The Fat Stem Cell Count Mirage…
This past month, while on the lecture circuit, I again heard many wild claims about how many more stem cells there were in fat than bone marrow. The most recent claims now have this fat stem cell count number at 2,000 times more stem cells in fat. Are any of these numbers correct? Where did all of this information come from?
First, as you’ve read here, bone marrow stem cells are better for creating cartilage than fat stem cells with 13 papers published as of this week that back that statement up. We also have far more research that bone marrow works well to help orthopedic injuries than we have for fat stem cells. In addition, when we’ve used fat stem cells in the past we’ve been unimpressed. So let’s explore the differences in stem cell content between the two in more depth.
When I asked a very knowledgeable physician who had a slide in his presentation that stated that fat had 2,000 X more stem cells where this slide came from, it turned out that it was prepared by the manufacturer of a fat stem cell processing device. When we both tried to search to find a reference to back this up, there was no scientific evidence that supported this claim. However, since digging further into this issue, I think I’ve found where the confusion began and how it’s been exploited by fat stem cell advocates without serious challenge. So where does this information come from? To begin that journey you first have to learn a bit about how many stem cells there are in fat.
As I’ve blogged before, stem cell counts in fat are often wildly inflated. This seems to happen when less sophisticated flow cytometry devices run by scientists who should know better erroneously count a fat or oil droplet as a stem cell. Confusion is also abundant in how best to count stem cells in the first place. For example, do you count them using a simple culture technique called CFU analysis or with a more sophisticated machine called a flow cytometer? Each has it’s strengths and weaknesses. One of the problems with comparing fat and bone marrow stem cell counts is that since the stem cells from each source grow at different rates, using a culture based method where you grow cells (the CFU method) is fraught with apples to oranges error issues. Hence, for this discussion we’ll use flow cytometry to discover the real differences between fat and bone marrow stem cell content. This is a complex machine that counts the markers on the stem cells, one by one, but very quickly.
First, let’s just look at mesenchymal stem cell (MSC) content. MSCs represent about 1-5% of the total nucleated cells in fat versus 0.1-0.5% for bone marrow. This has not only been published, but it’s also consistent with what we see in our lab when we look at the MSC content of both tissues. So that’s 10X more MSCs in fat than bone marrow. However, we have to be careful with that number, as there are many more nucleated cells in bone marrow. How many more? In one study each ml of bone marrow had about 100 times more nucleated cells per mg (roughly a ml) of fat. In fact, it’s this huge disparity in the total number of cells in each tissue that causes the nutty comparison numbers discussed above. For example, if you try to look at the percentage of stem cells out of bone marrow that form colonies in culture (the CFU number), it’s going to be minuscule compared to fat. However, this is expressed as a percentage of total cells, which are 100 times greater in bone marrow! Even the flow cytometry data above is expressed as a percentage of the total cells being counted, with there being many more cells per ml in bone marrow. So the numeric advantage of a higher percentage of MSCs relative to the total cells in fat is washed away by the fact that there are far fewer total cells in fat. Now let’s look at the other stem cells found in bone marrow that aren’t present in fat.
Bone marrow contains not only MSCs, but also Hematopoietic Stem Cells (HSCs) which I’ve blogged on previously are quite good at muscle repair. These aren’t found in fat in any significant quantity. How many of these HSCs are there in bone marrow? They represent about 1%+ of the total nucleated cells. So for our proprietary method of isolating stem cells from bone marrow, on average we get around 150 million total cells per ml of isolate injected (that’s only from one of the fractions in bone marrow that we isolate). So that’s 1.5 million HSCs per ml injected. Bone marrow also has endothelial progenitor cells (EPCs), which are key in creating new blood supply, which is often critical for chronic orthopedic injuries, many of which don’t heal because they happen in areas of poor blood supply. Finally, bone marrow also contains the newly discovered OCR cell which is specific for orthopedic tissue repair.
So does fat really have 2,000 times more stem cells than bone marrow? Nope. Does it have 500 times or even 10 times more? Nope. In fact, if you adjust for the fact that there are 100 more cells per unit volume in bone marrow than fat and that bone marrow has many more other useful stem cells than adipose tissue, the concept that fat has any more stem cells than bone marrow seems like a weak argument. In addition, once you add in the fact that bone marrow has three stem cell types critical for orthopedic tissue repair that aren’t present in abundance in fat, the “fat has more stem cells” argument gets even weaker. The HPCs in bone marrow alone (without the EPCs and OCR cells) shows that bone marrow has more orthopedic injury relevant stem cells than fat. If you then look at studies showing that bone marrow MSCs outperform fat MSCs for things like cartilage repair, the case for using fat stem cells to treat orthopedic injuries becomes extremely weak.
The upshot? The idea that fat has dramatically more stem cells than bone marrow seems like a lot of things these days in the stem cell wild west – an urban myth. The myth seems to have been perpetuated by adipose stem cell advocates who began to compare the percentage of MSCs in fat to bone marrow using the proportion of MSCs to total cells found in the tissue. The proponents of the “fat has more stem cells” myth then left out a critical number – that bone marrow has 1,000 times more cells per unit volume than fat. Oops! They also left out the fact that there are other relevant stem cells in bone marrow that aren’t in fat. In the end, when you look at the comparison critically, there are just as many if not more stem cells in bone marrow than fat!