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| 1 | Abcam | Direct reprogramming of somatic cells into induced neurons | 2787 | 24 | 49.1 | 10:30 | Hello, and thank you for joining us for today's webinar, Direct Reprogramming of Somatic Cell into a Doose Neurons. It's the first webinar in the series. It's my pleasure to introduce today's presenter, Dr. Benedict Burninger. Benedict is currently a professor of physiological chemistry at the University Medical Center of the University Minds. Benedict received his doctoral degree in 1996 at the Ludwig Maximilian University Munich for work on activity dependent regulation of neurotrophin gene expression. He then joined the lab of Professor Mumin Poo as a postdoctoral fellow at the University of California San Diego to study fast actions of neurotrophins in synapsis and growth colon. After a brief stay at the Colinska Institute to equate himself with the rapid development of the neural stem cell field, Benedict returned to Munich and eventually obtained a position as a lecturer and senior lecturer at the Ludwig Maximilian University Munich. In 2012, he received a call to the Johannes Gutenberg University of Minds. The work of his laboratory focuses on lineage progression of adult neural stem cells and on direct conversion of brain resident cells into induced neurons. Joining Dr. Burninger today is ours Cracallus, research area marketing coordinator here at App Kim. At this time, I'd like to hand the presentation over to Dr. Burninger. Thank you, Sarah, for this kind introduction. Thanks to App Kim for organizing this webinar and thank you, the audience, for attending this webinar about direct reprogramming of somatic cells into induced neurons. Hopefully, during the talk, it will become clear why I like to start the webinar with a citation from the Earth clinic, a poem by the Chairman, Poit Guter, if you are not willing, I'll use force. It's just what we are telling in a metaphorically to somatic cells when we reprogram them into neurons. This webinar will cover the following topics. First, I will try to explain in a few slides the basic concept on the lying direct lineage reprogramming. That is, the reprogramming of one cell type into another without going through a poor repotent intermediate. Then we will discuss the most common strategy to identify the right reprogramming factors that can trigger lineage reprogramming. This will be followed by an overview over the achievements during the last few years of converting far more blasts into induced neurons, a line of research that has gained considerable momentum. Then I will present you work mostly from my own group, which has focused since quite some time on the possibility of converting cells present in the brain into neurons. First, we will see that astrocytes are an interesting target for lineage reprogramming into neurons. And towards the end of the webinar, we will then look at an example of cells present in the adult human brain that can also be reprogrammed into neurons. And thus demonstrate and further opening potential therapeutic wing those of opportunity. During this talk, whenever I refer to work from colleagues, you will find this citation as indicated here. This figure, for example, is from a review by Sauer Melton. What is lineage reprogramming? Conrad Hall-Woddington coined a classical metaphor for the process of cell differentiation during development. An apigenetic landscape characterized by values of different levels and hills to separate them. A cell is modeled by a marble ball rushing down from the top to the valleys. The pathway takes, decides in which valley it will find a settle, providing a metaphor for the acquisition of a specific cell fate. Since valleys are separated by hills, cells cannot change easily their fate. The green marble represents a pluripotent cell, while the blue marble, let's say a phaboblast. The question now is how to push the cell uphill again. In the case of reprogramming towards a pluripotent state, such as it is achieved by induced pluripotent stem cell technology, you need to push the marble all the way up the way it came. In case of direct lineage reprogramming, often referred to as trans-differentiation, the idea is to directly move from one valley to another. And that's acquiring a new cellular identity. Clearly, this is a very nice image, but how does it really work? Independent of the mechanisms involved both reprogramming strategies promise to revolutionize medicine. Essentially, they represent alternative ways of obtaining desired cell types like hard cells, liver cells, and of course neurons and grier. For the first time it is possible to obtain large quantities of cells of human origin. These in turn can be used for disease modeling and drug discovery, but hopefully one day also for cell-based therapy of the many devastating diseases such as Alzheimer and Parkinson's disease. Now back to the mechanism. Simply far we can look at it this way. Each cell fate is characterized by a regulatory network of factors, typically transcription factors that maintain a specific state through reciprocal feedback interactions. This can be called a program, let's say green. Now to change to a program red, we must activate new nodes in the network that were inactive when the cell was enacting the program green. This may be done by overexpressing transcription factors or microRNAs. During successful reprogramming this will now lead to the progressive stabilization of a new network of interacting factors. Depicked in red and a deep stabilization of interactions that characterized the state green. Now what is the basis for selecting the right factors? As I'm also a lot from Harvard University discuss in the recent science review, a good choice for the right reprogramming factors is inspired by development. Factors that drive neuronal specification in the developing CNS are good candidates for reprogramming other somatic cells into neurons in vitro and perhaps also in vivo. The other big question concerns the cellular target or which cell type you want to reprogram. This can include cells outside the CNS such as skin phyroblasts. But if we want to move reprogramming into the vivo setting, we must select cells that reside in the brain such as clear or as you will also see non-neural cells such as perisides. Back to the factors. One way is to identify transcription factors and one way to identify transcription factors and microarrays that can be used for reprogramming is to screen for them through microarrays or RNA sequencing within the embryonic brain tissue. From these you can now obtain an arsenal of viral vectors, lentiviruses or retroviruses and in fact you're starting cell population of choice. So sometime during which reprogramming should take place, you start to evaluate the outcome and conduct functional assays such as patch clamp recordings in case you try to obtain neurons to prove that cells really change the identity. What are the criteria for a cell to fulfill to be called a neuron after reprogramming? First, the phenotype should be stable even once the reprogramming factors are switched off. Of course at the same time the properties of the cell of origin should have been lost by the cell. Otherwise this would indicate incomplete reprogramming. In case of neurons it is very important also to derive cells of a specific subtype. For instance if you want to model Parkinson's disease you may want to specifically generate midbrain dopaminergic neurons such as occur in the substantiomagra. Finally, these cells must exhibit the electrophysiological characteristics of you decide top of neuron. | ↗ |