A new style of MSC immunotherapy – Instructions included

Author: Holly Wobma, 09/22/16

If you have been following stem cell news lately, you know that there have been several recent Food and Drug Administration (FDA) meetings regarding how to classify stem cells, which ultimately affects if and how they will be regulated. There are many medical practitioners, scientists, and patients who would like to see these therapies on the market, but just as many people in the community want those therapies to be offered responsibly.

What may not be obvious from these discussions is how these therapies work at the cellular and molecular level. Clearly, stem cells must do something in order to be therapeutic. Fortunately, a tremendous effort is being dedicated to addressing this question, and some of the insights we are gaining may enable us to create “smarter” stem cell therapies.

Let’s take a look at mesenchymal stem cells (MSCs), for example, which have been the focus of hundreds of clinical trials and are a common cell type being marketed in private clinics.

MSCs can be isolated from a variety of tissues such as fat, bone marrow, dental pulp, and amniotic fluid, and can be differentiated into “mesenchymal” derived cell types – osteoblasts (bone), chondrocytes (cartilage), adipocytes (fat) and endothelial cells (blood vessel lines) in the lab. Not surprisingly, one of their therapeutic mechanisms may be their ability to differentiate into and replace these tissues in the setting of injury.

However, recently much focus has been on their ability to act as “medicinal signaling cells” in their undifferentiated form.

Specifically, MSCs have the ability to secrete growth, angiogenic, and immunosuppressive factors, which make them promising for application in wound healing, ischemia, autoimmune disease, and transplant rejection.

While they secrete these paracrine factors to a small extent at baseline, they become even more immunosuppressive in response to certain environmental cues, such as inflammation. You can think of them as the cells that restore balance to a disturbed environment. When they see inflammation, they counter with anti-inflammatory signals. When they see hypoxia, they counter to promote blood vessel growth.

A common regimen for most MSC therapies right now is to inject culture-expanded cells and let them “react” to the internal environment of a patient. However, based on our growing knowledge of how to modulate them with environmental cues, some labs are getting pretty creative. Take, for example, Dr. Todd McDevitt’s lab (Gladstone Institute and University of California – San Francisco).

In Dr. McDevitt’s recent study published in Stem Cells Translational Medicine, he exposes his MSC aggregates to heparin microparticles loaded with the pro-inflammatory cytokine IFN-γ. He shows that packaging the MSCs with this cue helps to boost their immunosuppressive phenotype by increasing the production of the immunosuppressive protein indoleamine-2,3-dioxygenase (IDO). Furthermore, packaging the IFN-γ in a biomaterial (i.e. the microparticles) promotes sustained release and a longer IFN-γ lifespan than simply injecting IFN-γ into the cell culture media, and this, likewise, leads to a more prolonged secretion of IDO.  The overall effect is that the IFN-γ-loaded microparticles serve as a long term “reminder” to the MSCs as to how to behave as an immunosuppressive therapy, enabling them to inhibit immune cells for longer.

Figure 1: The McDevitt lab recently showed mesenchymal stem cell (MSC) spheroids containing IFN-y loaded microparticles have sustained indoleamine 2,3-dioxygenase (IDO) expression and enhanced immunomodulatory activity (Zimmerman JA et al. 2016 Stem Cells Trans Med pii: sctm.2016-0044). Credit: Carmen Wong, CCRM

The McDevitt lab recently showed mesenchymal stem cell (MSC) spheroids containing IFN-y loaded microparticles have sustained indoleamine 2,3-dioxygenase (IDO) expression and enhanced immunomodulatory activity (Zimmerman JA et al. 2016 Stem Cells Trans Med pii: sctm.2016-0044). Credit: Carmen Wong, CCRM

Moving forward, it would be interesting to next test this regimen in an in vivo model, to bolster our knowledge of how to administer MSC aggregates and to see how metabolism affects the microparticle lifespan.

While it is unclear what the FDA will decide in terms of the regulation of stem cell therapies, it is abundantly clear that with our growing knowledge of their mechanisms we may develop better and better therapies for when they become more widely used.

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Holly Wobma

Holly Wobma

MD/PhD student at Columbia University
Holly is an MD-PhD student at Columbia University in New York. She recently (2011) completed a Bachelor of Health Sciences Honours Degree from the University of Calgary, where she pursued research related to nanotechnology and regenerative medicine. In addition to research, she enjoys participating in science outreach roles. Previously, she contributed to an award-winning Nanoscience animation produced by the Science Alberta Foundation (“Do You Know What Nano Means?”), and served on the board of directors for the Canadian Institute for Photonic Innovations Student Network. Holly's lab tweets @GVNlab.
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