00:00200:30 Hello, my name is Patrick McCulloch, and I'm a clinical professor of orthopedic surgery at Houston Methodist Hospital. And today I'm going to be talking about mesenchymal stem cells or MSCs as used for orthopedic purposes. And in a previous video, we discussed what an MSC is and what makes them tick. And in this video, we're going to talk a little bit more about our experience in the lab of how we're hoping to get these to become more readily available as a cellular therapy.

00:3021:00 for our patients. So, MSCs, as we know, they have the properties of self-renewal so they can make more and more stem cells, which can then differentiate into other tissues. And when it comes to MSCs they can differentiate into all of the tissues for orthopedic purposes. So, bone, cartilage, ligament, tendon. But normally they're quiescent.

01:0021:30 So we have them all throughout our body. They’re in all of our tissues. And they're in higher concentrations in some tissues than in others. But they're at what we call G0 for cell growth. And however, they can then be activated to turn on and start doing something. And whether that's replicating or signaling to other cells, they become activated for different reasons. And one is homeostasis.

01:3022:00 So homeostasis is maintaining the normal status quo. So for example, in the gut lining, we're changing the gut lining cells like every few days. And that means that stem cells are then, dividing, creating new cells to replace those. Or in our hair, for example. So we have hair that grows and then it falls out. But stem cells actually signal to the dermal papilla, “hey, it's time to make a new hair cell.” And so that's the homeostasis mechanism.

02:0022:30 They can also respond for other reasons like injury or surgery, where tissues have been damaged, and we need some type of response. And stem cells play an important role in that. And the role of stem cells is to activate local cells to come and help with the healing response. To recruit new cells into the area to help with healing.

02:3023:00 And then they also direct that response with what we call immunomodulation. So these I think of as sort of the four antis. So they're anti-inflammatory. And that's a reason why people who have had stem cell treatments will often say they felt way better because we know they're powerful anti-inflammatories.

03:0023:30 As to whether they actually change the natural history of that disease process, well that remains to be seen. But anti-inflammatory, they're anti fibrotic. So they help to prevent scarring and stiffness. They're actually antibacterial which would be really important around the time of an injury or surgery. And then the fourth anti is anti-apoptosis. So apoptosis is programmed cell death. And that happens after injury.

03:3024:00 So there's a first wave of inflammation and then a whole bunch of cells then die off in a second wave from programmed cell death. But if you can stop that then you're adding to the number of cells that can help with the healing response. And that's how they respond. But we've got a couple problems. One is that they're pretty rare. So they're present in all of our tissues. They're present in higher concentrations in some tissues than others like our bone marrow, for example. But in our bone marrow,

04:0024:30 We have between 0.01 and 0.001% of the cells in the bone marrow are stem cells. So it's a very, very small number. We have a second problem, which is that they decline over time from two things. Age. So it's a natural process to have fewer and fewer stem cells. And also disease. So they can become less active

04:3025:00 and fewer numbers in certain disease states. When we look at diabetes, for example, well, stem cells from diabetes are not particularly potent. They don't seem to grow as well as stem cells from a healthy patient. The other thing is, for example, if we look at rotator cuff tears, which are really common as we age. Well, if you look at the footprint where the rotator cuff tendon pulled away, that footprint in diseased rotator cuff patients has fewer stem cells than in people without a rotator cuff tear.

05:0025:30 So is that a response to the injury or the disease, or does or does that maybe one of the reasons why it happened in the first place? So we've done a lot of work in our lab, looking at different sources of stem cells and how to get them to patients. And there are basically two different strategies that people have used. And here we have to spend a word talking about the Food and Drug Administration, the FDA. So the FDA, has what's called the minimally modified use.

05:3026:00 So minimally modified use means you can take tissues out and spin them in a centrifuge, for example, and put them back in. And that's a strategy that a lot of people have been using because then it does not require FDA study or approval. So for example, bone marrow and fat are both good sources of getting stem cells. However, the numbers are really low. One of the bone marrow products that's commercially available is what we call bone marrow aspirate concentrate,

06:0026:30 which is when we take a sample of the bone marrow, we spin it in a centrifuge, and then we can inject that back in. And it's unclear if that helps with symptoms or improves the natural history or healing rates of various conditions, but it's allowable by the FDA. However, remember, we have a small number of stem cells in our bone marrow, and when we concentrate that we have a smaller volume, but we don't have any more stem cells. And in fact, when we've looked at bone marrow aspirate versus bone marrow aspirate concentrate in our lab, well, the concentrate didn't grow as well. In fact, we were unable to culture stem cells with several of the samples from bone marrow aspirate concentrate.

07:0027:30 Another approach is then to take fat. And so some people will take fat. And I'll call these globules.

07:3028:00 So another minimally modified way of getting some cells or tissue is to micronize fat, for example. So if you take fat and break it up so it's in a bunch of little globules, if you think of like shaking your salad dressing, well that's something then that can go right back into patients. And it does have stem cells in it. But to me I don't consider those stem cell treatments. Those are really just tissues that you're giving back. What we're interested in is getting these small number of cells from different tissues and then culturing them.

08:0028:30 So we have one cell and then we culture it until we have many cells. And how many cells we need is unclear. But in some clinical studies done outside of the United States, we're typically looking at something like 50 million cells, which takes culturing them over time to get a sufficient quantity to perhaps get the response that we need. So we're looking at it not just as, hey, let's find some tissues that are easy and don't require FDA approval, and we'll just put them in. But we don't know whether they modified the disease or not. We're looking at actually growing patient's own, so autologous, stem cells for a truly cellular therapy.

08:3029:00 And we have a cGMP facility, which not everyone has, but that is a clean room where we can actually grow cells with such purity and sterility that the FDA allows us to put those back into patients.

09:0029:30 And that's our Johnson Center that we have here. So because this is a large academic center, I feel like this is sort of our responsibility to help answer some of these questions. And we have the lab to be able to do it. And the thing specifically that we're looking at is, hey, how well do we think MSCs could help with repair? So there's been a lot of talk about, ACLs and whether we really need to take out the ACL and reconstruct it. Maybe we can do a repair of some kind, plus some cell therapy, and maybe that will make a difference, right?

09:3010:00 When we think about rotator cuff tears, so very common in adults. And we do a nice operation where we fix it, and it looks beautiful. However, not all patients do great. And in fact, when we look the re-tear rate can be relatively high. So is there an opportunity here with cell therapy to help direct that repair response? And then we have other things like not just repair but regeneration.

10:0010:30 So if you have a significant injury, for example, a hamstring injury, hamstring injuries are incredibly common in sports. And it's a one of the main reasons for loss of time for sports. And so we don't have a ton of treatments for helping to get people back faster. But if we could regenerate new muscle tissue rather than getting scar tissue in the area, that then causes re-injuries and other things, then that would be a great use of these potential therapies. And the third main category we think about is maintenance. So they're involved in homeostasis. That's what they naturally do. So do we need to wait until someone has an injury or surgery to call them up off the bench?

10:3011:00 When perhaps there could be a role in maintaining someone's stem cell balance and helping with an injury prevention strategy. And the other is as we're losing stem cells over time and they're becoming less active in the anti-aging category, which is a really hot topic in research now, is there an opportunity to take someone's stem cells and rejuvenate them, or give them back in various parts of their bodies to help keep our cells as young as we want to be?

11:0011:30 And that's all I have for part two of this talk. Thank you.