| 1 | The Sheekey Science Show | Rejuvenating the heart – is it possible? (Cellular reprogramming) | 14019 | 763 | 56 | 81.3 | positive | 11:41 | Rose if I only had a heart. So hello and welcome to the Shiki Science Show. Well hopefully you all have hearts. Unlike the port in man from the Wizard of Oz. But speaking of wizards, we're going to be talking about some spellbinding science in this video that will surely get your blood pumping. Partial reprogramming of the heart. Or as the researchers call it, referable reprogramming of cardiac myocytes to a fetal state drives heart regeneration and mice. Cool. So the heart of the study begins with well, the heart, that good old important organ that pumps blood around the body as part of the circulatory system, to deliver oxygen and nutrients and remove waste products. And it keeps on pumping without us even thinking about it. Unfortunately though, the heart is still prone to damage, especially for example from heart attacks, which reduces the functional capabilities of the heart. Not so good. But do we need to worry, can the damage be fixed? Well, to repair damage in the body we have stem cells. Stem cells are cells that look like stems. And joking, stem cells are cells that have the potential to both defied continuously, but can also differentiate into specialized cells. A specialized cell in this case being a heart cell, or cardiomyocytes, the more fancy name. For example, you can find stem cells in the intestine to replace cells lost in your gastrointestinal tract, and skin stem cells that are constantly replacing skin cells lost at the surface. The heart however, greatly loses its ability to repair tissue damage shortly after birth. Now this could be the reason why we don't seem to see tumor formation in the heart, but since the cardiomyocytes can't be efficiently replaced, instead the damage is patched up with the fibrotic scar, and the scar tissue reduces the functional capabilities of the heart. So the ideal solution would be to replace these cardiomyocytes or to form new ones. But how? Well, this nicely leads on to the huge topic of cellular reprogramming. Cellular reprogramming is all about, well, reprogramming cells. Okay, well, if you must know, it refers to the process of refreshing a cell's identity. So like a skin cell has the identity of a skin cell, it does what skin cells do, and so converting a skin cell to something different would change the identity of the cell, and the another way of thinking about it is you reprogram that cell. And what has been shown now in numerous studies is that the identity of a cell can actually be erased. For example, the Nobel Prize winning work by Shunya Yamanaka showed that fibroblacells could be reprogrammed to become pluripotent stem cells. So going from a specialized cell to a stem cell, and this happened when the cells were given four factors, opt-4, sucks-2, c-mic, and k-l-f-4. These are more commonly referred to as the Yamanaka factors, or OSKM, as I may refer to from now on. Another phrase I will probably use in this video is the differentiate, the opposite of differentiation, when you go from a stem cell to a specialized cell type. So the differentiation is the reference of this process. Although here, they suggest that the differentiation is more like partial reprogramming. The cardiomyocytes can acquire the ability to replicate like a stem cell and like cardiomyocytes in fetal hearts, but they haven't completely lost all of their differentiated features. As cardiac cells possess special features and have a certain structure that enable them to perform as cardiac cells and get your heart contracting. But this structure is not suitable for a cell to defide, which is why you need this differentiation process to enable the cardiomyocytes to replicate and to potentially repair the tissue. So, would it be possible therefore to regenerate the heart? Could these Yamanaka factors be used to replace or reform new cardiomyocytes? Well, this nicely leads us back to this recent research paper that tried to further explore this. So, what they needed to achieve was to get these heart cells, these cardiomyocytes, to replicate by entering mitosis. Due to much published data so far on the Yamanaka factors, this seemed like a logical approach to follow. Though they were also interested in testing why the reprogramming would work without CMIC since this factor is a cancer oncogene. In other words, in some cancers, this protein is overactive. So, this would just leave OSK. And before going straight to infevil with the mice, they first tested whether they could get cell cultured issues of the cardiomyocytes to grow. However, neither Mika-Lone nor OSK was able to co-acidase these cardiomyocytes to replicate. So, they had to stick with OSKM. But there are other tricks that they can use to mitigate against the potential tumourogenic effects of CMIC. One is controlling timing of the expression of these factors, i.e. when they get activated and for how long, or maybe that's already two things, and then thirdly, they can control the dosage how much CMIC is going to be expressed, so whether it's a little amount or loads of it or some are in the middle. So, how do they actually test all of this? Well, they use a genetic mouse model that only expressed these factors in cardiomyocytes when they were given doxycycline, so it was an inducible system. And so, because they could induce it with this drug, they could time when these factors were activated in the mice. So, firstly, they just did this in normal mice, and six days with doxycycline showed signs of de-differentiation, such as the presence of smooth muscle actin, suggesting that the expression of these factors were having an impact. However, pro-longed exposure shows more complete reprogramming, showing new plasms, cancerous groves, after 21 days of expression. And these groves could even be maintained, even if the mice stopped receiving doxycycline. They also tested pro-longed expression, but with a lower amount being expressed, so with a weaker continuous expression, however, they still saw new plasms by seven weeks. So, the data so far suggested that the degree of cardiomyocyte de-differentiation and proliferation depended on when the expression occurred and how much expression that was. So, so far, pretty much followed what we thought. You have to be careful regarding how much of these factors are expressed to get just the right amount of reprogramming before a cell loses its identity completely and goes out of control. But, does this partial reprogramming, the short-term expression, have any benefits for repairing the heart after damage? Well, as I mentioned, they were studying mice, and to see how the OskM factors could repair damage in their hearts, well, they had to induce some damage. So, they follow a protocol whereby they can induce myocardial infarction in the heart. And to test how the factors could help with repair, they expressed the factors over six days prior to the event, one day after the myocardial infarction or six days after. And in each of these conditions, they gave the mice the doxycycline for six days, so to have that kind of partial reprogramming. So, effectively, we have pre-treatment, acute treatment, or therapeutic treatment. And in all cases, they saw that the amount of scar tissue was reduced when there was expression in over of these cases compared to the control mice. And they saw it improves cardiac function in the mice treated with doxycycline before and during the myocardial infarction. So, it seemed at this point that either the pre-treatment or the acute treatment was best in terms of heart regeneration. As they point out, adults cardiomyocytes improve left ventricle systolic function after myocardial infarction, particularly when reprogramming is initiated as early as possible. So, it's important to point out that what happens in this case was partial reprogramming, which is the potentially safer alternative to full cellular reprogramming, as it enables the reversal of cellular age of cells without them fully losing their identity. Now, you might be thinking, Yamannaka discovered the factors years ago, why is it taking so long to get to human therapies, why are we still looking at mouse models? Well, numerous reasons, but three main reasons, safety, efficiency, and effectiveness. As we've just seen in this research paper, it was only the short term application of the factors, a partial reprogramming approach that was most effective and appeared the safest for the mice. That is, no cancerous graves. As you can see nicely summarised in this figure, continuous expression of the Yamannaka factors caused complete de-differentiation and the development of cancerous graves. And prolonged expression caused irrefutable de-differentiation, such that the cells' identity was erased and they couldn't effectively mature into adult cardiomyocytes that were needed for the damage repair. It was only the short term treatment that caused irrefutable de-differentiation that enabled the cells to partially reprogram and enable the adult cardiomyocytes to re-enter the cell cycle and regenerate the cardiac tissue. Now, many challenges lie ahead. This was done in mice. How long exposure would be safest and most effective for humans? Is there a way that this can be done without semit? The fact that is commonly overactive in cancer. What would be the best delivery of these factors into human patients? Obviously, if both targeting and tight dosage needs to be carefully assessed, this may pose many challenges for human translation. As identification of molecular thresholds that promote de-differentiation but avoid a point of no return will be critical to engineering and safe therapy. But what is most exciting is that there is evidently regenerative potential. And lastly, it raises the question of whether partial reprogramming could cause de-differentiation of other post-mitotic cells such as maybe neurons. And so maybe in another video we can help out the scarecrow with this brain. Anyway, I hope you've enjoyed this video. Leave a comment, always keen to hear your thoughts and if I like it, I may even give it a heart. Anyway, that's all for this video. 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