What are possible side effects of stem cell therapy ? Patients often reach out to ask about such risks They usually refer to unproven stem cell clinics.
Today’s post addresses the scope of stem cell therapy side effects and risks based on available hard data. It’s also important to discuss possible unknown risks.
Stem cell risks at unproven clinics | Why do stem cells pose risks | Tumors| Impact of lab growth | Infections | Blood clots | MSCs | Other risks | Intranasal stem cells and exosomes | References
Side effects at unproven clinics
In this post I am focusing on the risks primarily associated with unproven stem cell clinics. Not for established methods like bone marrow transplantation, which have their own risks including the shared one of infection.
Recent publications in journals have helped clarify risks. This literature includes a study by my UC Davis colleague Gerhard Bauer and a special report by The Pew Charitable Trust. Gerhard’s paper presents the types of side effects that appear more common after people go to stem cell clinics. After closely following this area for a decade I was familiar with many of the examples of problems.
One of the highest profile examples of bad outcomes was the case where three people lost their vision due to stem cells injected by a clinic.
I have included a YouTube video below on stem cell therapy side effects as well.
Stem cell power brings possible risks
Why do stem cells pose risks?
One major reason is that stem cells are uniquely powerful cells.
By definition they can both make more of themselves and turn into at least one other kind of specialized cells. This latter attribute is called potency and the process of becoming other cells is called differentiation. The ability to make more of themselves is called self-renewal.
The most powerful stem cells are totipotent stem cells that can literally make any kind of differentiated cell. The fertilized human egg is the best example of a cell having totipotency. The first few cell divisions after that retain the totipotency. Next in the power lineup are pluripotent stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). These cells are not directly used in therapies.
Adult stem cells are multipotent, which means they can make just a few types of specialized cells.
What is the best type of stem cell? The “best” type of stem cell depends on the condition that is trying to be treated and may not be the most powerful.
In any case, the power of stem cells is one reason they also pose risks along with mishandling that can cause infections. Stem cells are not always easy to control and misdirected power can do harm.
Let me explain and start with the side effect that seems most concerning to most people but is probably the rarest. Tumor formation.
Potential tumor formation
If someone injects a patient with stem cells, it’s possible that the self-renewal power of stem cells just won’t get shut off. In that scenario, the stem cells could drive the formation of a tumor.
Why wouldn’t a transplanted stem cell always eventually hit the brakes on self-renewal? It could be that the stem cell has one or more mutations. For any stem cells grown in a lab, within the population of millions of cells in a dish, there are going to be at least a few with mutations that crop up. That’s just the way it goes with growing cells in a lab. The longer you grow them the more mutations they will have on average.
Even stem cells not grown in the lab have the same spectrum of mutations as the person they were isolated from. It may seem odd to think about, but we all have some mutations.
Research suggests it takes more than one cell with cancer-causing potential to make a tumor in experiments in the lab, but in actual people, we just don’t know. Many cancers may arise from one stem cell gone awry. If a clinic injects 100 or 500 million cells, a one-in-a-million rate of potentially dangerous cells means that 100-500 such risky cells end up in the patient. The risk of getting an actual tumor may still be low but I wouldn’t take those odds.
The encouraging news here is that the incidence of tumors in stem cell clinic customers, particularly in the U.S., appears extremely low.
Can cells never grown in a lab still pose a tumor risk?
The odds of getting a tumor are far lower for cells never grown in a lab but it’s still possible. Oddly, receiving someone else’s stem cells (we call this allogeneic) might pose a lower cancer risk because your immune system is going to see those cells as foreign from the start. It’ll reject them. Still, an immunocompromised state could play a role.
Some stem cells, especially those with mutations, might be able to somewhat fly under the radar of the immune system to some extent. This could allow them to grow into a tumor.
The Pew report does a nice job of summarizing risks and there are several reports of tumors.
Infections, a relatively common stem cell therapy side effect
The possibility of infections after stem cell injections is another risk that is often discussed. Infections from injections of stem cells or other biologics are probably the most common type of side effect. Bacteria can sometimes already be in the product that is injected. Or germs can be introduced by poor injection or preparation methods by the one doing the procedure.
The distributor Liveyon had a product contaminated with bacteria that sickened at least a dozen people who were hospitalized. Some of them ended up in the ICU. A few may even have permanent issues.
Infection risk usually does not arise from the cells themselves.
Stem cell therapy side effects: blood clots in the lungs
Another risk is the potential for blood clots.
In the case of adipose biologics life SVF, they mostly consist of a mixture of a dozen or so other kinds of cells found in fat. Fat cells just live in fat so they aren’t supposed to be floating around in your blood. As a result, after IV injection, many fat cells are thought to get killed right away by the immune system or the microenvironment. While in the blood, fat and other stromal-type cells, whether dead or alive, may catalyze clot formation, which is dangerous.
Some of these cells end up landing in the lungs. There many cells are probably being killed and there’s also risk of blood clot formation.
Notes on MSCs
Unproven clinics mainly sell MSCs.
MSCs could have some powerful uses in medicine. I can already see a few rigorous clinical trials that look exciting.
However, the way some unproven clinics use MSCs can be highly risky.
Such cells just shouldn’t be injected willy-nilly into dozens of places in patients including into people’s eyes. Further, what are called “MSCs” by some unproven clinics may also not meet even basic lab standards and may not have the potential of other MSC preps. Some such clinic preps are likely just fibroblasts or mostly dead cells.
MSCs produced in a rigorous manner in clean labs by experienced teams are likely to be a far superior product than that typically made by just any strip mall clinic. I don’t endorse any cell therapy clinic selling MSCs at this time, but some are doing far better than others. They do research and publish papers.
Properly conducted injections of unmodified, high quality MSC-type cells or marrow cells into joints or for other orthopedic conditions by qualified providers in theory should pose almost zero risk of pulmonary emboli or cancer. Clinics using excellent procedures and cell products also should pose a very low risk of infection, a risk more similar to getting medical procedures in general even unrelated to stem cells.
Overall, I’m not sure I believe such MSCs even from the best clinics can provide lasting benefit for diverse orthopedic conditions, but the overall risks associated with them should be quite low there relatively speaking.
Other risks
Patients have also asked me about other potential risks of cell injections.
I wrote a post about possible graft versus host disease in stem cell recipients. This would only happen in people receiving someone else’s stem cells and probably only with IV administration. It’s not clear if GvHD is something that happens to patients after going to clinics selling allogeneic cells. With no immunosuppression, it should be highly unlikely.
Beyond outright tumor formation, it is also possible that stem cells may become an undesired or even dangerous tissue type that isn’t technically an actual tumor. The example that comes to mind is the practice mentioned earlier of some clinics injecting fat cells into people’s eyes. What seems to have happened in some cases is that the mesenchymal cells (MSCs) or other cells like fibroblasts that were injected turned into scar tissue, which caused retinal detachment.
In addition, we have seen indications that patients getting IV infusions of stem cells might be at some risk for heart attacks. Perhaps via clot formation. For example, read this piece: Cellular Performance Institute death.
One of the challenges is that it can be difficult to figure out if heart attacks or other outcomes were linked to the actual stem cell procedures or just incidental. Many patients getting stem cells may already be at higher risks for these issues. In any particular case, one can ask: was the cell infusion linked to the death? I’m not sure we could ever know. Such outcomes should be carefully tracked and analyzed. One challenge is that adverse events at hundreds of unproven clinics may never be reported or otherwise come to light.
Intranasal stem cells and exosomes
Specific routes of administration may pose unique risks as well. For instance, intranasal stem cells are getting popular with some unproven clinics and could lead to cells or other material ending up in the brain. Intranasal delivery of stem cells could have real promise such as for treating brain conditions, but you need rigorous clinical data to back that up. You need to work with the FDA and send them data. Clinics without such data are already selling the procedure.
Other products in the regenerative sphere that are not stem cells may be risky as well for various reasons. For instance, an exosome product harmed quite a few people in Nebraska. Some problems may relate to product contamination. Here again, exosomes may have promise for some conditions but should not be sold already as therapies at this time.
Finally, stem cells and other cell therapies also pose unknown risks because of their newness and power.
We also just don’t have long-term follow-up data to have a clear sense of all major risks after people go to clinics.
In general, so much depends on collecting good data before trying to make money form vulnerable patients.
References
- A special report by The Pew Charitable Trust on stem cell therapy side effects.
- NEJM article on vision loss after going to a stem cell clinic: Vision Loss after Intravitreal Injection of Autologous “Stem Cells” for AMD.
- Concise Review: A Comprehensive Analysis of Reported Adverse Events in Patients Receiving Unproven Stem Cell‐Based Interventions, Stem Cells Translational Medicine.
- P. Marks and S. Hahn, “Identifying the Risks of Unproven Regenerative Medicine Therapies,” Journal of the American Medical Association 324, no. 3 (2020): 241-42, https://jamanetwork.com/journals/jama/article-abstract/2767586.
- Website on FDA adverse events reporting system.
- CDC article on Liveyon infections.
- It’s important to talk to your physician about possible stem cell risks before making decisions. This post is not intended as medical advice.
I would add the risk of “Emptying one’s wallet” and potentially of “Emptying one’s life savings”, something that 100% for certain has been widely observed at these stem clinics. A great majority of these clinics I’d argue, and I believe I can prove it with data, they spend far, far more on slick marketing than they ever spent on actual, bonafide, high quality medical research to backup their vast claims of “cures” or near “miracle cures” and so forth. These clinics which a great many to me are nothing more than the latest variants of Snake Oil LLC Inc or whatever, they’ve invented an entire new lexicon of terms to help pitch their “cures” and “treatments” to help people part with large sums of cold, hard, cash, often enough to leave them literally broke or destitute. Terminology like “The cells will find and home-in on the damage, like a heat seeking missile, and heal it”. Really ? How ? And when you ask how, you get a lot of hot air and nothing much else. They love the word “inflammation”, as in ALL human disease is somehow a pathology of that ever present supposed evil inflammation. I always wondered this scenario then: I am scheduled to get say, my knee injected, cause you know, that ole inflammation is causing my old sports knee to go bad. But, the day before, I wack my finger with a hammer real hard working in the garage. So, when they IV drip me with their magic cells – how come the stem cells don’t all rush to my now read hot, big ole swollen finger (homing in, heat seeking missile style, you know) and bypass my less inflamed knee ? How does that work exactly ? And then, when a person spends $5K or even $10K on their magic IV drips and nothing worked, literally nothing got even slightly better – we know well from lawsuits and many, many public testimonials that the answer is pretty much always, “You need more cash only treatments of course” and the lexicon invented word(s), “Cause see, the treatment this time didn’t “take”, you know, like it didn’t “stick” but some more drips and injections and we’ll get them cells to “take” the next time”… “so see the front desk and pay some more cash please”. This stuff, it’s so wild west and so snake oil of old to me – it’s fraught with not only medical risk, but just the risk that every Tom, Dick and Harry will hang a shingle out and suddenly (via a 3 or 4 day training seminar) be the local “stem cell clinic expert, and heck: no risk, no harm guaranteed, just come on in and we’ll fix ya right up”, which is exactly what’s been seen from sea to shining sea.
In regard to tumor risk, some additional thoughts: Pluripotent stem cells, when undifferentiated, form teratomas. In fact, this is one of the assays to determine whether the stem cells are pluripotent: implant them in immunocompromised animals and look for the formation of teratomas. Therefore, the tumor risk of undifferentiated embryonic stem cells or induced pluripotent stem cells is very high.
The risk for adult stem cells has not been determined. As you note, the longer cells are in culture, the more chance they have of accumulating mutations. This is why it is important to only grow cells to 80-90% confluence. The original methodology to obtain transformed cell lines was to grow cells to post-confluence and keep them there. In those conditions, cells that had mutations that removed contact inhibition and increased proliferation would be favored, with the transformed cells growing in multilayers in a 2D culture. I wonder how most stem cell clinics grow their cells. Do they grow them to post-confluence?
Michael F. Clarke’s original work on cancer stem cells — https://www.pnas.org/doi/10.1073/pnas.0530291100 — indicated that as few as 10 cells could initiate a new tumor. An ongoing discussion is the source of cancer cells, including cancer stem cells. Are cancer cells differentiated cells that have 1) dedifferentiated and 2) lost growth control or are they adult stem cells that 1) have lost growth control and 2) then partially differentiate? There is evidence for both possibilities. For your article, the danger would be more acute if the second alternative is the source for cancer cells, particularly cancer stem cells (or tumor initiating cells, a term I prefer). If we follow your calculations of one-in-a-million cancer stem cells and the clinic injected 100 million adult stem cells, that would mean 100 cancer stem cells. This is well over the minimum number of cancer stem cells that Clarke observed as sufficient to start a tumor.
OTOH, I have never seen a report of a tumor arising from an injection of adult stem cells and Baur’s article does not list any. Regenexx has done hundreds of injections into the knee and never reported a tumor there. So perhaps our concern is unfounded. Maybe cancer cells do not arise from adult stem cells. Or maybe culture conditions do not foster those mutations. Or maybe the natural defense mechanisms against abnormal cells eliminate any possible cancer cells.
Unproven stem cell clinics have already given adult stem cells a bad name and made the field difficult. I hope they do not add to the damage by culturing cells post-confluence and increasing the risk of tumor formation.
I also have not heard of Regenexx having a patient get a tumor.
Uncultured adult stem cells are highly unlikely to cause a tumor including in part because they tend not to engraft. Even cultured MSCs, if handled properly, are unlikely to have much risk of tumors but it is relatively higher risk than ones not grown in a lab.
It’s important to note that MSCs can in theory cause the wrong tissue to be present in a location like contractive scar tissue in the eye causing blindness, which has actually happened several times. More than 10 years ago there was a report of bone arising in eyelid due to adipose MSC injection, causing problems. I’m not sure that was ever confirmed though. These kinds of rare outcomes from ill-advised procedures could technically be considered production of benign tumors. Not sure I buy that definition though.
More generally, in this updated version of this post I have included some statements about the relatively low risk of bad things happening at regenerative clinics using non-lab-grown adult cells that also do research, have vast experience, and do procedures properly.
Unfortunately there are 100s of clinics that are more about profiteering with less experience.
I just had a consultation with a clinic that I am potentially going to go through for stem cell therapy for my SLAP tear. I see a lot of positive and negatives but I was hoping that you could provide a few questions that I could ask the Dr. that would help me determine if I found a good clinic or if I should keep searching. Any help is appreciated.
@Brian,
It’d help in thinking about possible questions if you could pass along what kind of cells they will use and are they your cells or some premade product? Also, do you know — are they going to use anything else too like PRP?
One broad question to ask: what happens if you aren’t happy with the results? Also, how long do the results last? What if you feel better for 1 month and that’s it? Does the clinic do actual research publish results or have in the past?
Thank you so much for the timely reply! I was advised that the stem cells that would be used for my shoulder would be umbilical cells from a donor. As of right now there is no plan for PRP. I was told that the general result in patients claim they are 50-100% better than before the procedure. The clinic is also attached to a Spine and Sports medical center here in Buffalo NY.
Hi Brian,
I would ask — who is the supplier of the umbilical cord cells and how reputable are they?
Also, are the umbilical cord cells actually living cells and how do they know?
Going along with that, how is the product guaranteed to be sterile and free of pathogens? Do they have test results on that?
One of the challenges with umbilical cord products is they have a higher risk than say bone marrow or fat cells of being contaminated during the birth process like with E. coli, etc. On the other hand, if the product is sterilized, it usually kills all the cells and maybe makes other stuff in the prep less useful like the growth factors in there.
How many cells will they use and why? How do they know what’s the best dose of cells?
Since this place is in Buffalo then they are required by law to work with the FDA before doing anything clinically since umbilical cord cells are drugs. To my knowledge, no clinic has approval to use umbilical cord cells in the whole US. Some people tell me that they don’t care about that kind of thing, but it’s worth mentioning since the lack of working with the FDA often means there are less data to back up what the clinic is doing and how their supplier preps the cells. The FDA has issued many warnings to suppliers of umbilical cord and other birth-related cells and those warnings almost 100% of the time raise serious issues about poor practices related to risks of contamination. Just something to think about.
I cannot begin to thank you enough for actually helping me out with these questions. Thank you so much!