I recently interview Arnold Caplan, the father of the MSC field, and published part 1 of the interview (you can read it here).
Today in part 2 we cover more topics of great importance related to MSCs including propagation, placebos, and patients as well as publishing.
A hot topic in the stem cell world more generally, but especially in the MSC field is what happens to stem cells when they are grown in a lab. Many important questions are being asked. Are the propagated stem cells basically the same as the starting stem cells? If not, how are they different? Should people be concerned about getting transplants of propagated cells?
I asked Caplan about how MSCs react to growth in culture. He acknowledged that MSCs grown in culture do change. “The longer you culture MSCs, the less they can differentiate,” said Caplan, “however, the MSCs retain their ability to inhibit immunosurveillance and to secrete trophic factors”. As discussed in the first segment of this interview, Caplan’s view is that it is these two functions rather than any stem cell-related properties of MSCs that are of the greatest therapeutic importance.
Caplan also mentioned another way in which culturing might change MSCs and in this case have clinical significance. After transplantation, high passage MSCs are more likely to become coated with clotting factor in the donor’s body and become trapped in the lung, reducing their efficacy. Thus, perhaps as is true with so many types of stem cells, lower passage is likely to be safer and more effective.
We also discussed how MSCs are likely to work clinically. One topic was the very important 2012 paper from Katarina LeBlanc’s team on autopsy data from patients who had received MSC transplants. The paper argued for quite limited engraftment of MSCs in support of the idea that nearly all transplanted MSCs do not engraft and rather function in a “hit and run” way to aid patients.
Caplan also acknowledged that many patients receiving MSC transplants (or transplants of other stem cells or even other kinds of medical interventions) definitely experience a significant placebo effect. The placebo effect that some patients experience with treatments can be substantial, up to 30%. However, Caplan passed on the experience of many physicians who are transplanting MSCs in RCTs where, according to Caplan, the doctors can easily tell which patients received placebo and which received stem cells, because those who received MSCs are doing so much better.
Interestingly, Caplan also pointed out that paradoxically for some patients, allogeneic MSC transplants might be more promising than autologous. In this regard, he mentioned how MSCs from healthy people appear to be more functional than MSCs from multiple sclerosis (MS) patients.
Caplan mentioned that there are 100s of patients receiving MSCs worldwide. I asked him why then are there so few publications. Caplan responded, “if only they would publish it would help everyone and the field.” I also would like to see more publications in this area.
Stay tuned for part III of the interview coming up in a few days.
11 thoughts on “Interview with Arnold Caplan Part 2”
Great interview. Could you clarify why it is paradoxical that “allogeneic MSC transplants might be more promising than autologous”? Not only if the donors are healthier, but what about umbilical derived stem cells both from blood and tissue? Aren’t those long telomere cells young, full of life and vibrant?
Allogeneic transplants are far more likely to be rejected, trigger harmful immune reactions, and have unique potential risks such as virus transmission (Hep, HIV, etc), transmission of cancer cells from donor to recipient (who might be immunosuppressed), etc.
aren’t MSCs immune-privileged and unable to produce tumors? Don’t they persist transiently and also may be irradiated after the effect occurs?
main advantage seems to be the low passage advantages(far better than ASC that show reliable senescence–and often used as controls), scalability(especially in hesc-hemangioblast derived), and limited batch to batch variation characteristic of autologous methods. All this would seem like supporting evidence that hesc is the gold standard with promise in ips if scalability is figured out. Wondering if this is inaccurate, this seems like a good place for clarification…thanks.
Thanks for the comment, Alan.
Immunoprivilege is not a “yes” or “no” proposition. MSCs may have a tendency to escape immune detection to some extent, but this likely varies depending on the patient, the MSCs, the clinic’s SOPs, etc.
In terms of tumor risk, “unable” is a very strong word, especially when you are talking about transplants of billions of heterogeneous stem cells grown in culture in a lab that may (or may not) be following good cell culture technique, etc.
Still MSCs clearly have huge promise.
I’m not sure what you mean with your statements about iPS and hESC–is this is relation to MSCs or a separate question?
Thanks for the clarification paul.
I suppose the statement on ips and hesc was based on my understanding for their ability to create more efficacious and increasingly abundant(loosely termed in relation to ips) tissue. The premise that hesc are best-suited for MSC translation was based on my classification of MSCs in an immune-privileged and tumor-free status– which I now suspect is a bit of a grey area. In addition, their ability to creating an effect while also subject to being irradiated.
I was also specifically talking about an early and unpublished study in EAE. I was really hoping to get a clearer interpretation of the risks involved in relation to hesc-msc translation. I imagine that a robust assay and labeling system is needed to move this forward…if possible.
Thanks Paul. We’ve seen the MSC Safety Meta Study that you wrote about stating your objections. Could you cite some studies that show where MSCs have caused any SAE, GVHD, tumors or anything else?
I grant you that embryonic and fetal cells potentially have these issues but I have not seen any data about MSCs, and I would like to see some data especially regarding umbilical derived MSCs if you have it.
This is a question that I cannot get a good answer to. Paul, can you cite some studies?
Great read so far. I have heard Dr. Caplan speak twice in person and his matter of fact demeanor, and his injected self deprecating humor is very refreshing. He is a pioneer in this field and I want to hear more…..Yet Paul— if Dr. Caplan coined the phrase MSC’s he should at least tell us which pronunciation is accurate. I have heard him talk so I have changed the way I pronounced it to match his.
I agree! I find myself going back and forth between the 2 ways to pronounce it.
excellent interview Paul.
Hearing what this guy has to say is very refreshing. Interestingly, his theory is supported by the claims of Robert Lanza and Advanced Cell Technology. In their studies of experimental autoimmune encephalitis(EAE), it was discovered that even passage-matched MSC from normal bone marrow did not stop paralysis. One injection from Hesc-MSC lowered the clinical score from 2-4 to <1 and "almost knocking the disease right out".
I don't imagine ACT will publish this data until it is thoroughly examined for IP consideration. For what its worth, Dr Caplan is once again ahead of popular opinion in my book. Looking forward to the next series and especially for the Gary Rabin interview. Thanks again.
Serious questions and observations
“The paper argued for quite limited engraftment of MSCs in support of the idea that nearly all transplanted MSCs do not engraft and rather function in a “hit and run” way to aid patients”.
LIMITED or TARGETED, limited makes no sense. XXXX (note, comment edited by admin)
If it is paracrine or growth the targeting is still a critical factor. Once this is established or even concurrently why not do a dose dependent and passage limitation study in the context of standardized care plus cell therapy. Using a comprehensive cohort design and randomizing 2x would be a mitigating factor re the issues of bias and patient self-pay.
Saying I wish people would publish is a cop out and is the same thing as saying nothing at all. In fact how can one say this and at the same time criticize video testimonials or deficient research studies from other folks? Personally not a fan of bad evidence but if you have evidence in the form of ‘everyone says it works but no one will publish’ why not put your money where your mouth is or just say no one cares enough to bother producing good evidence???
To say the cells head for the lungs is only looking at one method of delivery. If they are heading for the lungs when encapsulated in situ where is the evidence that this happens, Who has tracked this?
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