Defining the mesenchymal stem cell therapy

by Alexey Bersenev on January 31, 2013 · 2 comments

in under discussion

Since 1991, when Arnold Caplan coined the term Mesenchymal Stem Cells (MSC), these are an ongoing debates on the right naming and assays for this type of cells. I’m following these debates tightly and posting regular updates on StemCellAssays blog. The big question is how to unify the terms and assays for MSC in clinical trials? We are (professionals) reaching the point, when everyone in order to discuss would clarify first: “What do you really mean by MSC therapy?” In order to analyze data from multiple clinical studies and draw the conclusions about efficacy, we have to agree on the nomenclature and product characterization first. Here are some confusing questions:

  • Are MSC really stem cells and, therefore, is therapy really “stem cell therapy”?
  • Is it “cell therapy” or “cell transplantation” or both?
  • What is the purpose of MSC therapy – long-term cell persistence and “regeneration for life” or short-term effects and rapid clearance?
  • Should we consider MSC therapy as “regenerative medicine”?
  • Could the same markers and assays be applied for clinical MSC-based products, derived from different tissues and aimed for different diseases?

Right now “mesenchymal stem cells = MSC” used as very generic term for variety of heterogeneous cell populations, isolated from different tissues and applied in different clinical indications. But we have a problem with this approach, because most of the current MSC therapies are transient and irrelevant to stem cell function. For example, MSC could be used for engraftment and regeneration of bone tissue or as transient immunosuppressors or growth factors producers in multiple sclerosis and stroke. Many professionals don’t even consider MSC as stem cells. So, should we use different terminology for these completely different types of MSC therapy?

In the recent review, Paolo Bianco and co-authors, discuss these issues and describe “the clash of two concepts“. The authors harshly criticize the current concept of “MSC therapy” (pro-Caplan), because it has nothing to do with “stem cell biology”. The real MSC therapy, in their opinion, was inherited from Friedenstein’s studies in 1960s/ 1970s and developed further by Paolo Bianco and Pamela Robey as “skeletal stem cell” concept. The key picture, which nicely describes the difference and clash of two concepts was presented in the review. It is so good, that I was not able to resist and re-drew it:

MSC_defined (Adapted from Bianco, et al. 2013, modified)

I think, they nailed it!

The vast majority of MSC clinical trials are representing Caplan’s concept of “medicinal cells” and should not be called as “stem cell therapy”.

Clearly, intravenous infusion of cells that do not engraft cannot be defined as transplantation. Effects of infused cells that are neither transplanted nor engrafted and do not regenerate tissues do not reflect a stem-cell or regenerative function, and their pursuit should not be presented as a stem cell–based or regenerative therapy.

MSC represented 62% of “stem cell therapy” clinical trials in 2012. So, if we take out MSC, the value of “stem cell” trials from total “cell therapy” will shrink significantly.

Why is it important?

… as the range of clinical conditions considered potentially treatable by systemically administered MSCs expands and relevant clinical trials are initiated, it is the mere intravenous infusion of nondescript cultured connective tissue cells in patients that becomes confused with, but proposed and presented as, a stem cell–based therapy.

This creates expectations in patients and their families that are not likely to be met.

The second important point is that clinical trials can not precisely address the mechanisms of therapeutic action and question of dispensible/ indespensible role of MSC as paracrine regulators. So, we need to do more science before present it to the public as “stem cell therapy”:

Conversely, tipping the balance of experimentation in favor of clinical trials rather than reproducible experiments also has an impact: it leaves in the shadow the need to define and tackle specific mechanisms and pursue solid, conclusive evidence.

I’d like to point out that, presenting all MSC therapy as “stem cell therapy” or/and “regenerative medicine” also creates inflated expectations of general public, which is willing to support and fund clinical translation, based on belief in “stem cell magic”. I’m personally in favor of calling transient (or medicinal) MSC therapies as “cell therapy” instead of “stem cell therapy”. What do you think?

{ 2 comments… read them below or add one }

Robert Sexauer February 1, 2013 at 10:04 am

I found this to be an interesting post. That said, I think it misses the mark in several important areas. In treating many disease states, cells will be needed delivered intravenously as well as transplanted locally to a specific target tissue. And in most cases, more than one treatment will be required for clinical efficacy.

I don’t see this as a clash of two concepts at all. And I think Caplan is correct in his most recent publications as he describes these cells as signaling cells. Not too hard to miss his points as to the systemic effects that supplemental cells may make in various disease states.

I’ll give you one simple example. Take an athlete with degeneration in the knee and loss of cartilage. The effective treatment (with one type of cell classification) is stromal vascular fraction. The harvested cells from adipose tissue, and make no mistake, these cells are vascular cells from the blood vessel walls, need to be administered intravenously and by local injection into the knee joint. I suppose you can term it a transplantation as well as a systemic treatment. Bottom line, it works in the clinic. MRI evidence is showing us the results of new cartilage growth. And, that is only one example. We are seeing some interesting results from MS patients as well. Treatments are IV based and intra-muscular and localized injections to limbs in some cases.

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Alexey Bersenev February 3, 2013 at 10:25 am

Robert,
Thank you for the comment.
Are you trying to say that in treating many conditions MSC will be (should be/ could be) administered in both routes – systemically and locally in the same patient? If so, I’d disagree on this. I think, when you know the mechanisms of action and purpose of the treatment, you can clearly define from which administration mode patient will benefit the most. If you look at all clinical trials and published clinical results on MSC, there is a clear distinction of these 2 ways of cell administration.

I think, everybody agree with Caplan on his view of MSC therapy, including me and the authors of this review (Bianco’s camp). He explicitly wrote that this therapy has nothing to do with MSC stemness and therefore it’s not stem cell therapy. Everybody understand and agree with his point. It doesn’t solve a problem, but instead polarize the community. That’s why he proposed to rename MSC from “stem cell” to “medicinal signaling”. 2 different concepts, 2 different modes of therapy under the same name – I see a clash (also because this debate is ongoing for 2 decades without resolution).

How to name it “transplantation” or “therapy” is also ongoing debate and there is no agreement. The authors propose that if there is not long-term engraftment – there is no “transplantation”. I’d disagree on this distinction.

I think, everybody would agree with your bottom line – whatever works for patients! But this argument (which is vastly presented by physicians and “business people”) doesn’t solve a fundamental problem described in the post and debate is still ongoing. I think, we are as professional community should discuss and agree on terms and nomenclature in order to use the same language and analyze the data.

What I’m proposing is very simple thing at this point – use term “cell therapy” instead of “stem cell therapy” and therefore stop over-hype and sell to public “stem cell magic”. Fat-derived SVF is the typical example of it.

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