Mesenchymal cells or MSCs: definition, stem cell fraction, & trial map

I confess that 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 and 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

Some MSC History What are mesenchymal cells?What should the MSC acronym stand for?Clinical potentialHype over MSCs

mesenchymal cells, MSCs, mesenchymal stem cells
Human MSCs or mesenchymal cells grown in the Knoepfler lab.

Some 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, namely 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 that the various preparation protocols lead to 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) and that dish of cells often would be called “MSCs”. In that cellular mix, however, were many other cells too including adipocytes, blood vessel cells, blood cells, fibroblasts, pericytes, and more. If this sounds kind of like SVF or stromal vascular fraction to you, your instincts are right on the money.

The same kind of processing 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.

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 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.

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 over 1,200 publications on PubMed for just one kind of search for these cells.

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 cells, mesenchymal stem cell, MSCs, clinical trials map
Mesenchymal stem cell clinical trials map, generated from Clinicaltrials.gov via search data.

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).

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 potential has drawn interest for the possibility of MSC-like cells being used 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 messConfusion 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.

9 thoughts on “Mesenchymal cells or MSCs: definition, stem cell fraction, & trial map”

  1. I am a 70 year old male who underwent a hematopoietic stem cell transplant July 20 2016.

    9/25/21 I had an infusion of 300 million MSCs at a Clinic in Mexico for $9000.00. I was/am looking for a treatment to modulate my “chimeric” immune system associated with my peripheral blood stem cell transplant that was done 7/20/16 at City of Hope in Duarte CA to cure the AML leukemia I was diagnosed with in 3/19/14.
    I am currently and have been suffering from the scleroderma that the transplanted blood system is/was manifesting in my tissue. The standard of treatment is/has been high dose prednisone and various medications that lower the vitality of the white blood cell line. Mainly kinase inhibitors with regard to b-lymphocytes and T inflammatory cells. Pharmaceutical medications like tacolimus, sirolimus, Jakafi, Ibrutinib, and the latest KD-025 recently approved by the FDA. These drugs modulate the immune system by inhibiting the production of key immune system cellular components that are associated with causing inflammation of the skin and eye. The donor’s immune cells attacking the host’s tissue, graft versus host disease.

    The main problem with this is the patient is susceptible to infection, and the drugs affect red blood cell and platelet production. The patient needs to have a CBC every month to keep an eye on the whole system. The condition is termed chronic GVHD (chronic graft versus host disease); it is this phenomena that eventually clears away any stray leukemic cells that might have evaded the chemotherapy, and helps prevent a relapse of the cancer. After approximately 2 to 3 years the chance for relapse is is down to 1%.
    The medical community has been performing this procedure for over 44 years, yet the ability to treat GVHD is still in a rudimentary state.
    I thought that an umbilical cord derived MSC treatment might help lower the inflammatory effect going on in my system, repair tissue damage manifested by the scleroderma, repair blood vessels/heart tissue affected by the chemotherapy and the GVHD, modulate the immune system to up regulate T-regulatory cells, lower C-reactive protein, and generally improve my quality of life.
    Why does the MSC treatment cost so much ? I found a company that supplies various cellular products for research, and for use by clinics to offer MSC treatment ( https://www.vitrobiopharma.com/pages/research-products-1 ).

    I’m interested in knowing the process from purchasing 500,000 MSCs from Vitro Biopharma in Golden CO.for $655.00, to expansion, to the point where 300 million cells would be used for a systemic infusion. This would help me understand why the price was $9000.00 that I paid out of my pocket. There has been extensive research into MSC treatment with most of the PubMed papers recommending further development and research of this type of treatment. I have a friend who had a MSC injection into his knee and the meniscus tear was repaired. Why is the FDA dragging its feet on this type of medical application ? Why isn’t there more research to develop FDA approval ? Mesoblast Ltd. has three products available in Japan and Europe but not in the USA. Pluristem Therapeutics of Israel also have products in development.

    On 9/16/21 I visited the oncologist assigned to my ongoing case at City of Hope prior to my trip to Mexico, he mentioned in our conversation “maybe that (MSC treatment) is all I need”. He mentioned that they are looking closely at this new regenerative medical area. Looking at the scleroderma manifest on my body he said he thought it was severe, and the treatment option was 2 weeks of high dose prednisone, with restarting Jakafi and belumosudil. I can’t use Ibrutinib because it gave me A-fib. I’m sure this is a dilemma for most SCT patients.

    1. @Neil,
      Thanks for sharing your story. You ask a lot of good questions. As to the price tag I think a good portion of the mark up is that the clinic wants to make a large profit. It’s that simple. Growing the cells in the lab also costs money. However, you should be aware that growing MSCs for weeks to get 300 million substantially increases their level of risk.

      Also, note that the MSCs I saw on the Vitro Biopharma page that you linked to said for research only. Even if some are in theory for clinical use, once they are expanded in a lab by a clinic or another supplier they become a new product that is unlikely to be approved for clinical use yet.

      I don’t think the FDA is dragging their feet on stuff. They are required to be rightly very careful. In terms of the FDA and Mesoblast specifically I’m not clear on what went on.

      I’d also say that what Mesoblast is doing is light years away from what stem cell clinics are doing. It worries me when they are discussed together because they are so different.

      My best to you!
      Paul

  2. Admin, you are a bit late to this party, aren’t you?

    Caplan, AI (2017) Mesenchymal stem cells: time to change the name! Stem Cells Transl Med 6:1445–1451. doi: 10.1002/sctm.17-0051

    Gomez-Salazar M, Gonzalez-Calofre ZN, Casamitjana J et al (2020) Five decades later, are mesenchymal stem cells still relevant? Front Bioeng Biotechnol 8:148. doi: 10.3389/fbioe.2020.00148

    And if you want my take on what’s going on:

    Dutton R, Abdi F, Minnetyan L et al (2020) A computational technology for specific counting of perinatal and postnatal human tissue stem cells for transplantation medicine. OBM Transplantation 4(3):24. doi:10.21926/obm.transplant.2003117

    It’s just vertebrate tissue cell biology. Really not that complicated at all; and shouldn’t be surprising either, if it weren’t for all the magical and mystical thinking of those who have not simply opened a textbook in tissue cell histology and tissue cell physiology. The same thing is going on in EVERY isolated stem cell-containing tissue cell preparation.

    1. I’m including more general resource pieces these days about important topics like MSCs.
      If you read my piece, I also have some different views than Caplan about the naming. A little too much magical medicinal thinking out there.

      1. Caplan also has a financial stake as well in tying the focus on the signaling portion as well. Money always complicates the matter with direct bias.

  3. Not sure if your review clarifies the common misuse of terms. There is certainly a lot of confusion and misuse of terms and probably way too many terms to be useful. I would agree that the term “stem cell” should be use more carefully and properly.

  4. Hi Paul- I’m more cynical than you are. I need proof of mechanism of efficacy before I’ll give any credence to an “MSC” trial. I think we should just call them mesenchymal cells…and what’s the difference between them and fibroblasts?

    By the way, I was around when Arnie Caplan named the cells that he’d cultured from chick embryos – amazing that I’m still alive, right?

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