight into molecular mechanisms. They are more amenable than the 3D cultures that I will talk about in a second to things like drug screening, because obviously there's a monolayer. If we put a small compound into the media, there's a uniform exposure of those cells to that compound. However, there are some limitations. And one of the limitations of the 2D approach is of course, because we're growing the cells in a monolayer where disrupting the architecture and the structure of the cells. And so they are organized, for example, into layers like we would see the neurons organized in the brain. And so it's trying to address that. We complement our 2D models by using these 3D systems called cerebral organides. It's a very similar principle in that we are mimicking the very early stages of development of the brain. However, this time we're doing it in 3D. So these are non-adherent, they're floating cultures, probably about the size of a lentil. And as you will have seen from some of the images I used, the advantage of this talk is you get different cell types, occupying kind of different spatial regions of the organoid. They also have cost-commit limitations. I mean, in both systems, they're missing cell types such as microglia, they're missing a vasculature. And the cerebral organides tend to be a bit more variable compared to the 2D cultures which tend to be quite homogeneous. And so that's the reason that we use both approaches to complement one another. | ↗ |