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The definition of stem cell therapy

Today everyone is talking about stem cell therapy everywhere. It’s hot, it’s popular, it’s sexy. But nobody ask the very important question: “What is the real stem cell therapy and how can we define it?” I’ll try to answer this question and propose a definition.

It seems very simple to say “injection of stem cells with therapeutic purpose is a stem cell therapy”. Unfortunately, this current assumption is too far from reality and could mislead the public and professionals. I’ll try to explain why I think so. I’d like to look at 3 parts of this problem – quantity, purity and function of stem cells in therapeutic cell product. I’ll discuss about adult stem cells.

In reality nobody never inject pure stem cells. It’s always a mix of different cell populations. It could be a mix of different stem cells, progenitor cells or mature cell populations from the same or different lineages. In any case – it’s never pure. Even if the percentage of well defined stem cells in heterogeneous cell mix is relatively high (aka enriched stem cells), we still have some accessory cells (let’s call them contaminants), which could possess therapeutic value. Also, we always have to keep in mind that any given tissue contain a tiny population of adult (tissue-derived or resident) stem cells. For example, in blood transfusion we transfer some circulating hematopoietic stem cells, but we never call it “stem cell therapy”.
The bottom line 1: In definition of stem cell therapy we can not rely just on the presence of stem cells in transplanted cell suspension/ tissue.

But what if we start to enrich stem cells? The stem cell enrichment is definitely increasing a probability of their contribution into therapeutic effect (aka potency), because of depletion accessory cell-contaminants. But in many cases enrichment doesn’t play any role. For example, hematopoietic stem cells (HSC) transplantation in hematological malignancies. We can take the whole bone marrow or lineage negative fraction (~ 20x enrichment for HSC number) or CD34+ sorted fraction (~ 40x enrichment) or sort pure Lin-/CD34+/CD38-/CD45RA-/CD49f+/Rho- [1] (~ 400-500x enrichment). If we transplant any of these cells in conditioned patient, we will get the same result – life-long engraftment, multilineage blood chimerism and leukemia eradication. It’s clear “stem cell therapy” and it does not depend on degree of stem cell purification.
The bottom line 2: In definition of stem cell therapy we can not rely purely on degree of stem cell enrichment (purification) in transplanted cell suspension/ tissue.

Now, the most important part. The biological function of stem cell which determines the potency of the transplanted cell suspension should justify our “therapeutic purpose”. In other words – if population of stem cells in any given cell suspension/ tissue underlie the mechanism of anticipated therapeutic action, it’s a “stem cell therapy”. This issue is extremely important in so-called “non-homologous use” of cell therapy. For example, let’s look at bone marrow mononuclear cells (BM MNC) – the most frequently used source for cell therapy. If we use BM MNC for cardiac repair or diabetes, many types of cells could cause therapeutic effects in the heart or pancreas – myeloid hematopoietic progenitors, lymphoid cells, putative endothelial progenitors, HSC or mesenchymal stromal stem cells (MSC). Only if therapeutic effect is exclusively attributed to the latter two (HSC or MSC) populations, we can call it “stem cell therapy”.
The bottom line 3: In definition of stem cell therapy we should solely rely on anticipated mechanism of therapeutic action, which should be exclusively attributed to stem cells, but not to progenitor or mature cells.

Finally, the mechanism of therapeutic action by stem cells should be proven and based on evidence. Few examples:
1. If adipose tissue-derived stromal vascular fraction (SVF) highly enriched for mesenchymal stromal cells (MSC), we would guess that this population cause therapeutic effect in cosmetic applications. But if anticipated mechanism of therapeutic action is a collagen synthesis, it could be attributed to fibroblasts from SVF as well. I don’t think we have any evidence, which indicate that MSC of SVF exclusively do this job.
2. If we use CD34+ purified cells (which is very heterogeneous population) in cardiac cell therapy and expect stimulation of angiogenesis as a mechanism of therapeutic action, we should not call it “stem cell therapy”. At least 3 different cell types within CD34+ population could contribute to this effect – HSC, myeloid hematopoietic progenitors and putative endothelial progenitors. As you all know, stem and progenitor cells are fundamentally different.
In both cases we don’t have evidence for exclusive stem cell effects, therefore, we should not call it “stem cell therapy”.
3. Bone marrow and cord blood transplantation in hematological malignancies is a proven “stem cell therapy”. The evidence is based on long-term observations of life-long persistence of transplanted stem cells which exclusively contribute to multilineage blood formation. Please note that at the beginning (first few months) bone marrow transplant in leukemia could act as a “progenitor cell therapy”, but later stem cells exclusively underlie the life-long blood support and cure.

The definition:
Stem cell therapy is a type of cell therapy in which therapeutic efficacy exclusively attributed to the potency (function) of donor stem cells, presented in any quantity and purity.

Special considerations:

  1. This definition is applied to adult or/and neonatal stem cells but not to embryonic stem cells. In case of embryonic stem cells, use of any derivatives could be called “stem cell therapy” or “stem cell-based therapy”.
  2. Long-term persistence of stem cells after transplantation is not included in this definition. Stem cells could hang out in the body just for a little while but do the whole anticipated “therapeutic job”.
  3. In all unclear cases where we have no evidence, we should use more general term “cell therapy” (by default) instead of “stem cell therapy”. Bear in mind that we frequently have no idea what is the mechanism of therapeutic action of transplanted cells and what cell type actually do the major job.
  4. It is a working definition. I’d like to hear your opinion in order to polish it. You can give your examples in comments and we can discuss what is “stem cell therapy” and what is not.

Final remark:
I think it’s a very important issue, because currently professionals and mass media over-use and over-hype adult stem cells and the “stem cell therapy” term. It’s not just a matter of semantics! There is a real danger of uncontrolled branding [2] of stem cells. Widespread use of “stem cell brand”, which distorts reality, can mislead the public and discredit stem cell research field.