Historically, the main route of proposed healing via stem cell therapy was cell replacement. In this way of thinking the transplanted cells engrafted (took up home) in the patient’s tissue and replaced dead or diseased cells. However, interest continues to grow in other possible modes of healing by stem cells that don’t rely on cell replacement. In today’s post I cover 4 other possible mechanisms for stem cell therapy to aid health.
Secreted factors
An alternative, not mutually exclusive model to cell replacement is that stem cell transplants have beneficial effects via the factors they directly secrete. These growth factors, cytokines, and other molecules (collectively sometimes called “the secretome”) could have a positive impact by a number of mechanisms. After stem cell transplantation, these factors might tell endogenous stem or precursor cells to start growing. They could tell some cells not to die, while encouraging others that are beyond hope and might actually be mediating toxic effects to go ahead and croak. (Incidentally, you might have seen the research (mentioned here) supporting the notion that senescent cells hanging around the body are actually actively harmful and removing them could fight aging. There’s even a germinal field of “senolytics”.) Secreted molecules might also stimulate angiogenesis, aiding in tissue healing. It’s a fact of life that secreted factors produced by transplanted stem cells would also pose risks such as sparking cancer or enhancing the growth of an already existing, undetected tumor.
Immunosuppression
Another popular, related idea is that infused stem cell specifically have immunosuppressive functions. In this way of thinking, although injected stem cells don’t stay around a long time, while present they tell the immune system to “cool it”. It’s an interesting concept, but not concretely proven. Let’s say for the moment that it sometimes happens. In that context, we have to be very aware of risks associated with this hypothetical stem cell-mediated immunosuppression. For instance, patients may get sick from an infection or developing a tumor as a consequence of reduced immune activity. The immunosuppressive route of function has been discussed the most for mesenchymal stem cells or whatever you prefer the MSC acronym to stand for these days.
Exosomes
An additional idea invokes a different kind of “secretion” by cells. In addition to making molecules that are dumped out directly into the interstitial space, the blood, or onto neighboring cells, stem cells (and really all cells) make what are called exosomes. These are little, budded-off membrane-bound packages full of many different molecules. Exosomes can then deliver their soup of factors to other cells. There is a lot of legitimate excitement about exosomes and their possible clinical potential. Unfortunately, there is abundant hype too. Also, some unproven “exosome therapy” is already being sold to patients. Of course, if exosomes can have potential benefits, their function as little packages of potent molecules will also pose some risks, which at this point are not well understood. While exosomes are not “stem cell therapy” they are a related approach.
Drug delivery
This last notion is related to the first three ideas above, but involves more time in the lab. Stem cells can be engineered in the lab to produce (or be loaded with) drugs that they then can secrete or in theory deliver with exosomes or even by cell fusion. In this way designer stem cells, once transplanted, can potentially deliver medicines to a diseased tissue. This delivery could even be on a cell-to-cell basis (I could say one cell acts as doctor and the other as patient, but I won’t), rather than systemically as most pharmaceutical drugs are given. For example, imagine stem cells loaded with chemotherapy delivering it directly to a brain tumor like a glioma.
Risks here include that the stem cells give too much drug, that the drug is delivered to the wrong cells, that the drug given by stem cells is uniquely toxic, or that the designer stem cells themselves engraft and grow into an undesired tissue or have some other negative effects. That last possibility is perhaps avoidable via a built in cellular suicide switch.
You can see an illustration of envisioned stem cell-based drug delivery to a diseased region of brain in an illustration by Taylor Seamount for my book, Stem Cells: An Insider’s Guide, above.
Overall, what other possible, helpful non-cell replacement-based roles for transplanted stem cells come to mind?
Also, see my new post on stem cell therapy side effects.
The technologies used in the cell therapy field are adaptable to the lab-grown, cell-based meat industry, and vice versa. Would love to chat more on this and get your audience thinking about the intersection and synergy of these two fields.
I would be delighted to join in such a discussion – thinking out of the box is where the future is.
Funnily enough I have worked for a large cell therapy company doing cell culture media design, a biotech (designing serum free clnical grade media) and a start up doing cultured meat production (cell culture secialist), so this is an area with which I am quite familiar. There are definitely some commonalities, but also some big differences.
Hi Brenton – yes – here is a link: http://www.LIFNano.com. This is my company’s site. Also I have a recent overview in Current Pharmaceutical Design, 2017, 23, 1-8 1: Neurodegenerative Disease: A Perspective on Cell-Based Therapy In The New Era of Cell-Free Nano-Therapy. Very happy to discuss further re biomarkers for MS where I have some novel ideas.
Please may I insert a plea for “synthetic stem cells” ? NanoBioMed provides a cargo of growth factor, within a nano-scale biodegradable biocompatible PLGA matrix, targeted by a surface binding moiety. Prepared in bulk. Safe and universally applicable. After extensive pre-clinical trials showing efficacy and safety, we are currently moving to clinical trials for Multiple Sclerosis. The cargo is the stem cell factor “LIF” (leukaemia inhibitory factor)” LIF is myelinogenic, neurogenic, and tolerogenic. These properties deliver both neuroprotection and reset self-tolerance – key needs for those who suffer from MS.
@su do you have a link to this or to NanoBioMeds website/clinical trials?- I’d be interested in reading some more about the technology and how it might help in MS. I’m currently doing some work related to biomarkers to track MS relapse/progression
If one admits that besides regenerating diseased tissue, stem cells can be a source of growth factors, have a role during immuno-suppression or be a source of exosomes … then mesenchymal cells will suffice for cell therapy. No need of hES/iPS cells or anyother kind of stem cells. Because MSCs are anyways not stem cells … they are endothelial pericytes and only facilitate regeneration
The issue with trying to engnieer stem cell derived CAR-T or other blood cell therapies will likely be rejection of the cells by the host, or alternatively GVHD. There’s a good reason autologous cells are used for these therapies. On the subject of MSC/immunosuppression I dont think people appreciate how big of an effect the methods used to expand the MSC have on the efficacy of immunosuppression. Growing cells in FBS, as is common, almost completely kills this ability. I spent a long time developing serum free, xeno free media for human MSC and looking at suppression of proliferation of activated T-cells and the difference between FBS and serum-free cultured cells was night and day.
@Brenton, That’s really interesting on the FBS effect. Did you publish that? What’s the mechanism of the FBS effect?
@paul no, unpublished. I was working in biotech and publishing wasn’t a top priority, sadly I have years worth of experiments that will never get done! I think the underlying mechanism is likely due to a maintenance of ‘stemness’ if you will when the cells are cultured in the absence of FBS. I have an inkling this is due to the growth factor milieu of FBS not being great at maintaining cells in an undifferentiated state compared to a defined media where you can choose your mitogens of choice. The two most prominent differences I saw between FBS cultured and serum-free cultured cells were the early loss of chondrogenic potential in FBS and the loss of immunosupressive capacities. Platelet lysate based media were also a lot better than FBS for these 2 traits.
Probably this is already going on but if not it seems inevitable that stem cell reprogramming to T-cells and NK cells will impinge upon the CAR-T cells (chimeric antigen receptor T cells) phenomenon. These spectacular immunotherapies seem to have only one drawback – source cells are derived from autologous patient T cells or a allogenic donors, but they seem to be short lived. So make T-cells in mass from hematopoietic stem cells and do all the engineering in line before therapy.
George, were you thinking here of IPS cell-like reprogramming or transdifferentiation to make T-cells and NK cells?
One more brief comment on using IPS or other sources of cells for cell therapies is that even small changes to protocols means that the cell therapy product is classified as a new drug, necessitating a re-do of ALL the preclinical data and clinical trials, which is hugely expensive. I worked with a large cell therapy company using MSC as a therapeutic and even a change in the media used to grow the cells would have meant a return to first principles and a complete do over, which for obvious reasons is not likely to happen.
Thanks, Brenton. Interesting observations! On a different but related topic, does culture in FBS mean carry through of cow antigens in the product that would be used in the patient?
I think this is a big unknown. From all the clinical trials and studies done to date it doesn’t appear to be the case (or at least a negative of the therapy)- there have been no adverse reactions reported due to immune rejection of bovine antigens that I know of. It may be that the therapies could work better if the cells were cultured in a more appropriate (FBS free) media but until they are compared head to head it is impossible to say. I think given the homology between bovine/human proteins that you could imagine being carried through into a patient (receptor bound mitogens for example or other bound/internalized proteins) there may not be a huge immune issues as they might be degraded internally or shed in such low quantities as to not be problematic.
It’s an open interesting question then as to why FBS culturing of cells for transplant seems to be tolerated on the immune front.
Hi Paul, I only know of Fate Therapeutics’ program in deriving NK- and T-cell lines from master iPSC lines, but I guess if transdifferentiation were efficient then this would be an option too. It was just blue sky thinking but Brenton´s comments below get right at the difficulties of “off-the shelf” lines. With a bit of fantasy one could create non-immunogenic master lines from stem cells or a set if banked lines that are HLA matched to patient subpopulations, but I expect (hope) these issues with allogenic stem cell sources will be sorted out for all uses in the fullness of time as the potential market is too big to ignore.
Hi George,
Yes, I was thinking of Fate as well, but wondered about other efforts in this area, including transdifferentiation if that were possible. Are you familiar with Universal Cells (acquired by Astellas)? Its focus more broadly is on universally compatible cells.
http://www.universalcells.com/
Paul
Interesting – Universalcells´ gene editing technology is one of many new ones in the post-CRISPR era (yes already!), and like others, the area of universal donor stem cell generation is a very attractive future market. But to win the race, these cells will have to go through many preclinical and clinical studies and that will be expensive …cue Astellas. I guess we will see other companies pushing a novel gene editing tech also being acquired. (note to self: call stockbroker on Monday).
This seems incredibly important to me. Seems like an article every stem cell supporter should read!!!