AASCP Lecture: Best Tissue Source of MSC's Part 2 - Joy Kong, M.D.

The last one that they, in that study they compared its anti inflammatory inflammatory properties. So they use this LPS induced inflammatory model. And then again comparing to bone marrow and adipose MSCs, umbilical cord blood derived significantly can down regulate the inflammatory cytokines and then they secrete a level of a particular type of protein that's anti inflammatory protein and that is closest closely associated with upregulation of anti inflammatory properties. So they have, you know, they decrease inflammatory factors and increase anti inflammatory factors. Okay, so what about some other comparisons? So orthopedic, let's say we're talking about orthopedic use of these cells. Umbilical corduroy MSCs, they produce three times as much collagen as bone marrow derived MSE. So you guys can all look up these articles and then bull pork MSC also has greater mineralization when they're cultured in this osteogenic culture. So helping them to push them in the direction to become bones. So they have greater mineralization properties. And then if you put them in a chondrogenic culture then they tend to, you know, they form more of these chondrogenic pellets compared to bone marrow derived MSCs. What is that side? Hello, that side bar. Just wondering. And then other comparisons. So cancer. So when it comes to cancer potential that's kind of like a sore point. Everyone's a little worried about that. At least I am in my practice. What do I tell patients? Because there has been pro cancer evidence about these cells promoting cancer growth. What about these, what I'm using in the clinic. So when you compare the cancer causing potential. So this study, they looked at umbilical Cord blood derived MSEs versus adipose derived MSCs, the effect on the glioblastoma multiforme. So so both in vitro and in vivo, both studies, you know, both experiments show that umbilical cord derived inhibited the tumor growth whereas adipose derived actually promoted the tumor growth. And there's, you know, different tumors respond differently to different type of cells. But you know, this is a direct comparison between the two. So they showed umbilical cord blood derived mscs induced apoptosis through this tumor necrosis factor related genes. And then this particular gene is more strongly expressed by local cord blood derived MSC than adipose derived. So genetically they produce more things that can cause a death of these cancers. So that's in that study. And, and then another study showed that umbilical cord, which Orton's jelly is a major part of umbilical cord that does not induce teratoma and do not induce tumor. And it's also associated with, it's not associated with enhanced tumor growth and can even reduce solid tumor, including breast cancer, carcinoma, ovarian carcinoma and osteocarcinoma. And let's look at angiogenesis, important for tissue growth and survival. Umbilical cord derived, you know, Wharton's jelly is the major part of umbilical cord has stronger expression of angiogenic factors and immunomodulatory factors. So some of these factors, such as the BFGF and hgf, they are known to have anti fibrotic properties. And that's probably one reason that they were seeing positive results in even liver cirrhosis or lung fibrosis or even fibrosis in the heart after MI, because it can break down scar tissue. And then Wharton's jelly, MSCs are also able to induce the endothelial cells to migrate more efficiently than bone marrow. So if you can induce endothelial cells to migrate better, of course you can, you know, that would enhance the effect of angiogenesis and then neuroprotection. We're all very interested in neuroprotection. So words jelly derived MSCs, they have better neuroprotective effects than those from bone marrow. Derived MSCs more effectively decrease L death and apoptosis. And the gene expression pattern also shows a predominance for neuroprotection. So in Wharton's jelly, most of the genes that are expressed so you can see cell proliferation, neurogenesis, nervous system development and blood vessel development. Whereas bone marrow MSCs, there's more expression of the genes that are dedicated to ossification and skeletal development. So I talked about umbilical cord MSCs. So within the umbilical cord, so I mentioned there's Wharton's jelly, there's vein, artery, umbilical cord, lining membrane, so amnion, chorion, subamnion and perivascular region. So what's interesting about the umbilical cord MSCs, so first of all, they express a high level of embryonic genes that makes them almost in between embryonic stem cells and mature adult stem cells. So this is very exciting because we like, in a lot of ways we like embryonic stem cells, but we're also afraid of them because we don't know how to control them. And as far as differentiation, so just looking within the umbilical cord, The Wharton's young EMSCs and the whole cord derived, so if you process the whole cord, they have the best osteogenic potential compared to the cells from the cord artery, the cord vein or the lining of the cord and then the warts and Jelly. MSCs also can differentiate into all these cells. So a lot of research have validated this. Cardiomyocyte neurons, glia, oligodendrocytes and hepatocytes. And then let's look at the gene expression. And it's interesting, it's an interesting site on looking at different compartments. So the umbilical cord mscs secrete you know, more things for nervous system and behavior. These, you know, the neurological side of development and then the chorionic membrane derived and more cardiovascular hematological system development, gene expression and amnion more cellular growth. So kind of make intuitive sense when you think about, you know, where the membranes lie during the development. So I want to talk about, you know, all these different forms of treatments. So there's the most popular way is to use a person's own, right autologous transplant that can be from bone marrow, fat, blood, all kinds of dental pulp. You know, people can use a lot of different things. So the advantage is that there is a perfect match and then that makes it, that allows it to have a higher chance of long term engraftment. So that sounds great. But then we know now that even when you transplant cells from your own body, the chance of engraftment is pretty low. Just like when you transplant cells from allograft from another person's body. So that's not their main function. The main way that these cells exert their benefits is by the paracrine effect and about all the things that I was talking about. So that's, you know, you have to keep that in mind. And what are the disadvantages? So it is invasive and convenient. So there's, you know, pain, scarring, wrist infection, that all are very real and it takes a lot of time. So for doctors it is more cumbersome and the quality control is more difficult. I think that's one reason FDA was having some issues with it because doctors are not laboratories, right? Doctors offices are not CHGMP laboratories. So to actually produce products, produce something that's good for human use, how do you ensure quality? How do you know that you are complete era? You haven't gone through the FDA inspections. You're not really a laboratory. Maybe you've taken a course learning how to use the equipment. So those are the things that you think about. Of course different equipments have different ways of extracting that gets into a whole other area. So it's a little bit inconsistent as far as what Kind of cells you're getting. And then when a person ages or the person's sick, the quality and quantity of the cell cells do decline. The, the bone marrow when you're younger is red and when you get older and older gets more and more yellow. And then in fact there's more and more toxic buildup, there's no question about it in adipose tissue and the stem cells in these person's own, you know, whether it's, you know, even the 25 year old, you know, a lot of them, these people getting treatment are you know, in the 50s, 60s, 70s. So the cells are definitely less potent. They have shorter, shorter telomeres. So DNA is less protected, they're less versatile. So they don't, they can't differentiate as to many types of cells, the inflammatory factors and growth factors secreted are less, they get old faster and they're not as neuroprotective. So also in these, when you think about stem cell stem cells extraction you're trying to get is not just the cells itself, right? There's also what's in, in it because we talk about growth factors that's in these products, Secretolin and all that stuff. So as a person ages, the growth factors that's in your tissue also declines. And some of the growth factors are not barely existent. That's still really prevalent in a young person. So I don't know, you guys all know the research study in Stanford is kind of fun. Side note, when I did experiment on mice, all these old mice, they were, you know, they lost some of the marbles. They couldn't remember how to do the maize very well. And their furs, they just don't look very good. So they give them human blood derived human blood, I think transplant. So the ones that got the old person's blood still look old. They didn't change. The one that got the young person's blood started to look younger and behave younger. They were able to remember the mates better. So the question is, that's what the research team was asking. What's in a young person's blood that's making these mice acting young again? So then they nailed it down to one protein called TIMP2 protein. T, I, M, P, TIM2 protein. And then when they give the mice just a Tim2 protein, the mice were having the same effect. So that's what's interesting. That's just from a young person's blood. I think that was probably someone in the 20s. That protein is existing a much higher concentration in a newborn. I can't Even compare. So when you look at all these other factors that we're not looking at, it's great. Okay, so we're getting cells from the fat bone marrow, but what about all the other things that comes with it? Are they as therapeutic? What if you can get more out of these extractions? And then another interesting side note is that a lot of these cells are given IV for treating all kinds of systemic issues. But if you just create an injury, you just did liposuction or just drilled into the bone, where are the cells going to be attracted to? It's their nature to be attracted to areas of injury and inflammation. So the cells are going to be like, oh my God, there is where I need to go to repair. So that's just something to think about. And then of course, it's difficult to achieve frequent and regular dosing who are going to keep getting liposuction done over and over, especially if you want to have a regimen initially every month or every. Every few months, you know, if someone needs maintenance, treatment. So that's all going to be a little difficult with autologous. And then so now we're looking at the perinatal allogeneic. So we're giving these birth tissue products to somebody. What are the disadvantages? So one possible, you know, one disadvantage that people do talk about is potential mismatch, right? It's from a different person. Of course, it's not the same. But what's interesting about advantage of these cells is that they have very little HLA2 markers, which is what marks us as foreign. But they do have HLA1 markers, which is important because the HLA2 markers are what marks as different people. HLA1 markers marks us as human. So your own NK cells are not activated and you start attacking it. So it doesn't, it's not immunogenic, so it doesn't produce the kind of effect. And another thing that's interesting so because other speakers have talked about getting donor cells from bone marrow. But if you compare cells from these umbilical cord tissue, what's interesting is that these are the birth tissue that had just come out of the mother, had just gone through this incubation period in a different human, they do produce factors that prevent the mother from rejecting them. So they have an innate, this more potential of actually staying the body and be unharmed and be okay. And that's what they were. It was interesting research done. I didn't list here, but bone marrow transplant matching matched. So matched transplant birth versus unmatched. The first Tissue product, the unmatched actually survive better. People do better when it's unmatched birth tissue versus matched adult tissue. So very interesting. There's something special about being just born. And so, okay, maybe it's less likely to engraft because from a different person. But again, you talked about, you know, the engraftment is not the major, major way that these cells function, but there are still some, there's some engraftment, maybe about 1 to 5%. Nobody knows the exact answer. I've asked lots of world authorities and everybody was telling me this is like a, you know, six million dollar question and what are the advantages of using perinatal tissue? So first of all, there's no matching necessary actually. What's interesting is that the tissue bank, the business going, actually declining. Less and less people are doing that because I think more people are realizing that you really don't need to do that because you can just get an off the shelf product, it's a lot cheaper and the quality is very much assured. And then the cells are very primitive, right? They proliferate faster, they differentiate into more types and they also interesting in these products, they contain more pluripotent stem cell population. So they have, you know, more embryonic characteristics like the B cell that you guys talked about in cord blood. And there are other cells in the core tissue. So and the cells has longer telomeres, they get old slower, they have less accumulated genetic changes and they have more growth factors that's associated with use. And they're easy to obtain and they're abundant and there's no ethical considerations. Perfect. And so, you know, just to kind of recap, you know, give you a little bit of specific numbers, what's special about umbilical cord tissue? This is my favorite tissue has very high MSC content. So it's up to one in 200 cells in the perivascular region that are MSCs. One out of every child, 200 mics. Whereas you look at cord blood, it's one out of 2 million. There are only a thousand to 5,000 MSCs in an entire unit of cord blood, which is about 100 cc's on average. And the MSCs are more primitive. They're actually sequestered earlier in embryogenesis. So these are younger cells, very interesting. Even different from the baby cells, these are even younger and they have more pluripotent markers and they can have ability to develop into, you know, cardiac cells and neurons. They're more neuroprotective and more angiogenic. And then this is just A picture, you know, to kind of give you a quick overview of different types of cells. Right. So autologous and very popular prp. You know, okay, this stopped working. So PRP and you know, you can see on the right hand side, autologous, what it has and what it does. And so bone marrow, so that lack young cells and lack certain cytokines. And then the amniotic fluid is very popular, but have almost no cells. Very, very little cells. So little that the FDA doesn't really allow amniotic fluid products to be called stem cell products. And then you have the umbrella core blood, which has a lot of cells. It's great. But then there are not that many MSCs, like I mentioned. You know, I think it's. They will be pretty likely to have 0.01%. And then so when you look at all the tissue sources, the umbilical core matrix, it really comes out as a winner. And then another side note that's really interesting. I just want to share that with you guys because people, I used to be jealous of clinics overseas that can expand cells because they can just grow it to whatever number they want. It's like, how convenient. You, you give people 100, 200 cells or even a billion, they just grow on trees. And I can't do that in the US But I went to this conference, there was research done by oxalcells. It was really pretty fascinating. So in March they presented this data, they tested clinical efficacy of these cells. So when you use this control, so it's not mse, and then you use mscs, native mse, native means has never been touched by enzymes, chemicals, they've never been expanded in culture. So then, so you get this kind of, this much effect, right, using 10,000 cells. And then you give 10 times the number of cells, then look at clinical effects, is this much. But then you. So these are still native cells. Then they give 10 times the number of expanded cells. So these cells have been grown in culture, and at 10 times 1 million versus 100,000, the clinical effect is less, quite a bit less. So that's really interesting because that kind of give me comfort, gives me comfort that, you know, this is probably why our product is so effective. Even though I'm giving them probably 1/10 or even 1/20 of the number of cells that I can give compared to Panama or Mexico. So this is very encouraging. So the last thing, as of 2016, this is the stat in the U.S. i don't know what is 2018, but 80% of what all the stem cell therapy going on in this country is autologous. 17% is amniotic fluid, and only 3% is umbilical cord. So people, you know, there's the old tradition is autologous. But I do wonder, you know, people look at these new evidence, this new science, you know, will people be more open to start using something that's more powerful and easier? And you can enhance the clinical effect like I talked about, you can have this much effect or this much effect. So what I want patients to get this. So that's my presentation. Thank you.