The recent review of Paolo Bianco and group of co-authors harshly criticized a definition and a concept of mesenchymal stromal cells (MSC) as “medicinal cells” or “mesenchymal stem cells” (aka Caplan’s definition). They also criticized a definition and minimal criteria of MSC, proposed by ISCT in 2006 and widely accepted now by professional community. Because I’ve recently proposed a revision of MSC criteria by ISCT, I was especially curious about their opinion and view on it. They called it “an awkward position”:
Crystallized in a widely cited position paper that assumed to set the criteria for defining MSCs for general use, the view finally became dominant that every nonclonal culture of cells from any connective tissue would represent a culture of MSCs.
On the basis of this loose set of criteria, MSCs can indeed be grown in culture from virtually every tissue. Not validated by proper in vivo and clonal assays (Box 2), the artificial properties seen as ‘defining’ features of MSCs are simply widely shared properties of connective tissue cells. They do not imply any true stem-cell property or the true ability to form bone, cartilage or adipose tissue in vivo. The confusion introduced by these criteria has major consequences when translational implications are considered.
If you follow this debate for the last decade, you may know that Paolo Bianco and Pamela Robey stand for MSC as “skeletal stem cells” with a primary function in vivo – to regenerate a bone. They said that in vitro criteria, proposed by ISCT are unreliable and don’t represent function in vivo:
If they are predicted based on unreliable in vitro criteria, all the properties of the MSC to be harnessed in patients (such as the ability to regenerate bone, in the simplest scenario) are predicted unreliably: placenta, menstrual endometrium and bone become conceivably equivalent sources of cells for efficient bone regeneration, but they absolutely are not.
And finally, as a consequence of this misconception, “medicinal MSC” confused with true MSC (skeletal stem cells) and falsely presented as “stem cell therapy”:
More generally, 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.
So, “MSC community” has been divided for quite a while. Divided for 3 camps:
Camp 1: Paolo Bianco, Pamela Robey + Paul Frenette and Paul Simmons view MSC as “skeletal stem cells”, which must be self-renewing and persisting in vivo. They should engraft and regenerating skeletal tissues for life. Primary source is bone marrow. This is continuation of Friedenstein’s school.
Camp 2: Arnold Caplan views MSC as “mesenchymal stem cells” or “medicinal cells”, which can be used for therapy of wide variety of diseases via intravenous infusion. They should not persist (this camp doesn’t want ectopic bone formation!) or engraft. Their function is irrelevant to both – skeletal tissue regeneration and “stemness”. This therapy is very close to combination of drugs with extended pharmacokinetics and pharmacodynamics.
Camp 3: ISCT Committee members, who are trying to find a “middle ground” and define MSC in order to apply some standards. We need these standards and guidelines in order to compare, analyze and draw some definitive conclusions from results of multiple different clinical trials.
What camp are you in and why?