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:
(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?