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Cell Reprogramming

Author: Laura Pintado

Do you think people can't change?

Surprise! That's not completely accurate, psychologically and biologically speaking. I could go on all day discussing both perspectives, but for the purpose of this blog let me focus on the latter one, more specifically from a cell biology point of view.

First off, your body is made of 37.2 trillion cells, forming all your tissues and organs. This is possible as during development, a variety of complex molecular processes take place, helping cells to specialize into the many different types going from neurons to blood cells. You could imagine cells are like students, all learning the basics at primary school, and later on, some specializing and becoming scientists, while others become dancers, writers, or bakers. In the same way that all these people are important and relevant to constitute human society, different cells are crucial for the complexity of the human body. Because let me tell you something, the baker making the best pistachio brioche in Milan is definitely making my life easier and happier, while at the same time my trainer made me not to become fat and unhealthy. Ultimately, this enables my neurons to release endorphins and my adiposities not to get lazy.

On this wise, how does this sophisticated meringue happen? During development, different cues are available and affect cell fate. The way cells communicate with each other is not by WhatsApp voice-messages, as we currently do, but by releasing a variety of molecules which act as external cues. By doing this, they coordinate cell division and differentiation at the right time. Also, the internal aspects of the cell contribute to this journey. For example, they have specific sets of genes whose expression guides their behaviour and indicates where they belong. This set of properties enables cells to develop unique features and particular functions. Basically, cells aim to acquire a final type of identity, more or less like an ID card. Maybe, and just maybe, you are wondering how cells can become so different from each other if they come from the same fertilized egg and contain the same DNA? Well, the way I picture it is by thinking of Netflix. So, the listed genre you can find on this platform could easily be represented as the different cell types (comedy as fat cell, action can be neurons, or romance as cardiac cells, why not?!). All the movies you can find and play within each of these categories represent the specific set of genes for each cell type. In that scenario, neurons could be composed of genes called Kill bill (Vol I and II), Inception, The Equalizer, Twilight (yeah, mutations can happen but that’s another story). This basically illustrates how cells express (in a particular and differentiated way) the genes necessary to become one or another despite having the same DNA, which in this case is represented by Netflix as the common streaming platform.

But now imagine taking a completely mature and differentiated cell and transforming it into a completely different cell type. To continue with my example, you would have to imagine taking a total neurotic cell playing "Django" or Tarantino for that matter and change it into a chill careless cell within the "Love Actually" type, or even a cell which could enjoy watching fossil documentaries. In science, we have a fancy term for when this occurs, and that's cell reprogramming. This is similar to when a Pokémon evolves from one state to another. For instance, Charmander goes from his initial state to Charmeleon (intermediate state), and finally reaches the powerful Charizard (image below). This is great, but wouldn't be nicer if Charmander could directly transform into that cool dragon state and skip that teenager look? Yes, and in molecular biology it is possible to do so with cells, which is known as direct reprogramming or trans-differentiation. So, we get to directly obtain Charizard from cute Charmander.

But exactly why do we want this if we can already reprogram cells? One limitation encountered when converting cells is that, during the process, they can become pluripotent in an intermediate state (Charmeleon). This refers to when cells get too excited and start dividing like crazy, which is something we obviously to avoid. Why? Because the possibility to join the dark side just like Darth Vader did is high, and cancer happens. This is like life, is all about balance. Does Dolly the Sheep ring a bell?

Having that in mind, we need to consider that unlike any other tissue in the organism, neurons are unable to regenerate upon damage or degeneration in the nervous system. In this context, directed cell differentiation aimed towards the restoration of nervous tissue holds great potential, not only for regenerative medicine and replacement therapy but also for disease modelling purposes. What is important here is that this could make us better understand the precise mechanisms behind cell-fate conversion in mature cells. Meaning that we could overcome common issues, such as tumorigenesis, that have been encountered since the pioneering studies done in 1997 by Wilmut or by Takahashi and Yamanaka. In this context, a critical point to consider is the selection of the starting cell. In my case, astrocytes will be used for a number of reasons: first, they comprise the largest population of glial cells within the nervous system; secondly, up until now they have been the main targets of the vast majority of research in this field. Nevertheless, these are not the only cells to be employed, with many other somatic cells such as fibroblasts being selected.

To wrap things up, direct reprogramming is a rapid way by which researchers can generate the cells they need in the laboratory. In my case, we initially wondered how external cues such as inflammation can affect the conversion from astrocyte to neurons. Later on, we thought about how we could facilitate this process by temporarily silencing astrocytic-specific factors. Lastly, we are eager to even increase the yield of neurons by making astrocytes a little bit younger. How? Well, not by applying anti-aging creams for sure, but by exposing cells for a short time to a protein called YAP. This particular protein is indirectly involved in cell proliferation and apoptotic suppression (cell suicide) by controlling gene expression.

Honestly, how on earth do we manage to do this? As if taken from a cooking book, we throw in the dish containing our cells a meticulous selection of proteins and chemical compounds that are capable of modulating key signalling pathways in the cell. These "ingredients" will provide cells with the little push required for them to change. You could also think of them as psychotherapists providing people with the proper tools to modulate people’s behaviour. But caveats! The way and time we administer them are crucial, so first, we use a virus to infect our cells and promote the proper gene expression to become beautiful neurons. Only then, we give them other molecules to further enhance neuronal fate induction, followed by a second phase of neuronal maturation. To make it simpler, we properly feed Charmander to be powerful Charizard. However, despite how dreamy all this may sound, the trans-differentiation process entails molecular mechanisms that are not fully, nor well, understood yet. Therefore, there is an urge to improve current technologies to generate pure and efficient cells to dig into the understanding of cell differentiation.

Before leaving, let’s look back to can people change? Few things are needed to answer this query: for cells it’s a natural thing and after this blog post now we know they also do it with external help, even after fully being specialized. Considering that people are made out of cells, I am pretty sure it's safe to say that indeed people can change. On top of that let me strike you with the fact that every 7 years the cells in your body are completely replaced so, hell yes, people change! It’s neither easy, nor fast but possible. You never know, you could become a scientist and help to the untangling of this muddle.

References and links:

(Loi et al., 2003; Takahashi & Yamanaka, 2006; Wilmut et al., 1997; Kelaini et al., 2014; Zhang et al., 2016; Kempuraj et al., 2016; Fang et al., 2018; Janowska et al., 2019; Heinrich et al., 2010; Torper et al., 2013; Liu et al., 2012; Liu et al., 2013; Masserdotti et al., 2015; Brulet et al., 2017; Tanabe et al., 2018 & Yang et al., 2019; Li et al; 2019; Aravantinou-Fatorou & Thomaidou, 2020; Zhang et al., 2016; Guo et al., 2014).

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This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 813851.