Cytocentric Visionaries: Donald Phinney
Part Two: MSC vs Exosomes and Therapies
In Part One, Chief Scientific Officer Alicia Henn talks with Dr. Phinney about his publication in Nature Communications, ”Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs”[Phinney et al., 2015]. Here we continue that conversation and discuss why exosomes have an advantage over MSC cells (interview edited for length).
What direction are you taking your exosome research?
DP: I’m fascinated that there are so many papers suggesting that exosomes have as many applications as MSCs. The idea for a number of years has been that MSCs are a unique cell therapy product because they can adapt to their microenvironment. Various companies’ websites clearly state that their therapy is advantageous because if the cells are in an ischemic or inflammatory environment they can respond appropriately and produce paracrine factors to mitigate the effects of that environment.
What’s interesting is that exosomes seem to be nearly as potent as MSCs in some disease cases, but obviously without a genome and the ability to adapt to conditions. Comparing the effect of exosomes and MSC in disease models may help dissect some of those differences.
If you think of MSCs as exosome-producing factories that home to areas of disease or inflammation in the body to churn out exosomes on site, would it be better to treat with MSC than exosomes themselves?
DP:I would agree that that would be a better approach because of the idea that the cells are adaptive and can respond to different conditions. It would be a great scenario if it was the injured microenvironment that actually induced exosome production.
So you’d do exactly what you said, put the MSCs in and they have mechanisms to home the sites of injury. If that actually induced exosome production, it would be great. I’m not really an expert on exosomes so I don’t know what kind of signals drive cells to produce large numbers of exosomes.
Obviously, if the exosomes are efficacious, they may be easier to use from a clinical perspective, and we need to understand how we can generate large numbers for therapy. Over the years, we studied many MSC populations from many human donors. Some donors just cranked out the exosomes and others didn’t. Is that production a stress response to oxygen or something else? That is something we are pursuing right now.
Is MSC donor heterogeneity a major problem?
DP: In the MSC field there are these crazy anecdotal stories where companies have an individual holed up at a hotel because his MSCs are great for manufacturing. That’s how problematic donor heterogeneity has been, both from an experimental and clinical point of view.
We have a new paper coming out where we have actually embraced heterogeneity. We studied many different human donor MSC populations and we were able to identify a signaling pathway that deconvolutes heterogeneity. When this pathway is active, the cells are very stem-like, grow very rapidly, and are very potently angiogenic. They look like the perivascular cells that people suspect exists in bone marrow and that most people think are the origin of MSCs.
Interestingly, if this pathway is downregulated, the cells lose their rapid growth and angiogenic potential and they gain competence to undergo stimulus-driven differentiation. The MSC also upregulated anti-inflammatory and immunomodulatory proteins, some of which drive cellular differentiation. So we have started to construct a hierarchy of the different effector and stem-like functions which we showed are coordinately regulated. You can drive a pro-angiogenic cell to an immunomodulatory cell, and this affects its ability to differentiate.
One of the problems in the field is that people just do this mass generation of cells for therapy and there aren’t very good release criteria to evaluate potency. Clinical manufacturing is all about what we need to do to generate five billion cells for a phase III trial. You unwittingly select for rapidly-growing cells or those donor populations that grow really well. For example, MSCs are used for arthritic joints. You can imagine if you manufacture a selected population of cells because they grow well and then they turn out to be very pro-angiogenic, those would be contraindicative for joint therapy. You would want to use those for ischemic models.
Our data says that we’ve got a way where we can drive those cells down the hierarchy or push them back up. We think that this can really help in terms of developing manufacturing schemes that are tailored for a particular disease type. We’re not quite there yet but we’re making progress.
A Senator from Wisconsin has authored a bill directing the FDA to set standards for cellular therapies including MSC. Do you think the biology is at a point where we can define what standards we need to set?
DP: It’s funny because the FDA has standards and some would argue that they’re not rigorous enough. For example, for cell therapy the FDA mandates that 70% of your cells be viable to infuse them into an individual. That means that 30% can be dead and we all know that dead cells are actually fairly toxic. We don’t really want to infuse those into someone.
It’s a difficult thing because you don’t want to impede science and you want to make sure you maximize patient safety. It’s warranted in the sense that the MSC field has gone a little crazy and MSCs are being used to treat any imaginable disease indication.
Paolo Bianco, who unfortunately recently passed away, wrote an article in Nature Medicine that was very critical about using MSC for non-skeletal diseases. He compared it to alchemy, which most in the field thought was too harsh. Fly-by-night clinics have been spotlighted on the news where they promise cures for incurable diseases. In fact, I get a lot of calls from people asking “should I get cell therapy for this?”
At the state and national level, more regulation is needed to limit these clinics that are profiting off of therapy that’s not validated at any level, but it’s hard. People are desperate when they have serious health conditions and they want some form of treatment, but it is important to educate the public and speak out against therapies that aren’t validated.
In Part Three, we continue our discussion with Dr. Phinney about how the Cell Cycle Is the Redox Cycle and how All MSC are Stressed.
Phinney, D. G., et al. (2015), Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs, Nat Commun, 6, 8472.
About the Author
Alicia D Henn, PhD, MBA
Alicia Henn has been the Chief Scientific Officer of BioSpherix, Ltd for two years. Previously, she was a researcher at the Center for Biodefense Immune Modeling in Rochester, NY. Alicia obtained her PhD in molecular pharmacology and cancer therapeutics from Roswell Park Cancer Institute in Buffalo, NY and her MBA from the Simon School at University of Rochester in Rochester, NY.