Till & McCulloch Meetings 2012 – Reflections on Caplan’s view of mesenchymal stem cells

by Alexey Bersenev on May 6, 2012 · 4 comments

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Arnold Caplan is a scientist, who coined a termmesenchymal stem cells” in 1991 for the type of bone marrow cells, previously known as “stromal stem cells”. This term became widely adopted. He gave a very interesting talk during plenary session of Till & McCulloch Meetings. I’ll try to summarize his current view on “Mesenchymal Stem Cells” (MSC) biology and clinical applications.

Caplan said that a term “Mesenchymal Stem Cells” got him in trouble later, because not everyone believed in their “stemness”. More than a year ago he proposed to use an alternative term “Medicinal Signaling Cells” instead of “Mesenchymal Stem Cells”. According our recent poll, professionals didn’t adapt yet a new MSC’s name.

Caplan believes that MSC are progeny of pericytes – the cells, attached to blood vessel’s wall in all tissues and organs. So, they are not stem cells, but progenitors. Ironically, nobody call pericytes as “stem cells”, even though they are MSC’s ancestors. Importantly, he thinks that cell definition should be functional – based on biological role in vivo. Right after blood vessel injury, pericytes give MSC progeny. MSC get activated in inflammatory environment and express their “medicinal” functions – immunomodulatory and trophic. So, MSC’s biological function has nothing to do with “stemness”. He noted: “We should focus on what these cells can do medicinally instead of what they can differentiate to”. Also, Caplan thinks that MSC have nothing to do with stroma. So, no to “stem” no to “stromal” in definition. As he said: “Turn your “stem cell brains” off and think!”

I’d argue, that in normal condition, bone marrow MSC have a stromal/ structural role as hematopoietic stem cell niche. Unfortunately, Caplan completely ignored this very basic MSC function, described by Alexander Friedenstein and Joseph Chertkov more than 30 years ago. I don’t think we can define and name a cell type, based only on their function in pathological conditions. Should it be two different names – “stromal” for normal condition and “medicinal” (activated stromal) for pathology? It is very confusing!

Caplan views MSCs as a “drugstores”, which can produce 10-20 biologically active substances. He thinks that FDA standards should not be applied to “live drugstores”. He said: “We can’t use Pharma logic in regenerative medicine”. I was thinking – why every MSC-based therapy developer trying to show “tri-lineage differentiation assay” in preclinical protocol and put it in product characterization? Based on medicinal signaling cell logic, it doesn’t make any sense. Almost all clinical trials in regenerative medicine currently assess medicinal functions of MSC, which have nothing to do with “stemness”. So, probably just one good potency assay is enough for product characterization. Ironically, everyone call it “stem cell therapy”.

From the recent therapeutic trends, Caplan is really excited by antibacterial function of MSCs. These cells can make natural antibiotic-like substances (LL37) in contact with bacteria. His data confirm and complement of studies by Matthay’s group. He also impressed by use of MSC in veterinary medicine. He credited Vet-Stem, which have treated more than 5000 horses for tendons injuries with 75% of cure rate. Finally, as a founder of Osiris, he noted: “Osiris data on Crohn’s disease is spectacular!”

Caplan concluded that we have to accept the paradigm shift from MSC characterization in vitro (tri-lineage differentiation) to medicinal function, which is irrelevant to concept of “stemness”.

{ 4 comments… read them below or add one }

James Eliason May 7, 2012 at 9:31 pm

I think of them as stromal cells when they are in situ and fibroblast progenitors if they are in culture (CFU-F). I call them mesenchymal stem cells to others because 1) most people in the field understand what I am talking about and 2) the term stem cells has become fashionable. This means that I have relaxed my standards a great deal in my old age. Back when I was a graduate student, postdoc and young researcher, we tended to be much more strict in our terminology than is currently the case.

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Alexey Bersenev May 8, 2012 at 11:18 pm

Good points James!
For the 2nd I call it “the term stem cell become branded”. I’m getting a lot of comments about my “craziness” about terminology. People say “it’s matter of semantics”, or “it doesn’t really matter for clinicians and patients”.
I’d be ok with that, if people admit that the naming doesn’t reflect the reality and have nothing to do with science. Just be honest. Unfortunately, people refuse to admit.

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Owen Bain May 8, 2012 at 10:28 am

Not sure about ‘Medicinal signalling cell’ terminology. For indications such as GvHD, Chron’s, myocardial infarction, IHD etc. their medicinal function is most likely due to paracrine effect, whereas for tendon, bone, cartlidge repair research groups are edging towards a more tissue engineering route of loading scaffolds with primed or differentiated MSCs. So, product characterisation is dependant on intended use.
In addition, as James touched on, MSCs in situ and in vitro culture/expansion are different entities.

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Alexey Bersenev May 8, 2012 at 11:13 pm

Owen,
Exactly my point. I agree with you. He didn’t mentioned tissue engineering and homologous use of MSC. I guess, he was trying to avoid to give a credit to Friedenstein for “stromal” and Bianco for “skeletal” SC. So, I cite his phrase about regenerative medicine for a reason – to reflect his view. Obviously, using MSC on a matrix for bone repair is a regenerative medicine and it’s nothing to do with their “medicinal” properties.
Even if we accept the lineage: (1) pericyte –> (2) MSC (aka stromal?) –> (3) activated MSC (aka “medicinal”), should we treat 2 and 3 as different entities or as different functional state of the same cellular entity? If connection between pericyte and activated (medicinal) MSC, make sense, why “stromal MSC” should be associated with pericyte? And what about fibroblasts?
http://stemcellassays.com/2012/04/mesenchymal-stromal-cells-fibroblasts/

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