Dr. Joy Kong presenting at 6th Annual Cell Surgical Network conference - June 2019

One of the things that Dr. Kang loves doing is speaking engagements. And to that effect, we're here in Beverly Hills, California at the Beverly Hilton. We're here at the Cell Surgical Society's conference, the sixth annual. And this is something that you really love to be a part of. Speaking engagements and really encouraging people to understand stem cell therapy, right?

Yeah, absolutely. You know, we have to get the word out. And I definitely enjoy having a large audience where I can really go down the nitty gritty of the science and interact with. And I see a lot of enthusiasm in there. Yeah, it's definitely very exciting.

What's the theme of your talk today?

I'll be talking about how to pick the best source of stem cells for their patients. So there are many sources of stem cells, oldest being bone marrow, and then comes adipose derived stem cells. And then the last, newest one is birth tissue derived. So I want to show the doctors what are the differences and could there be one source that's better? Is there one that's safer and more effective? And what are the research evidence that's out there? So I wanted to present this evidence that I found through all this search. So I just think every doctor, if you want the best results for your patient, you need to know the science. So I want to give that knowledge to the doctors. I know that the stem cell field is really rapidly expanding and of course we all started with bone marrow transplant, then that one developed, progressed into fat derived stem cells. And the newest kid on the block is the umbilical cord derived cells. The thing is, what I believe is that all forms of cell therapy are very beneficial. So it's my mission in helping my patients is to give them the very best. Because cell therapy is very expensive and patients are placing a lot of trust in us. And if I can give them something that will be the safest and has an edge in the therapeutic response, I feel is my responsibility to provide that. So that's kind of my journey when I got into cell therapy is to look at the science and look at what may be the best form of therapy. So we all know MSCs are important and the previous speaker, you know, was providing some valuable information on the mscs in fat, in fat tissue. So I want to talk about, you know, one of the most valuable, one of the most valuable component is mscs. What's the best source of MSC and what are the evidence out there? Because my opinion doesn't really matter. What I want to present is what has been shown. So what are MSCs? So first of all in. You know, a few decades ago it was believed that hematopoietic stem cells were the only form of stem cells that are still existing in the body. And I'm going to go a little fast because I know we don't have a whole lot of time. So MSCs have, you all know what MSCs are in vitro. They can progress into different connective tissue. And there are many names and they all, you know, comes down to MSCs. But those are the common names that you will see referred to in the literature. And Dr. Kaplan did propose it to be renamed medicinal signaling cells. He felt that's more accurate in reflecting what the cell's functions are. And they are derived from parasites which are in all our vascularized tissues huddling around the blood vessels. And so every tissue specific stem cell, and this is, you know, the really cool part, is in contact with mesenchymal stem cell. So in a way they're kind of like a conductor in this symphony that they have their hands on all these specific cells that can regenerate local tissue. So they have this coordinating effect. And why are they important? So first of all the trophic or the paracrine, you know, through paracrine mechanisms, the trophic benefits. So these cells have the ability to home into areas injury and inflammation and induce changes by secreting different peptides. The previous speaker talked about the three mechanisms, the growth factors and peptides and exosomes plus mitochondria transfer. So all these are important mechanisms and also they're highly anti inflammatory. By secreting different anti inflammatory cytokines, also immune modulating, it can help shift your immune system to the side of anti inflammation rather than staying at this inflammation stage. And they're also anti apoptotic. So let's say someone had stroke and not just the cells that got cut off, the blood supply got cut off that are dying, neighboring cells started to get signals from these dying cells that they should go down the route of death as well. So mesenchymal stem cells have the way to basically give them the signal saying no, you don't have to go down that route. So that can preserve more tissue after damage and also has antimicrobial properties. It can secrete antimicrobial peptides and has been shown to be effective against bacteria, virus and protozoa. The other thing. Yes, the other thing is that it can assist in breakdown of scar tissue. This is incredibly helpful. We talked about peyronie's, but they've shown that in liver cirrhosis and also in post MI tissue fibrosis. So what I want, the question I want to answer is if MSEs are everywhere, are they all the same? Are they equivalent? Can we just get it anywhere? So we all know about bone marrow aspirations. That's earliest kind of stem cell therapy modality. And then we go into the fat derived stem cells and that's SVF that you guys are very familiar with. And my question is, does age matter? So the issue is MSCs do stay in your body for a lifetime. You want them to be there. They do great, gradually diminish because we use them up or they can start dying off. They sense as well. So but the fact that they stain our body for their, for our entire lifetime also make them prone to receive cellular damages. So that the damages can lead to cell death, senescence, loss of regenerative function or even neoplastic changes. But the neonatal mesenchymal stem cells are spared of these pro aging factors. So I want to show you the evidence because like I said, my opinion doesn't really matter. I was digging into literature to find what has been shown. So here's one study that shows that when adipose derives mesenchymal stem cells from the aged person, they actually are significantly compromised in their ability to support vascular network formations. So that means when a person gets older, when they try to heal their wound, these MSCs are not as efficient in supporting the wound repair. And here's another one. Bone marrow derived MSCs have less myogenic potentials and engraftment properties than early younger MSCs. So less ability to help muscle repair and regeneration and less able to stay in the tissue. And bone marrow MSCs also exhibit age related declines in the inflammatory response. So what it means is that these bone marrow derived MSEs have less ability to secrete the right signals to attract MSE migration. So and then mounting the immune activation and repair more evidence. So here's looking at gene expression. When adipose derived stem cells, when a person, you know, the source gets older and older, the genes related to senescence also start to accumulate. So you show more gene, you see more gene expression showing up. And age also alters the availability of certain types of adipose derived stem cells and their angiogenic potentials. So when the aging occurs, these cells has less ability to help form new blood supply. Also when bone marrow MSCs are getting older, they found out in those cells there are more and more reactive oxygen species. And what's interesting is that these older cells, this one is in adipose derived stem cells. These older cells Are also more sensitive to the effect of the reactive oxygen species, which means that it's a double whammy. First of all, they had more reactive oxygens that have accumulated in the cells, and then they're also more vulnerable. And let's look at some more evidence. So when they compare young MSCs derived from a person 1 to 5 years of age compared to older MSCs, which is someone from 57 years of age, and they looked at their ability to help cardiac repair after MI, and they showed the younger cells outperform the older MSCs. Another example of the differences when we look at the differentiation potentials of MSCs. So an MSC from a young individual actually can develop into neuroectodermal tissues, Whereas bone marrow derived MSCs from an older person have lost that ability. So there's a change in their function. And we all know we've all been exposed to a lifetime of different factors, you know, toxins, you know, radiation, and something even as, you know, banal as insects. And that can inhibit the potential of these MSCs. Adult Older MSCs will have less of a potential to help regenerate or differentiate into cartilage. And then also their ability to form bones are not as good, are impaired. And so our lifestyle also do affect our quality of our MSCs that's in our body. They showed that adipose derived stem cells from high fat fed mice had higher potential to differentiate into adipose cells rather than forming endothelial, you know, assisting endothelial differentiation. So by what you're eating, you're altering the pathways your cells are able to develop into. And also the potentials of your cells change when you're obese. So they've shown that in obese patients, your ability of forming bone has been impaired. So they showed how much bone, the mineral nodules, how much they're able to form. And obese patients, cells can form less mineral nodules and smaller nodules. Metabolic diseases very common, like diabetes, can also, it changes the milieu of where the cells are at. So all your cells affected, including the mesenchymal stem cells. So metabolic diseases like diabetes have been shown to diminish the cell's ability to establish vascular network, both in vivo and in vitro. And we all know that, you know, obesity and, you know, overweight issue is very high in our country. So that's something to keep in mind when we are giving people cell therapy. Are we giving them a good source? So perinatal. So the youngest kid on the block, you know, we, you know, these were discarded in the past and they found out that there's a lot of valuable components in these tissue. You know, after all, it's, it's what was supporting the development of life. So you can see the umbilical cord, the cross section, two arteries, one vein, and what's in the middle, the matrix. That's the Wharton's jelly, that's gelatinous material that's actually filled with mesenchymal stem cells. And what's in the blood vessel are the umbilical cord blood. And There are about one MSC in every 2 million cord blood cells that's floating in the blood. But in the Wharton's jelly, up to 1 in 300 cells are MSCs. So Wharton's jelly is a very rich source of MSCs. You can also get them from the amniotic membrane. So the main cell type in umbilical cord blood is hematopoietic stem cells. So that's the most abundant stem cell type. Whereas the Wharton's jelly or cord tissue, the most abundant type is mesenchymal stem cells. So I want to talk about within these, some direct comparison actually was done between umbilical cord blood derived MSCs and bone marrow and adipose derived MSCs. So I want to show you some evidence of that. So this one study was very thorough. They looked at growth profiles, comparisons between these three types and cellular senescence and anti inflammatory properties of these different cell types. So let's look at the growth profiles. They were looking at the proliferative capacity of bone marrow versus adipose. Bone marrow adipose derived cells. What they showed is that when the cells, when you keep growing them in culture, they will stop growing. For bone marrow adipose derived cells, they will stop growing at generation or passage 11 to 12, whereas the umbilical cord blood derived mice will continue to grow. So it has about three, four generation more. So there's more generations and more kind of more potentials and life left in, in these cells. And the growth rate also are different. The umbilical cord blood mesenchymal stem cells have the highest growth rate, so they have the shortest doubling time in growth and adipose derived is the lowest. And they're looking at their ability to form colonies. So forming ability to form colony of course demonstrates the health of the cells and the vitality of the cells. And they've shown how much, you know, how much of these fibroblasts are able to be formed from the mesenchymal stem cells. So umbilical cord blood has the most amount of colony forming bone marrow next and then adipose derived is the last one. And then we can look at cellular senescence. You know, cells get old. And what's interesting is that you probably all know when cells get old, not only do they stop functioning and not doing their job, but they're actually actively secreting factors doing damages to local tissue further promoting decline when we age. So let's look at the senescence associated protein, this beta galactosidase expression at passage 6 when you pass these cells into the sixth passage, umbilical cord blood derived MSEs have no senescence, whereas bone marrow derived has 11% and adipose derived has 13% cells that are senescent. And when you look at passage 9 to 12, so further passages, everyone has senescence, but still umbilical cord blood MSEs has the lowest level of senescence. And they also looked at other proteins senescence related. And they also have shown that umbilical Cord Blood Drive MSEs only weakly express these senescent proteins, whereas bone marrow and adipose derived MSE strongly express these proteins. And let's look at the anti inflammatory properties. So they were looking at just comparing their ability to mount anti inflammatory response. So they found out, comparing umbilical cord blood derived mics with bone marrow and absolute derived mics, that the cord blood derived mics can significantly downregulate the inflammatory cytokines and also they secrete more anti inflammatory proteins. So, so which means that not only they calm down the inflammatory aspects, but then they're mounting anti inflammatory kind of potentials. So there's, you know, attacking it on both ends producing the anti inflammatory effect. And then I want to show you a few other examples of, you know, what they've shown in different specialties. For example, like in orthopedics they found umbilical cord derived MSCs produce three times as much collagen as bone marrow derived MSCs. So, so again they're different, they're not the same MSCs. Umbilical cord MSCs also showed greater mineralization in osteogenic cultures and larger basically collagen pellets in these chondrogenic cultures comparing to bone marrow MSCs. So all these are separate studies. And let's look at cancer. This is a fascinating study because they were comparing the effect of MSCs on glioblastoma multiforme. So comparing umbilical cord blood derived MSCs versus adipose derived MSCs. And what's fascinating is that they've shown both in vivo and in vitro that umbilical cord blood derived mis inhibited tumor growth, Whereas adipose derived MSCs promoted tumor growth. So I know you know, cancer potential has been a concern, but there's very little evidence showing that birth tissue derived mscs has cancer promoting properties. Where there's a lot more evidence of adult sources, bone marrow fat derived that has cancer promoting properties as cell senescence they do, you know, including a lot of declines. One of the decline is tumor suppressing properties. So this is something to keep in mind, you know, I'm giving a person a therapy, could I be causing harm? Umbilical cord derived MSCs also they, they induce apoptosis, apoptosis more effectively than adipose derived MSCs partially through this particular trail protein that's you know, very much strongly expressed in umbilical cord blood derived MSCs. And so like I said, Wharton's jelly derived mics do not induce teratoma and do not induce tumors. And Wharton's jelly derived mics also are not associated with enhancing tumor growth and can even basically suppress solid tumor growth. And then let's look at angiogenesis. So how do they promote blood vessel formation? Wharton's jelly mics have a stronger expression of these angiogenic factors and then they also have immune regulatory molecules that they secrete more of these that can help promote angiogenesis. And they also produce more of certain growth factors that have anti fibrotic properties which can help promote prevent fibrosis and scarring and warts. And Jelly MSCs are able to induce endothelial cells to migrate more efficiently than bone marrow derived MSCs. So how are they communicating with the rest of your body? So these cells actually have a stronger ability to communicate with your body and attract the right cells to the area to help repair. And let's look at neuroprotection. So Wharton's jelly derived MSCs secrete factors that have better neuroprotective effects than those in bone marrow derived MSCs. And they're more effective in decreasing cell death and apoptosis then gene expressions in these cells in these different types of MSC. So they're different. Different. Like I said, you know, MSCs are not, they're not the same, you know, so this you can show, you can see the difference. Worms generally derived MSCs, their gene expression in the cells tend to tailor more toward cell proliferation, neurogenesis, neurotransmitters, nervous system development and blood vessel development. Whereas bone marrow derived mics are more, the genes that get turned on are more oriented toward ossification and skeletal development. So they become different MSCs. And I want to talk a little bit about the different type of MSCs, even within the umbilical cord. So they're not the same either in different compartments. They're so different. So I just want to, you know, we can look at different compartments. There's Wharton's jelly, there's the vein artery, there's umbilical cord lining and so perivascular regions. So all these areas and we can compare different properties even within these different sections. So let's look at, you know, how primitive the cells are. So they found out that Wharton's jelly MSCs have higher exposure expression of embryonic genes. And they, they suggest that warts and Jelly MSCs is actually a more primitive source of MSCs. So they were actually sequestered early in embryogenesis. That's why they've retained a lot of the primitive qualities. So they kind of, it's somewhere between embryonic stem cells and the mature adult stem cells. So that's a unique position that they're in. And let's look at their differentiation potentials. Wharton's Jelly MSCs and the whole cord derived MSCs have the highest ability to form to help bone formation versus the artery, vein and umbilical cord linings. Again, they have different properties and umbilical cord MSE also. So ordinance jelly MSEs can differentiate into heart muscle cells, neurons, gliatri, osteodendrocytes and hepatocytes in addition to the traditional ones. We know osteocytes, chondrocytes and adipocytes. So these are the properties that got lost in later MSCs, but was still preserved in the Wharton's Jelly MSCs. And then let's look at gene expression. How different are they in their gene expression? So amniotic membrane MSCs, they are more tailored toward cellular growth and proliferation, whereas the gene expression within the chorion membranes are more toward cardiovascular and hematological system development. And then umbilical cord at the core matrix itself, then it has more, it's more tailored toward nervous system and behavior. So you can see there's so much more to MSCs because they're all, they have their specific purpose and specific like specialty. So I want to talk about, you know, just briefly, you know, advantages and disadvantages. So advantages of autologous stem cell therapy is perfect HLA match and there's higher chance of engraftment. However, the science have shown that very little engraftment occurs. Even if you infuse your own mscs. By the time you've manipulated cells, you infuse the cells, they produce their paracrine function, they do some immunodulation the number of cells that are staying are small. I've asked a ton of leading scientists and they all said this is the five million dollar question. No one knows how much really stay. But the general consensus I get is less than 5%. What are the disadvantages? So it is invasive and inconvenient and the quality control is more difficult because the physicians are doing it in the office. So between physicians, between machineries and how they operate their facility, it's not a laboratory. So there's more variation. And then with age and disease, the patient do have less quantity and quality of their stem cells. So you can't get away from that fact. And the stem cells are less potent, they do have shorter telomeres, they are less versatile and they do secrete less anti inflammatory proteins and growth factors. And they senesce more rapidly and are less neuroprotective. And there's less number of concentrations, growth factors comparing to birth tissue if administered iv. Unfortunately, you know, if you have to get the cells from your own body, you have to create a wound somehow either through drilling into the bone marrow or do liposuction. You are creating an injury, you are creating a wound. If you do iv, that's one of the first places the cells will do because you just created damage and the cells will want to repair it. So that's something to keep in mind. And then it's difficult to achieve frequent and regular dosing. I use this for anti aging purposes for my patients. A lot, a lot of patients come to me every six months or every three months for IV infusion. I do it on myself every three months. I can imagine doing using my own cells besides not being as good as birth tissue cells. Also I can't imagine going through the procedure four times a year. So what are the disadvantages of perinatal cell transplant? So one thing is there are potential immune reaction issues. These cells, birth tissue red cells, they do have HLA markers which are important, important because it does mark us as different from, from other, other organisms. So your body's immune system is not going to attack and HLA 2 markers that could be immunogenic, but these cells burst. Tissue cells have very, very few HLA2 markers. And yes, it is less likely to engraft because it engrafts potentially your cells could attack. But what people don't understand is that engraftment of cells from another person happens all the time. I don't know how many of you know about this phenomenal microchimerism that's happening in everybody Especially it's easy to study in women because we can check to see if they have Y chromosomes. And they found out women that had male children have a lot of Y chromosomes. Not a lot, but definitely have Y chromosomes in their body and in many tissues, the brain, the breast, so in many, many areas, which means engraftment did occur during pregnancy. And interesting side fact, they found out about 60% women actually have Y chromosomes in their bodies. And they decided it's not just from have been pregnant or been in the womb with a, with a sibling that had died and somehow got getting some Y chromosomes that way. They think even by male and female sexual interaction that could have introduced the Y chromosomes into the female body. So it's fascinating. So it happens in nature. So I just, I want, you know, people to understand it is not as foreign as it sounds. And what are the advantages so quickly? The cells are more primitive, we talked about that. They proliferate, pass faster and more differentiation potentials and they have longer telomeres, the snare slower, they accumulate less genetic changes and they also have more pluripotent cell population and with more embryonic characteristics, yet without the risk of teratoma. And they secrete more abundant growth factors and the proteins that are associated with youth. And the cells are more potent in their anti inflammatory effect and their neuroprotection. And they're easy to obtain, convenient and it allows for frequent irregular dosing. And also there's no ethical controversy because these tissues would be thrown away otherwise. So about umbilical cord tissue. So like I said in Wharton's jelly, in the tissue itself, up to 1 in 300 cells are MSCs whereas the cord blood in only 1 in 2 million has, you know, is an MSC. So the MSCs are also more primitive in umbilical cord tissue and they're more, they have more pluripotent markers and they have ability to develop into cardiomyocytes and neurons and more neuroprotective angiogenic. So this is just kind of quick overview of the comparisons between different tissue sources and what kind of growth factors they have, what type of cells they have and percentage mics. So basically advantage you can see from the umbilical cord, the cord tissue has almost all the benefits. It doesn't have as many cells as cord blood. So cord blood has a lot of cells but not very, very many MSCs. And the last thing I want to mention is this whole question about expansion or no expansion. So FDA doesn't allow cell expansion unless it's under an irb study and a lot of people go overseas because they think they can get this huge amount of stem cell infusion. They go to Panama, Cancun, but is it better to have more? So this is a study that's very interesting. That was, it was done by Oxocell that presented last year's conference. They actually were looking at the clinical effects of expanded cells versus cells that are native, so never been expanded. So when you expand the MSCs the way they were showing it is co engraftment with hematopoietic cells and see how much actually engraft. So when you have no MSCs, there's certain engraftment rate. And when you have 10,000 native MSC, so never been expanded. So there's the level of, you know, the second bar, that's the clinical effect. And then you give 10 times that. Yes, there's a dose dependence, so it increased quite a bit. And then you give 10 times that of native MSCs, but then they're expanded. Look at the clinical effect, it actually comes down. So this kind of explains why we have patients who are going over to Panama and paying lots of money getting these expanded cells and then when they come back and using treatment of our products that actually have maybe one tenth the number of cells, but they get better clinical response. So this is just something I want people to really be aware and, and be able to counsel your patient because people are going to ask you is it better? So you need to know what have been found out there. So that's it. So I want to help people, help doctors to find the best source of MSCs so you can really maximize the benefit to your patients. So I want to leave you my email address in case anyone wants to contact me. So just my name, Joy call Kong md. So it's J O Y K O N G M D at gmail com. So you're welcome to ask me any questions after. Thank you.