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Is Bone Marrow Concentrate a Stem Cell Therapy?

Published on Nov 3, 2022

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This has been an interesting few years with regard to the regulations behind using the term “stem cell therapy”. It’s also been an interesting scientific ride as well. Today I’ll review the pure science of whether bone marrow concentrate is a stem cell therapy. I’ll cover the concept that bone marrow concentrate contains stem cells and that our current understanding of its mechanism of action is tied to that stem cell content. Let’s dig in.

The Regulatory Landscape

It’s very clear that the FDA and FTC do not like physicians using the term “stem cell therapy”. While the recent loss by the FDA at the hands of judge Bernal in LA regarding classifying adipose stromal vascular fraction as a drug has shaken that space up a bit, reading countless FDA documents makes it clear that the agency doesn’t like companies and practitioners using this terminology to describe treatment:

Given that our company both has affiliate clinics that use orthobiologics and also has several orthobiologic drug candidates in front of the FDA, I can see both sides of that argument. On the one hand, multiple court cases have determined that society benefits from doctors being free to use whatever works to help patients and to describe that in any way that helps patients conceptualize the therapy (1-3). On the other hand, many companies are pursuing multi-year expensive clinical trials to get the legal right to market stem cell therapy as an FDA-regulated drug.

Also, realize that we got here to what I call the “stem cell wild west” with an FDA sensitized to this issue because of a raft of companies offering to treat every known disease with “stem cell therapy”. The biggest offenders were clinics using demonstrably dead cell birth tissue therapies and advertising these as live stem cell therapies (19-22). This has made it difficult for legit medical providers offering orthobiologic treatments as they are often the baby getting thrown out with the proverbial bathwater.

Having said all of that, my focus here will be on the science and not on the regulatory argument.

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The Scientific Debate Behind the Term “Stem Cell”

One of my favorite lecturers on the face of the earth is Arnie Caplan, who is arguably the discoverer of what we currently call “mesenchymal stem cells” (MSCs) (4). Arnie is funny, irreverent, and has an uncanny ability to take complex hard science topics and make them digestible for physicians. He has also taken the controversial position that he wants to rename MSCs from “Mesenchymal Stem Cells” to “Medicinal Signaling Cells” (5). Let’s explore that debate.

First, MSCs live throughout your body (6). They are one of many different types of progenitor cells that are there to help with the repair of mesodermal tissues like bone, muscle, cartilage, tendon, ligaments, etc… Over these past few decades, we have found that this type of repair cell lives in all tissues and many have been given specific names. For example, the local repair cell in muscles is called a “Satellite Cell” rather than being called an MSC (7).

MSCs were first described by Dr. Caplan because, in the lab, they were able to differentiate (turn into) different cell types. He determined and then this work was confirmed by many others, that these cells were “pluripotent”. This means that they could turn into different cells of the same lineage type (mesodermal).

The impetus behind Dr. Caplan’s name switch is the idea that while MSCs can differentiate into different cell types in the lab, they can’t do this in animal studies. Hence, he feels they should lose the “stem cell” moniker and instead gain one that focuses on their paracrine actions (the medicinal signaling part). That last bit is because in these animal studies they seem to signal to other cells how to complete a repair job. However, that idea, like most generalizations, leaves out a bunch of important details that make a difference.

Allo vs Auto

The problem with Dr. Caplan’s assertion is that it’s based on animal studies that use allogeneic MSCs. That means that these animal studies use MSCs that are pooled from many animals to treat one animal. Why is it done this way? Because getting enough bone marrow out of a tiny rat to be able to culture in the lab is tough. It’s practically much easier to take small amounts of bone marrow from many rats and pool that and then isolate and culture those MSCs. Hence, 99.9% of the animal data we have on whether MSCs differentiate in animals is using allogeneic MSCs.

Why is this critically important to understand? We now know that allogenic MSCs behave quite differently in treatment than the patient’s own stem cells. When Dr. Caplan first published the MSC concept and for decades after, we believed that donor MSCs by their very nature could evade the immune system of the host animal (8). To a certain extent, that’s true, but more recent research has shown that it’s not entirely true. Basically, allogeneic MSCs are detected by the host as foreign using the killer-T cell system (9). This has also been confirmed as impacting clinical outcomes in equine studies (10). For example, when there is a close HLA match of the donor cells, the outcomes are better and when the match is poor, the outcomes suffer. That makes sense, as we know that happens in organ transplants as well. So while a donor MSC treatment may not cause a full Graft Versus Host Disease (GVHD) response, they do cause the host’s immune system to become sensitized to foreign tissue, making the second treatment with donor cells even worse.

It’s because of this fact that host immune systems are taking out donor MSCs that research shows that allo MSCs largely act through paracrine mechanisms. However, that’s quite different from human-level research using the patient’s own MSCs (autologous). Here we know that the MSCs stick around and differentiate, just like they do in the lab (11,12).

So should we change the name of an MSC from mesenchymal stem cell to medicinal signaling cells? I’m not sure it’s that important clinically, but for the purposes of this discussion, my educated opinion would be no. They do retain pluripotency when used in an autologous fashion. Hence, we may well want to change the name of allo MSCs, but autologous should likely keep that moniker.

Is BMC a Stem Cell Therapy?

Now that we’ve covered the regulatory and scientific controversies, it’s worth diving deeper into the research behind BMC containing MSCs and our current understanding of its MOA as being tied to those MSCs.

What is BMC?

BMC stands for Bone Marrow Concentrate. This is also known as BMAC or Bone Marrow Aspirate Concentrate. This means that the doctor takes bone marrow (usually from the pelvis as that’s the richest stem cell source) and centrifuges this to remove the fraction containing stem cells. This is then called BMC and re-injected to help bone, cartilage, muscles, tendons, or ligaments heal.

Does BMC Contain Stem Cells?

Multiple studies have shown that BMC contains both mesenchymal and hematopoietic stem cells (13). These cells can easily be culture expanded showing they survive in culture (14). There is little dispute in the literature that this is a true statement. Now you can argue, as discussed above, that we should rename these cells, but there is no debate that they are present, alive, and functional.

What is the MOA of BMC?

MOA means the mechanism of action, which is both a very important and slippery concept in medicine. What I mean is that our understanding of how a specific therapy works or its MOA is critical as that allows us to maximize the benefits and reduce the risks of that treatment. At the same time, the MOA of many common drugs and treatments we use every day is often poorly understood, not understood, or constantly being revised. For example, how do antibiotics work and what are the side effects? We have long believed that they work by killing off the bacteria causing an infection. However, recent research shows that they also change the mix of good and bad bacteria in the gut microbiome (15). Hence, there are legitimate questions being asked that after almost 100 years of use as a drug, our full understanding of the MOA of common antibiotics is incomplete.

So what is the current theory of the MOA of BMC? Right now we have the most evidence that BMC works through its MSC content. Why do we think this? There are now multiple studies, including our recently published work, that show that the clinical outcomes in diseases as diverse as fracture non-union, degenerative disc disease, and knee arthritis are tied to its CFU-f count, which is a proxy for MSC content (16-18). Hence, for the moment, the strongest evidence for the MOA of BMC is its stem cell content.

Now, none of this means that we may not discover stronger evidence at some point that BMC instead works through other MOAs. For example, it’s been proposed that its beneficial effects on knee arthritis could be tied to its A2M content (a natural chemical that blocks cartilage breakdown). However, in medicine, we always use the best available evidence.

So is BMC a “Stem Cell Therapy”?

Based on the best available evidence, BMC is a stem cell therapy. Again, this statement ignores the regulatory discussion which is not science-based but is more focused on the practicalities of regulating the wild west that this space has become. It also sidesteps the literature debate that began when the discoverer of MSCs stated that he wants to rename the cell type. So you could also say that BMC is a “Medicinal Signaling Cell” therapy if that floats your boat.

The upshot? At the end of the day, forgetting about the regulatory or the naming controversy, BMC likely works through its live stem cell content. Hence, it meets the scientific definition of stem cell therapy.

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References:

(1) 1. Alexander v. Smith & Nephew, 98 F. Supp. 2d 1299 (N.D. Ok. 2000) holding that FDA regulations do not impose a standard of care on practitioners.

(2) Buckman Co. v. Plaintiffs’ Legal Committee, 531 U.S. 341, 349-350 (2001); citing 21 U.S.C. § 396 (“Nothing in this chapter shall be construed to limit or interfere with the authority of a health care practitioner to prescribe or administer any legally marketed device to a patient for any condition or disease within a legitimate health care practitioner-patient relationship.”)

(3) U.S. v. Caronia, 703 F.3d 149, 155 (2nd Cir. 2012); citing U.S. Food and Drug Administration, Guidance for Industry, Responding to Unsolicited Requests for Off–Label Information About Prescription Drugs and Medical Devices (2011), at 2-3.

(4) Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991 Sep;9(5):641-50. doi: 10.1002/jor.1100090504. PMID: 1870029.

(5) Caplan AI. Mesenchymal Stem Cells: Time to Change the Name! Stem Cells Transl Med. 2017 Jun;6(6):1445-1451. doi: 10.1002/sctm.17-0051. Epub 2017 Apr 28. PMID: 28452204; PMCID: PMC5689741.

(6) Pittenger MF, Discher DE, Péault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen Med. 2019 Dec 2;4:22. doi: 10.1038/s41536-019-0083-6. PMID: 31815001; PMCID: PMC6889290.

(7) Campion DR. The muscle satellite cell: a review. Int Rev Cytol. 1984;87:225-51. doi: 10.1016/s0074-7696(08)62444-4. PMID: 6370890.

(8) Ryan, J.M., Barry, F.P., Murphy, J.M. et al. Mesenchymal stem cells avoid allogeneic rejection. J Inflamm 2, 8 (2005). https://doi.org/10.1186/1476-9255-2-8

(9) Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014 Mar;32(3):252-60. doi: 10.1038/nbt.2816. Epub 2014 Feb 23. PMID: 24561556; PMCID: PMC4320647

(10) Rowland, A.L., Xu, J.J., Joswig, A.J. et al. In vitro MSC function is related to clinical reaction in vivo. Stem Cell Res Ther 9, 295 (2018). https://doi.org/10.1186/s13287-018-1037-4

(11) Henriksson HB, Papadimitriou N, Hingert D, Baranto A, Lindahl A, Brisby H. The Traceability of Mesenchymal Stromal Cells After Injection Into Degenerated Discs in Patients with Low Back Pain. Stem Cells Dev. 2019 Sep 1;28(17):1203-1211. doi: 10.1089/scd.2019.0074.

(12) Geburek F, Mundle K, Conrad S, et al. Tracking of autologous adipose tissue-derived mesenchymal stromal cells with in vivo magnetic resonance imaging and histology after intralesional treatment of artificial equine tendon lesions–a pilot study. Stem Cell Res Ther. 2016;7:21. Published 2016 Feb 1. doi: 10.1186/s13287-016-0281-8

(13) Dolgalev I, Tikhonova AN. Connecting the Dots: Resolving the Bone Marrow Niche Heterogeneity. Front Cell Dev Biol. 2021 Mar 12;9:622519. doi: 10.3389/fcell.2021.622519. PMID: 33777933; PMCID: PMC7994602.

(14) Short B, Brouard N, Occhiodoro-Scott T, Ramakrishnan A, Simmons PJ. Mesenchymal stem cells. Arch Med Res. 2003 Nov-Dec;34(6):565-71. doi: 10.1016/j.arcmed.2003.09.007. PMID: 14734097.

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(16) Centeno CJ, Berger DR, Money BT, Dodson E, Urbanek CW, Steinmetz NJ. Percutaneous autologous bone marrow concentrate for knee osteoarthritis: patient-reported outcomes and progenitor cell content. Int Orthop. 2022 Aug 6. doi: 10.1007/s00264-022-05524-9. Epub ahead of print. PMID: 35932306.

(17) Pettine KA, Murphy MB, Suzuki RK, Sand TT. Percutaneous injection of autologous bone marrow concentrate cells significantly reduces lumbar discogenic pain through 12 months. Stem Cells. 2015 Jan;33(1):146-56. doi: 10.1002/stem.1845. PMID: 25187512.

(18) Hernigou P, Beaujean F. Treatment of osteonecrosis with autologous bone marrow grafting. Clin Orthop Relat Res. 2002 Dec;(405):14-23. doi: 10.1097/00003086-200212000-00003. PMID: 12461352.

(19) Berger D, Lyons N, Steinmetz, N. In Vitro Evaluation of Injectable, Placental Tissue-Derived Products for Interventional Orthopedics. Interventional Orthopedics Foundation Annual Meeting. Denver, 2015. https://interventionalorthopedics.org/wp-content/uploads/2017/08/AmnioProducts-Poster.pdf

(20) Becktell L, Matuska A, Hon S, Delco M, Cole B, Fortier L. Proteomic analysis and cell viability of nine amnion-derived biologics. Orthopedic Research Society Annual Meeting, New Orleans, 2018. https://app.box.com/s/vcx7uw17gupg9ki06i57lno1tbjmzwaf

(21) Panero, A, Hirahara, A., Andersen, W, Rothenberg J, Fierro, F. Are Amniotic Fluid Products Stem Cell Therapies? A Study of Amniotic Fluid Preparations for Mesenchymal Stem Cells With Bone Marrow Comparison. The American Journal of Sports Medicine, 2019 47(5), 1230–1235. https://doi.org/10.1177/0363546519829034

(22) Berger DR, Centeno CJ, Kisiday JD, McIlwraith CW, Steinmetz NJ. Colony Forming Potential and Protein Composition of Commercial Umbilical Cord Allograft Products in Comparison With Autologous Orthobiologics. Am J Sports Med. 2021 Oct;49(12):3404-3413. doi: 10.1177/03635465211031275. Epub 2021 Aug 16. PMID: 34398643.