Mixed Cells, Not Stem Cells

Two words, ‘Stem Cells’, are a kind of Rorschach’s test for patients, physicians and researchers.

Patients see visions of near-magical healing. Physicians see packed waiting rooms and researchers see rising impact factors. (Or two bears dancing.)

These different understandings and, therefore, expectations have given the words—stem cells—exceptional economic power and (misplaced) authority.

‘Stem Cell’ Clinics at a Strip Mall Near You

Two years ago, Leigh Turner, Ph.D. (an investigator with the Center for Bioethics at the School of Public Health in the University of Minnesota) and Paul Knoepfer, Ph.D. (with the Institute of Pediatric Regenerative Medicine at Shriner’s Hospital for Children and a member of the Department of Cell Biology at the University of California, Davis campus) counted the number of stem cell clinics in the United States.

Turner and Knoepfer found 351 U.S. businesses engaging in direct-to-consumer marketing of stem cell interventions at 570 clinics. Six states were hotspots for stem cell clinics—California (113 clinics), Florida (104 clinics), Texas (71), Colorado (37), Arizona (36) and New York (21).

After doing our own Google search, we’d guess that the number of such clinics have probably doubled since Turner and Knoepfer published their study in 2016.

What Are So-Called ‘Stem Cells’ Supposed to Do?

If these clinics are to be believed (and the FDA’s warning letter from August 2017 would suggest the majority are full of BS), the ‘stem cells’ they inject in patients will:

• Relieve pain and improve function in arthritic large joints
• Relieve soft tissue inflammation
• Grow bone
• Treat spinal cord injuries
• Treat immunological conditions
• Ameliorate cardiac disease and pulmonary disorders
• Treat ophthalmologic disease and injury
• Relieve urological disorders
• Treat Alzheimer’s
• Treat essential tremor diseases
• Address necrotic bone
• Provide a facelift
• Augment breasts
• Enhance sex

To be blunt, marketing has gotten way ahead of the science.

Mixed Cell Therapies, not Stem Cell Therapies

As defined by the NIH[i][National Institutes of Health] “Stem cells differ from other kinds of cells in the body. All stem cells have three general properties: they are capable of dividing and renewing themselves for long periods; they are unspecialized; and they can give rise to specialized cell types.”

Constance R. Chu, M.d., Professor of Orthopedic Surgery at Stanford University observes that PRP (platelet rich plasma) and other concentrated and minimally manipulated blood, bone marrow, adipose or amniotic tissue products are principally uncharacterized biologic materials of variable composition where the cell populations, if present, are mixed.

To quote the American Academy of Orthopaedic Surgenons (AAOS)/NIH U13 consensus statement recently published in the Journal of the American Academy of Orthopaedic Surgeons which described these mixed cell concentrations and therapiesⁱⁱ: “Stem and progenitor cells are the least abundant cell type in these preparations. Depending on the tissue of origin, only one in one thousand to one in one million cells harvested from healthy tissues are stem or progenitor cells that are capable of differentiating into one or more connective tissues such as bone, cartilage, and fat.²”

The Appeal of Mixed Cell Therapies

What makes minimally manipulated autologous cell therapies so appealing is that they are readily available. Furthermore, for specific indications and using very precise techniques, researchers are finding evidence of anti-inflammatory benefits.

One 2017, level 1, randomized control study of 111 patients with painful knee osteoarthritis (OA) found that a mixed cell therapy of leukocyte-poor platelet rich plasma (PRP) injections tamped down OA inflammation.

The level 1 study compared PRP to hyaluronic acid injections.

The investigators, led by Brian J. Cole[1], Vasilli Karas[2]and Kristen Hussy[3]reported that while there was no difference between HA and PRP at any time point in terms of the primary outcome measure—the patient-reported WOMAC pain score—there were significant improvements in other patient-reported outcome measures, with results favoring PRP over HA.

The investigators specifically measured a decrease in two proinflammatory cytokines, which suggest that the anti-inflammatory properties of PRP may contribute to an improvement of symptoms.

Other studies using leukocyte-rich platelet plasma also reported measurable anti-inflammatory effects in knee OA patients.

Leukocyte-poor or leukocyte-rich?

AAOS Jumps In

In February 2018, key academic and clinical thought leaders convened at Stanford University to tackle the toughest issues swirling around these biologic therapies. The two-day event supported by AAOS and Stanford Orthopedic Surgery was awarded an NIH U13 grant. Symposium Chair Dr. Constance R. Chu explains that “we brought together full-time clinicians with stem cell and clinical trials scientists, as well as government leaders in regulatory and funding agencies into an engaged and cohesive work group to provide consensus recommendations concerning the use of biologics to treat musculoskeletal conditions.”

From February 15 – 17, 2018, symposium participants confronted the biggest issues in commercializing biologic therapies.

For example, regarding “stem-cell” marketing and PRP-type therapies they wrote:

“The use of centrifuge-like devices and other mechanical methods to prepare minimally manipulated autologous cell preparations has been extended to fat, placenta, and many other tissues. These uncharacterized cell products have been marketed as stem cells and used to treat a long list of clinical conditions ranging from hair loss to retinopathy and, most commonly, orthopaedic applications.”

“The high prevalence of painful and disabling orthopaedic conditions such as knee OA [osteoarthritis] has also resulted in an exponential increase in the marketing of unproven biologics to relieve chronic pain.”

“Concerns over misinformation from direct-to-consumer marketing of unproven treatments have led to recent calls to action from professional organizations including the National Academy of Sciences, the International Society for Cellular Therapy (ISCT), the American Association for the Advancement of Science, and the AAOS.”

The symposium’s resulting paper; “Optimizing Clinical Use of Biologics in Orthopaedic Surgery” is available here:

Authors and symposium participants were academic and private practitioners, basic and clinical scientists from academia, patients, representatives from the AAOS, the National Institutes of Health (NIH), the American Orthopaedic Society for Sports Medicine, the Arthroscopy Association of North America, the International Cartilage Regeneration and Joint Preservation Society, young investigator selected through a competitive process and keynote speakers from the National Institutes of Standards and Technology, the Stanford Center for Innovative Study Design, and the FDA.

Rules of the Road for Mixed Cell Therapies

At the end of the two-day meeting which included a patient panel, the experts called for universal nomenclature standards for cellular therapies and biologics, standards for measuring and reporting the composition of these therapies and their clinical outcomes and establishing registries and clinical trial networks to accelerate rigorous assessment and optimization of regenerative therapies for musculoskeletal diseases.

Specifically:

• “The use of the term stem cells to describe minimally manipulated cell preparations is problematic and has created substantial confusion for patients, physicians, and the general public.”
  • Therefore: Refer to minimally manipulated cell products and tissue derived culture-expanded cells as “cell therapy” not ‘stem cell’ therapy.
  • And: Inform patients that these therapies are largely untested and uncharacterized.
• “Unlike conventional pharmaceuticals where a known concentration of a bioactive substance is administered to achieve a targeted biological effect, most biologics are complex mixtures of variable composition that are not easily assayed.” Blood products such as PRP and minimally manipulated autologous cell preparations lack consistent standards and the biological status of the donor and the preparation methods vary widely.
  • Therefore: Minimum information for studies reporting biologics (MIBO) checklists be used as a guide for study design and reporting (see link above for the checklist details).
  • And: For PRP and cell-based therapies, the MIBO should include specific items which were also listed in the symposium report (link above).
• “Address the variability in outcomes by identifying the biologic targets (e.g., cell proliferation, anti-inflammatory, antifibrotic effect) for PRP. This is needed to more precisely choose the optimal PRP formulation to focus treatment for each specific tissue and to ultimately reduce this variability. As an example, for rotator cuff tendon repair, the primary targets are considered to be provision of signaling molecules that drive cellular differentiation to reform the organized structure of the enthesis.

Absence of Evidence Isn’t Necessarily Evidence of Absence

There wouldn’t be substantial patient demand for biologic treatment of painful knees, shoulders, feet and other inflamed articulating sections of the musculoskeletal system if cell-based biologic therapies didn’t work on some level.

So, to paraphrase an old saying, absence of evidence isn’t necessarily evidence of absence.

Dr. Chu emphasizes that: “All of us are excited about the potential benefits of stem cells to treating some of our toughest clinical problems such as knee osteoarthritis and to potentially regenerate damaged and aging tissues. Our goals were to provide a consensus framework for delivering evidence-based care—so that patients are informed and protected from unproven treatments and that clinical practice be conducted in a way that does not compromise the development and introduction of well characterized new cell therapies in the future.”

This excellent symposium, in effect, showed how to bridge the gap between cell therapy evidence and marketing.

It delivered a clear impact agenda for improving the way we speak about these therapies, the way we clinically evaluate them and how we get to a place where physicians can use and optimize biologics in orthopedics—reliably and safely.

Kudos to all the symposium participants including, notably, Fei Wang, Ph.D. from the NIH and Erin Ransford AAOS Manager of Research Advocacy.

Here is the link to the symposium agenda.

The symposium’s consensus statement authors and/or editors were:

[1]Department of Orthopaedics, Rush University Medical School

[2]Department of Orthopaedic Surgery, Duke University Medical School

[3]Department of Orthopaedics, Rush University Medical School

ⁱChu CR, Rodeo S, Bhutani N, et al: “Optimizing Clinical Use of Biologics in Orthopaedic Surgery: Consensus Recommendations from the 2018 AAOS/NIH U-13 Conference

ⁱⁱStem Cell Basics I  Accessed July 17, 2018