Picture of Arnold Caplan, PhD

Arnold Caplan, PhD

Professor Arnold Caplan of Case Western Reserve University comments at the FDA/CBER meeting for Draft Guidances Relating to the Regulation of Human Cells, Tissues or Cellular or Tissue-Based Products in September, 2016.

Hi. My name’s Arnold Caplan, I’m a Professor at Case Western Reserve University in Cleveland, and I’m not speaking for the University, I’m speaking for myself as an individual.

In the late 1980s, I gave the term “Mesenchymal Stem Cells” to a cell which I was able to isolate from bone marrow, put into culture and expand in culture. That term is wrong, and I apologize for calling it a stem cell. It is not a stem cell. The assumption was that this cell was part of the stroma of marrow. This cell is not a part of the connective tissue or stroma of marrow, it is a perivascular cell, and as a perivascular cell it has a function only in cases of inflammation or injury. In this case, this cell comes off the blood vessel and does two things: from its front, it secretes a curtain of molecules which stop your overaggressive immune system from surveying the damaged tissue behind it. And from the back of the cell, it secretes a different group of factors which actually allow the tissue behind it to regenerate in a slow and unscarring process. This, therefore, is a cell which is medicinal in its function. And because I have such a delicate ego, I have written an article which asks my colleagues to continue to use the MSC nomenclature, but I’ve renamed this cell a “Medicinal Signaling Cell.” So therefore, when I lecture, I beg the audience to not use the stem cell nomenclature.

Having said that, I want to address two points of the Guidance Documents. Number 1: Everything I’ve just talked about is paracrine activity of cells. And so I would state that almost every tissue of the body is itself paracrine. Fat, in particular, has an absolutely essential paracrine activity as a tissue. And so, therefore, if you transplant or transfer fat from one tissue to another, you’re taking advantage of its paracrine activities, which are not covered whatsoever, as the last speaker pointed out, in your Guidance Documents. And so, therefore, I would suggest that the Guidance Documents could be augmented by talking about clinically homologous use. And so, therefore, a fat transferred to my knee, to my elbow, to my shoulder, are all comparably clinically relevant and could, therefore, produce a paracrine and/or clinically relevant activity, as some published studies have shown. So this is suggestion number 1.

Suggestion number 2 is that the Guidance Documents and the emphasis of the meeting on Thursday was to try to put at rest the illegal or irrational or unsupported use of cell-based therapy. My suggestion in this regard would be a registry. A registry which puts — of course protects the patient’s name, and identity — but puts the clinical symptoms under which they’re being treated and outcome parameter, lists sequential outcome parameters, so that one could determine whether a particular therapy was effective or not effective. If that registry was in realtime on a publicly accessible website, then we could determine, just as patients, whether a particular doctor’s office was producing clinically relevant results from any one of these therapies. I want to state, unequivocally, that this has been in practice for over 25 years for bone marrow transplantation, which the FDA supports and allows. So it seems to me that the FDA likewise, in helping to make sure that efficacious — clinically efficacious — technologies, are being used, should support also a registry for other cell-based therapies and/or tissue transfers.

It’s important, I think, that these Guidance Documents are based in science and in the reality, and this paracrine activity is one of the most important. And I, of course, will honor any decision this panel will make and help enforce it. Thank you.

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I’d just like to make one point: that there are published papers on MSC-like cells from a variety of sources — from fat, from liver, from heart, from kidney, from marrow — where the transcriptomes of those cells in culture have been analyzed, and they have a number of transcripts in common, and they have some unique transcripts for those tissues. So the fact that you can take fat-derived MSCs and you can take marrow-derived MSCs and put them in a variety of assays, including immunological assays, and get the same readout, is interpreted by me and many of my colleagues to say that — and what’s missed, I have to say, by many experimentalists — is that the MSCs have huge sensory capabilities. They can assay the microenvironment that they’re in, but they have a hard-wired response profile. And so, therefore, if you have stroke or you have heart attack, and an MSC’s given externally and goes to those two different sites, they will do the same sorts of things, but they will use different molecules and different molecular mechanisms. And we’re only now starting to understand some of those mechanisms.

In one study, at Case Western Reserve University, it’s very clear that the injured tissue sitting next to an MSC, compared to the normal injured tissue, is making 90 different transcripts, so the therapeutic proteins in all likelihood are coming from the host, not from the donor. And this is, I think, an important point, which is: these cells in vivo, when they are put back or energized in vivo, they actually are sentinels for injury and assist the host in regenerating tissues. So that’s why I have strongly argued for clinically homologous use.

My knee joints, my elbow joints, and my shoulder joints are all killing me at the moment because of my age and because I didn’t choose my father properly. In this case, the MSCs can have a very strong medicinal effect. One of the clear medicinal activities of MSCs is they make molecules whose names we know, that sit on opioid receptors, so the perception of pain is decreased without taking opioids. And so this is another clinical aspect. How can we call, how can we justify homologous use of taking fat-derived MSCs and only using them in fat, or having fat tissue that has dispersed MSCs in it, as a therapeutic modality? So again, I strongly oppose the concept that concentrated bone marrow is an MSC product because there’s probably five MSCs in concentrated marrow, but there’s a strong, very strong paracrine activity of concentrated marrow, the details of which, nobody knows. But it has some reported clinical outcomes.

And so, although a hundred years ago we ground up dog pancreases and gave it to diabetic patients with fabulous clinical results, it’s only taken us a hundred years now to fabricate insulin, human insulin, and deliver it to diabetic patients. The cell-based therapies that are being proposed and being tested clinically, in investigator-initiated clinical trials, are curative. That’s not what you can say about any insulin product currently on the market. And I think that’s an important aspect, and the aspect of curative is gigantically innovative.

And one last sentence is that the unexpected activity that MSCs make antibiotic proteins, LL37, that kill bacteria on contact, is currently being tested with an appropriate FDA approved I.N.D. in cystic fibrosis kids who have horrible lung infections. This can actually be curative for those lung infections if we can get this unusual antibiotic protein physiologically directed at the invading bacteria. This, I think, is an important, completely non-homologous use of these cells. And, however, from a paracrine standpoint, totally homologous.

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