Mesenchymal cells or MSCs: definition, clinical potential, challenges

I’m old enough to remember when the acronym MSC stood unambiguously for “mesenchymal stem cells”, but should it refer to a broader term like “mesenchymal cells”? The field has moved in that direction. I think that’s the best way to go too and I’ll explain why.

The goal of today’s post is to help you get up to speed on everything related to MSCs. I also address the broader area of mesenchymal cells including stromal cells. How much of the clinical potential of MSCs is due to actual stem cells? What are the clinical trials you should know about? How is hype impacting this area? Below you can also see a video version of this post that I did for our stem cell YouTube channel. Check it out and please subscribe to the channel.

What’s in this article

MSC History  |  What are mesenchymal cells? | Validation | MSC acronym meaning | Clinical potential |  Hype over MSCs

MSC history & how you make them

Back in the day when “MSC” simply meant “mesenchymal stem cells”, these adult stem cells were generally viewed as having the ability to differentiate into a few other cell types. This potential included bone, cartilage, and/or fat.

This would make them by definition a type of multipotent stem cells.

One of the challenges with characterizing MSCs has been consistency. The various preparation protocols produce a diverse array of cells in the final test tube.

For instance, you might take fat tissue, treat it with an enzyme to disperse the material, and then grow out whatever cells can be happy in “MSC media” (the liquid food of MSCs). That dish of cells often would be “MSCs”. In that cellular mix, however, were many other cells too. This spectrum might include adipocytes, blood vessel cells, blood cells, fibroblasts, pericytes, and more. If this sounds kind of like SVF or stromal vascular fraction to you, you’re right.

What are mesenchymal cells?

While there definitely are real multipotent mesenchymal stem cells in many MSC preps, these cellular collections are very diverse and often times the most common cell type in an MSC prep is not actually stem cells. Rather, the most common cell type in there is something called a stromal cell or mesenchymal cell. These cells, often related to fibroblasts, make up cellular and tissue connections between other cells. They can also physically be the building blocks of connective tissue type compartments, capsules of organs, and more. Some of the cells are actual fibroblasts. It’s likely that many MSC preps made by unproven clinics are almost entirely fibroblasts.

Subpopulations of these mesenchymal cells, despite having a dominant structural function (i.e. they are like living bricks you might say of the edifice of the body) can do many other things too. They secrete a soup of powerful growth factors that influence other cells. They can also secrete cellular vesicles, also known as extracellular vesicles or exosomes too.

There is the potential that certain structural mesenchymal cells might have some potential for stem cell-like functions too. Under stress, they might be able to produce other kinds of differentiated cells or even change themselves into other cell types, which is a fascinating possibility. Mesenchymal cell and MSC research is an exciting, rapidly growing area. There are at present about 1,500 publications on PubMed for just one kind of search for these cells.

It’s funny, because when I search mesenchymal cells on Google, an apparent quiz question comes up: mesenchymal cells are most commonly found in what tissue? The answer is kind of a tie between bone marrow and fat, although the adipose people always claim there are far more there.

MSC tracking and validation

The same kind of processing described in the above history section with a few different tweaks was (and still is) done with bone marrow to make MSC preps from it. These preps are generally thought to be somewhat less heterogeneous than the ones made from fat, but most often they aren’t just one cell type either. How can we track which cells are which? What would be the methods for MSC tracking to determine the actual percent stem cells? These are challenging questions. More below.

Some labs take a further validation step of differentiating the “MSCs” with a specific protocol to make fat, bone, or cartilage from them, and then stain the cells after a week of differentiation. More often than not at least some differentiated cells would be evident by specific staining, indicating the relative amount of multipotent stem cells in the mix. Usually the percentage of differentiated cells indicative of stem cell-like potential was rather low, such as less than 10%.

Other groups did more due diligence and did FACS sorting of the tissue preps for MSC markers before proceeding with various studies or uses.

Of course, some researchers and biotechs working with MSCs or MSC-like cells go even further and do extensive purification and characterization of their mesenchymal cells, which is the most rigorous way to go, especially if you are working in a translational and clinical sphere.

What should the MSC acronym stand for?

You can probably already tell from the earlier part of this post that “MSCs” as an acronym or name is really an umbrella term for many kinds of cells and cellular functions.

In the last decade or so the MSC field has collected a vast amount of data. These findings suggest that this simple acronym has a more complicated back story. In fact, the acronym story itself and discussion were both complicated and very interesting even quite a long time ago. The field has already been moving for a long time to use something like the following MSC definition: mesenchymal stromal/stem cells. This covers more bases. Just saying “mesenchymal cells” might do the trick too.

In my view, other possible new meanings for the MSC term, like “medicinal signaling cells” are just way too aspirational and that particular one extends well beyond what the data support. The word “medicinal” is a big problem there. While some types of MSCs may have medicinal properties for certain diseases, that has to be proven on a case-by-case basis, and it’s just as likely for some diseases that certain MSC preps could do nothing or even cause problems like generating scar tissue.

Mesenchymal cell therapy potential

MSCs or mesenchymal cells are probably most promising clinically via what they secret more so than what other cells that some of them might be able to make via stem cell-like properties. There may be certain cases where more fully characterized and purified true stem cells under the umbrella MSC term can be therapeutic via their multipotency.

Overall, in a broad search on Clinicaltrials.gov in 2021, I found more than 10,000 trials. While many of these may not be interventional, I think it’s likely there are at least one to two thousand (and maybe far more) trials where patients actually do get injected with some kind of MSC-like cells.

A more limited search for “mesenchymal stem cells” found 1,231 trials now. For historical comparison, I have data from a search I did in 2012, where I found around  281 trials. In 2012, the data pointed to China have the most “mesenchymal stem cells”  trials (see the old map in that 2012 post) and Europe and the US being almost tied for second, which is generally about the same pattern now in 2021 too (see data map I generated from Clinicaltrials.gov above).

This post on MSCs from the Stem Cell Network is also quite useful.

The secretome or secreted exosomes from these cells contains a vast array of molecules, but some of the more interesting have immunomodulatory properties. This means that they can decrease or increase aspects of immune system activity. This has sparked interest in MSC-like cells to treat COVID-19, which has sparked dozens of clinical trials. The jury is out on those so far, but we should be watching that area carefully.

Hype over MSCs & mesenchymal cells

Unfortunately, “MSCs” appears to be the favorite marketing term of many unproven stem cell clinics. Whatever MSC should stand for and whatever cells are actually in the preparations that the clinics inject into patients, these clinics are making big bucks. A lot of the money comes from the hype and sometimes fraudulent marketing by the clinics related to MSCs. Often it seems the clinics will say that MSCs can do just about anything.

You wonder if for the clinics MSCs stands for “magic stem cells.”

MSCs and mesenchymal cells have real potential to help patients, but it’s harmful to think of them as a panacea that can treat almost anything. I recommend a focus on the data from strong clinical work.

References

1. Medicinal signalling cells: they work, so use them, Arnold Caplan, Nature, 2019.
2. The ‘unwarranted hype’ of stem cell therapies, Jules Montague, BBC, 2019.
3. Clear up this stem-cell mess. Confusion about mesenchymal stem cells is making it easier for people to sell unproven treatments, warn Douglas Sipp, Pamela G. Robey and Leigh Turner, Nature, 2018.
4. If you want to learn more about the different core kinds of stem cell types, see my post on multipotent, pluripotent, and totipotent stem cells.
5. This post on MSCs from the Stem Cell Network is also quite useful.