Do Your Stem Cells Differentiate and Stick Around?

By Chris Centeno, MD /

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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 you’re 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 “turning into” 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 can’t 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 can’t 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 doesn’t 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 patient’s 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 didn’t 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 didn’t survive very long. So what’s the difference between this study and those? Using autologous cells in rats is almost impossible. Their little bones don’t 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 else’s stem cells injected into a patient get chewed up by the host’s 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 don’t 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 host’s immune system because they are considered foreign invaders (i.e. someone else’s stem cells), if they act at all, they can only exert their influence through paracrine means.

There’s Likely a Reason We’re Being Focused on Paracrine Stem Cell Effects

Don’t 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 else’s stem cells (allogeneic) in a vial. However, as shown, these cells don’t 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, “someone else’s stem cells get chewed up by the host’s immune system, so why again is it that we’re using someone else’s stem cells?” Oh yeah, because that’s the business model that pharma likes…”

The upshot? This new paper rains on the paracrine parade. That’s 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!

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3 thoughts on “Do Your Stem Cells Differentiate and Stick Around?

  1. Bonnie Daugherty

    in about five weeks I’m about to have stem cell injections in both knees. They will be taking bone marrow from my help blood from my arm and adipose fat from my abdomen. Has anyone on here had this and what are your thoughts?

    1. Regenexx Team

      Hi Bonnie,
      Here are the important things to look for in Orthopedic Stem Cell treatment: https://regenexx.com/blog/orthopedic-stem-cell-treatment/

  2. chris aytug

    Love this blog post. Excellent info, as well as the one on gut microbiome. Thank you so much for keeping us up-to-date on all the new research!

Chris Centeno, MD

Regenexx Founder

Chris Centeno, MD is a specialist in regenerative medicine and the new field of Interventional Orthopedics. Centeno pioneered orthopedic stem cell procedures in 2005 and is responsible for a large amount of the published research on stem cell use for orthopedic applications.
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