Dissecting 4 possible roles for stem cell therapy besides cell replacement by stem cell scientist Paul Knoepfler

Dissecting 4 possible roles for stem cell therapy besides cell replacement

February 6, 2019 Paul Knoepfler anti-agingexosomesGrowth factorssenolyticsstem cellsstem cells aging 3

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An illustration of stem cell drug delivery by Taylor Seamount Stem Cells: An Insider’s Guide by Paul Knoepfler.

Historically, the main route of proposed healing via stem cells 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.

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.

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?

Credit to Paul Knoepfler for this article.