Unveiling Stem Cells: The Impact of Culturing on Efficacy

Some of the research said that even 24 hour of culturing can drastically reduce the potential of these cells to home in like homing mechanism and to engraft meaning to stay in the place actually be part of the tissue. So it impairs both capabilities. Hi, this is Dr. Joy Kang. So today I want to talk about this issue of cell expansion. This question has been asked of me many times. Why do you think that people don't need to go overseas to large number of stem cells? Because aren't they better? Because you get a lot more. And there are even some people who say that culturing cells in a medium is like putting the cell in the Garden of Eden and then they just grow peacefully and happily and you actually get her get better cell quality. And that unfortunately is not supported by evidence. So I want to explain a little bit about what research has gone into this and what people have found may things in a bit of perspective. So it's not just my opinion. This is actually from various research that have been published. So for example, so the question of native cells, which means that they have not been manipulated, so they have not been changed by any chemicals or enzymes and they have not been grown in an incubator to huge numbers. So cells especially MSCs, they do have this capability to regenerate, right? They are really good at making more copies, but doesn't mean that they're making identical copies of themselves. So unfortunately their tendency is to make one identical copy and one copy that just a little different. Because that's what stem cells do. When they divide, they tend to gain some function while maintaining a copy of itself for future use. Right? That's why these are stem cells. They are keeping themselves available for regeneration. So if you can imagine, if you grow cells and one cell become one copy of the self and then a copy of something a little different and these two cells will divide. Of course, the one that's a little different is not going to divide back into the original cell, right? It's going to keep differentiating. So now you've got from one cell, one stem cell, then these divide into two cells and at the four cell stage you only have one stem cell left and three of the daughter cells. And then if they keep dividing, you can imagine in a soup of cells how many cells are still stem cells. So in certain circumstances they can divide into identical copies of themselves. But it takes very special particular conditions and that is not easy to maintain or achieve. So some of the research one thing is that this study published someone from this is a US study said that even a 24 hour of culturing can drastically reduce the potential of these cells to home home in like homing mechanism and to engraft, meaning to stay in the place, actually be part of the tissue. So it impairs both capabilities. So even though it's nice and easy to grow these cells, but it does alter their nature. And then here's a study in 2013 by a group of researchers in Italy and they found out that they were looking at these passages. So each passage is when you grow the cells to certain amount that you saturate the container and then you have to divide them and separate them out into different pieces, different containers or different cultures. And then that's the different passage. So it was way more than one generation, so different passages. So when you do early passage, that's what they consider passage two to three, comparing to late passage, which is more than five. And then you compare with things that have not been expanded. What happened was that they realized that genomic imbalances are happening even at the intermediate passage, which is just passage four. So about passage four, then you're observing genomic imbalance imbalances. And what's interesting is that these imbalances actually these cells that are carrying these imbalances have an advantage at proliferation. So preferentially these imbalanced genomically cells are making more copies of the of themselves. So and that makes it more dicey, right? You're getting cells that have been altered in certain ways and going what about comparing to see how well these expanded cells can work. So this is a 2014 study from the United States. So they were looking at what happens when you expand MSCs. So they do find out that there are changes in genetic expressions and there are reduced potentials, reduced surface adhesion related receptors that are really important for homing and for engraftment in live animals. And there's also loss of potential to differentiate, so potential to develop into different types of cells that have their own function and their own particular set of capabilities. So these are what's found out. And then when they compare that with uncultured bone marrow, actually mononuclear cells, this is interesting. So bone marrow cells contain a little bit of mscs, but have a lot of other kinds of cells. So these will be hematopoietic stem cells, endothelial progenitor cells and other kinds of progenitor cells. So it's a soup of cells from the bone marrow. And these bone marrow cells have never been expanded. Right. And they only have about 110 of the number to culture expanded MSE. So they have these different little microbeads that they were studying and to look at how well they can generate bone tissue. And then I realized that fresh uncultured bone marrow stem cells that have 1/10 number of MSEs compared to culture expanded MSE, these little microbeats, they have about similar capabilities to generate bone marrow. I mean bone new bones. And the rationale is that using the fresh uncultured bone marrow mononuclear cells that actually utilizes the synergistic effects of the MSCs that are in the bone marrow and all the other cell types. So this is why I have the philosophy of embracing different cell types in my therapies. Because I mean this is the, the only product. So I've developed, developed a stem cell product which is the only one that is in the, in the market that actually contains cells from the cord blood, that local core blood, which is very similar to the composition of bone marrow, just much younger. And the core tissue which is full of mics. But none of these are expanded. You can harness the synergy of these cells, but also even at a fraction of the number of cells, you can have, you know, in this study just as good of results. So synergy and you don't need as many cells. So if you compare the small amount of cells with the large amount of MSCs expanded, you know, as far as benefit, the combination of cells with small number MSCs achieve the same benefit. And there's another study that's in 2017, a Chinese study, we're looking at bone marrow MSEs at passage three. So the third passage compared with freshly isolated bone marrow. So again, this is similar, right? So the passage three were actually inferior to the fresh bone marrow soup of cells in their ability to regenerate cartilage and they had decayed in telomere activities and chromosomal changes that indicate senescence when it's compared with bone marrow stem cells. There's also a lot of variabilities among these. Passage 3 MSCs from the Bone marrow they have these variabilities probably indicate genomic instability. The telomerase and chromosome anomalies from the expansion can lead to impaired stemness and pluripotency. So basically impaired potential to develop into different cell types and how active and potent they can be. So their conclusion is that the in vitro culturing so outside of the body culture and expansion is not recommended for cell based therapy and that fresh bone marrow stem cells is the first choice. So that's interesting because these are a direct comparisons as far as MSCs themselves, comparing MSCs to MSCs, this is a study that was presented at a stem cell conference in 2018 that I was at. It talked about what happens when you expand mesenchymal stem cells. So this was presented by Axel Cell Research that was back in Salt Lake City. So they were looking at what happens when you use native, which means non manipulated stem cells versus culturally expanded cells. So what they showed was when you are not using msc, so these are not MSC cells and you look at their clinical efficacy to achieve certain results, it's very small amount, right? So that's basically control. And then when you use actual MSCs, but these are native MSCs, when you use 10,000 CE, you are reaching a particular result. We use 10 times that, but also native cells. So 100,000 native cells versus 10,000 native cells. You're using a heightened response. So this is a dose response difference, but now you want to use 10 times the last one, right? So instead of 100,000 native cells, you're using 1 million but expanded cells. Now the result is actually reduced. So you have a reduced effect of what you're looking for, what you're hoping to achieve. So more is not, not only not better, but it could be worse. So it could give you a reduced efficacy. Just because you're going overseas getting 100, 200, 300 million cells, then you think that it could be more beneficial, but it could be less beneficial than using a much smaller amount of cells. This is why I insist on using these native cells that have not been manipulated because of what studies have shown. The problem with expanding the cells is not just as reduced in this efficacy, but also there could be all kinds of added side effects. For example, when the cells are stressed in a culture, they could secrete a lot of inflammatory molecules and these can cause different type of response, inflammatory response, cytokine response. They can also start to express surface markers. These cells that are differentiating are, you know, changing and morphing. They could end up expressing surface markers that is the same kind of markers as the donor. Right? The donor is different from the recipient by the time you use this soup of cells in the recipient. But these cells have been changing, has been expressing what was in the donor before. Now you have a higher chance of rejection by the recipient. And this is probably underlying why we're talking about the cytokine storm because of these cells is because one, you have a lot of inflammatory molecules and two, you're generating the surface receptors or markers that can trigger rejection type of reactions. So all Of a sudden now you got malaise, fatigue, low grade fever, coughing, and just possibly lasting for a very long time. You know, we've had people who had extreme fatigue for two months after one of these therapies. It's not an isolated case. And sometimes when people do the first treatment, because in some clinics they do three sessions in a week, after the first treatment, they're doing fine. But after the second treatment, when your body, your immune system has been primed to these markers that the body doesn't recognize, now is mounting an immune response, by the time you get the third treatment is even worse, they get a lot higher response. So that's, you know, pretty indicative of a rejection type of response. So this is something that I think people need to understand that these are potentials. Just because you can grow the cells doesn't mean that these are, are completely free of consequences, that you can just keep growing them to large numbers. They do degrade and they can cause problems. Not only they can decrease in their effectiveness, they can also cause these side effects that I just don't see using these fresh, unmanipulated, unexpanded cells. So I hope this helps to clarify things a little bit. I hope it hasn't, you know, been too technical and that it does give people a some kind of understanding of just the type of rationale that goes into clinical decisions as to what kind of cells to use. Because are there are various things when it comes to stem cell therapy. The most important thing, the first thing is what are you using, what cells are you using? So that is a big choice. The other decisions are how much cells to use, how frequent to use, and where do you put it? And I can go over those in later episodes. So I hope you find this helpful and leave a comment if you like to, you know, have conversation. I always respond and please send this to somebody that may find this interesting. If they're looking at stem cell therapy. I know now it has become more and more mainstream, even though mainstream medicine has not quite embraced it. But in the eyes of the public, it's becoming more and more mainstream and it's, it's pretty exciting to see because people demand healing. They demand to be better, right? Life has a drive to heal itself, to get better. And if conventional medicine is not offering them that hope, that possibility, they come to something that's more on the edge right now as stem cell therapy one day is just going to be the centerpiece, but right now it's on the edge and more and more doctors are going to embrace it. So what I see in the clinic is the results are driving the response from patients are driving the volume from patients. So it's very exciting to see that as a doctor, that I can actually affect change and I can actually make some major transformations in people's lives and that people are taking their health into their own hands and searching for something that actually works. So I hope this is helpful and I look forward to talking to you again soon.