Regenexx Blog
by Chris Centeno, MD / July 4, 2019

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One of the biggest debates right now in regenerative medicine is whether stem cells act through differentiation or a paracrine effect. If youíre considering a stem cell treatment, knowing what all that means is important. Let me explain.

Differentiation vs. Paracrine
The type of stem cells being most often to treat orthopedic conditions are mesenchymal stem cells (MSCs). These cells were traditionally believed to repair damaged tissues via differentiating or ďturning intoĒ other needed cell types. Hence, for example, in a back pain patient, if there was a torn outer disc (called the annulus), then the stem cells would differentiate into the fibroblast cells that make up the annulus.

However, more recently, another way stem cells act has been popularly discussed. This is a paracrine effect. This means that they produce messenger chemicals that tell other cells how to repair the area.

Whether MSCs work primarily through differentiation or a paracrine effect has been hotly debated. It seems like you canít go to a medical conference on orthobiologics these days without an extensive back and forth on the topic. More recently, the paracrine camp has been winning. However, that conceptualization may be based on comparing apples and oranges, as a new study throws water on the paracrine concept.

Autologous Stem Cells Injected into a Disc Hang Around
The paracrine camp has pointed to studies that show that when stem cells are injected someplace in an animal model, some authors canít find them in that area for very long. Hence the theory was hatched that these stem cells work by directing a repair response and then dying off or going elsewhere. However, what if they did stick around a long time?

A recent study on 4 patients who had their own (autologous) stem cells injected into their spinal discs was just published last week. These patients had bone marrow taken and then through centrifugation, a bone marrow concentrate (BMC) was created. The MSCs in this prep were then labeled using an iron-based cell labeling agent. All patients decided eventually to undergo a spinal fusion surgery (although others in the bigger study did not), which is not surprising as BMC generally doesnít work well for significantly degenerated spinal discs. See my video below on that topic:

What was surprising is that living stem cells containing that iron-sucrose label were found 8-months later in 3/4 of the patientís discs. The fact that these cells integrated into multiple parts of the disc and that they were still many later definitely rains on the paracrine parade. If these cells didnít differentiate into needed cell types, what the heck were bone marrow MSCs still doing there? In fact, the authors determined that many had differentiated into cartilage cells (chondrocytes). This would be pretty close to the cell type normally found inside the disc (nucleus pulposus).

Why Did this Human Study Find Vastly Different Results than Animal Models?
As I have relayed, the paracrine camp got its start from animal studies showing that MSCs injected into various areas didnít survive very long. So whatís the difference between this study and those? Using autologous cells in rats is almost impossible. Their little bones donít allow the type of bone marrow aspiration that we can perform in human patients. Hence, almost all small animal models used for MSC experiments used pooled MSCs from the bone marrow of several animals. Why is this important?

The data that someone elseís stem cells injected into a patient get chewed up by the hostís immune system has been mounting. Ashlee Watts at Texas A&M recently did a nice study on this phenomenon. Her research is not unique. Hence, the reason these animal cell experiments show that MSCs donít survive likely has less to do with how they act and more to do with these foreign cells being targeted and destroyed by the immune system.

Rethinking Differentiation vs. Paracrine
My educated guess is that MSCs work through both mechanisms. If given half a chance, they will differentiate in real patients just like they do in the lab. If being hunted down and killed off by the hostís immune system because they are considered foreign invaders (i.e. someone elseís stem cells), if they act at all, they can only exert their influence through paracrine means.

Thereís Likely a Reason Weíre Being Focused on Paracrine Stem Cell Effects
Donít believe for a second the science has no conflicts of interest, in fact, the regenerative medicine field is ripe with conflicts. One of them is companies pushing the best business model that fits with pharma. This is someone elseís stem cells (allogeneic) in a vial. However, as shown, these cells donít stick around very long, so there needs to be a narrative that explains this away as a good thing. That narrative is that the cells act through a paracrine effect orchestrating a repair job that is actually accomplished by other local cells. Rather than, ďsomeone elseís stem cells get chewed up by the hostís immune system, so why again is it that weíre using someone elseís stem cells?Ē Oh yeah, because thatís the business model that pharma likesÖĒ

The upshot? This new paper rains on the paracrine parade. Thatís why you gotta love science. Just when we all had convinced ourselves that MSCs work one way, new research comes by that upends that belief!