I recently received an e-mail from the mother of a small child with cerebral palsy. She had a number of questions that I thought would make an interesting and perhaps more educational edition to the Stem Cell Mythbusters series. Here were her questions:
-I was wondering if there were certain growth factors used to expand cells that I should be looking for or some I should be avoiding. Growth factors are usually small proteins that can turn on or off certain cell functions. In this context, “expand cells” means growing stem cells in culture to larger numbers. First the growth factor question. To expand cells, usually growth factors are needed (think of them as fertilizing the stem cell “seeds”). Depending on the cell type, these can be growth factors like FGF (fibroblast growth factor), TGF (transforming growth factor), or VEGF (vascular endothelial growth factor). These growth factors turn on the right switches on the surface of the stem cells (or other cells) to tell them to grow. The big problem for the patients receiving these cells as therapy is that these are all “recombinant” proteins made in a lab somewhere and not drugs at this point. As a result, while these don’t seem very dangerous when used to grow stem cells used in animal studies, the human safety profile of these substances is simply not known. To avoid this issue with our Regenexx-C culture process, we use the patient’s own platelet lysate (platelets are taken from the blood and then popped open to get the growth factors out) to grow cells. Since the patient’s own platelets contain these same growth factors in human form and in perfect physiologic doses and combinations, this works quite well to eliminate the risks of recombinant growth factors. So to answer the question of which growth factors to avoid exposing a child to at this point-the short answer is all of them that don’t originate with the child. The long answer is that like anything else in investigational therapies, if artificial recombinant growth factors are used to grow cells in doses that dramatically exceed what the body usually sees, then bad things could happen. Since almost all existing culture processes use these recombinant growth factors, buyer beware. This practice could be safe or it could be quite dangerous, we simply don’t know. If the clinic has treated many patients with cells exposed to one or more of these recombinant proteins they should have tracked these stem cell patients systematically in a registry and be able to give you exact reports of what types of complications were seen in how many patients treated (see registry discussion below).
One last point is that the term “cell expansion” is thrown around by many clinics without the great majority of those clinics actually carrying out “cell expansion”. When cells are grown in culture, for the first few days they are literally “stunned” by being taken out of their natural environment and placed in flasks or another culture vessel. As a result, a “cell expansion” that takes only a few days isn’t going to grow many more stem cells in culture. True cell expansion takes weeks (usually 2 weeks in culture, sometimes slightly shorter or longer). Most human adult stem cells won’t grow for too much longer than 2-3 weeks and there are risks to culturing for more then 4-6 weeks. Any lab process that says it performs “cell expansion” that takes only a few days is likely really performing “cell conditioning”. This means cells are exposed to a growth factor or other drug to try and push them toward one type of tissue repair. As an example, some labs condition cells with Stromal Derived Factor (SDF) and/or VEGF to push cells toward a vascular/cardiac repair lineage (to make the cells better at treated heart problems). However, while cell conditioning can be an important step for a successful stem cell therapy, you won’t end up with many more stem cells.
You also mentioned in your report that expanded Mesenchymal stem cells seems the most promising for neurological problems. A lot of the clinics use expanded hematropoietic instead. There are many different stem cell types and two are mentioned here. Mesenchymal stem cells (MSCs) are found in many tissues and plentiful in bone marrow and adipose tissue (fat). They can generally assist in the healing of many different tissue types including bone, heart, cartilage, tendon/ligament, nerves, etc… Hematopoietic stem cells (HSCs) are mostly found in the bone marrow and are generally good at creating new blood cells or new blood vessels (which is why they are so good at helping heart patients). In the US National Library of Medicine right now there are only two papers published under MSC and cerebral palsy (CP). One recent study showed that in an animal model of brain injury to a fetus, MSCs were capable of repairing the brain damage. The other paper is actually more focused on MSCs from cord blood. Under the search terms HSCs and cerebral palsy there are 11 published research papers. One paper is actually about the use of cord blood to treat cerebral palsy. Another study looked at progressive brain diseases and giving patients a drug to mobilize both HSCs and MSCs from the bone marrow to the blood stream and this seemed to work in a few patients. Another one of these studies is about cord blood and the rest aren’t on topic. I also searched cord blood and CP and found 225 references. One study looked at a case report of 2 toddlers with CP who were treated with cord blood and drug injections to mobilize stem cells showing improvements in the children. Many of the references are again not really about the therapeutic use of cord cells in CP. There’s a good review paper on the use of cord blood in neurologic diseases focused on promising lab and animal experiments.
Focusing the search for research supporting the claim that any type of stem cell might help patients with brain injury, if one searches under MSCs and stroke, there are quite a few interesting references that are on point (180). One recent patient study in Japan showed that patients given IV infusions of MSCs had improvements in function and a decrease in the size of their brain lesions on MRI. Another study compared MSCs from bone marrow and adipose tissue and found that those from adipose tissue might be better to treat stroke. In reviewing this long list, there are many, many papers published on animal models of stroke and cerebral ischemia (like CP) that show that MSCs can effect repair of brain tissue. Searching under HSCs and stroke, not much is published. There is a paper that looks at a bone marrow nucleated cell fraction (the portion of the bone marrow that contains a bunch of cells including HSCs and MSCs) in stroke (rat model) that does show decreased lesion size (that’s a good thing). I have personally seen early clinical data using this same simply obtained stem cell fraction presented at conferences (not yet published data) showing that it can help patients with neurologic diseases when delivered precisely into the arteries that feed the brain. However, note that this is not a simple IV injection in an arm, but a more complex and higher risk procedure.
The upshot? If you had to place a bet on what cell type might help a child with cerebral palsy, based on the mass of papers published right now, it would be MSCs. In addition, based on a few publications and the experience from presentations and other publications from heart studies, a simple bone marrow nucleated cell fraction, when delivered precisely into the circulation of the brain, might help as well. This begs the question, if the data shows that isolated and cultured MSCs have the best data right now, why are clinics advertising that they use HSCs? The answer regrettably is that obtaining HSCs in a 1-3 day procedure is relatively easy, but few stem cell clinic labs around the world have evolved to the level of sophistication of being able to isolate and grow MSCs over a few weeks (in orthopedics we have developed that capability). Another question is if the data shows that delivering these cells directly to the arteries that feed the brain is likely better than IV (where most will end up in the lungs), why do most clinics inject IV? Again, ease of application. Finding a qualified pediatric interventional radiologist in a third world country who can safely deliver cells in an appropriate facility to handle the severe and life threatening complications that could arise with such a procedure is difficult.
This myth that HSCs are the cells with the most data showing efficacy in brain tissue repair is BUSTED.
One discouraging thing about looking for other children who have gone through stem cell therapy is the lack of before and after videos or real documentation of any improvements that might have occurred. Yes, the lack of objective data showing improvement in CP kids who have been treated with stem cells is discouraging. As I have blogged before, every stem cell clinic in the world treating patients has an ethical obligation to enroll every single treated patient in a stem cell treatment registry like the one run by ICMS. This means that every patient is tracked for complications and outcomes at set time points on an ongoing basis. To date, very few clinics do this and as a result, they are unable to quote any hard data on whether their procedure works or is dangerous or safe. As a result, my personal advice would be to only work with a clinic that is part of the ICMS registry process. To be registered, the clinic’s treatments have to go through an review board of physician colleagues, the lab and processes get accredited, and the every patient is tracked. Publication of this data at conferences and in medical journals is encouraged.