Researchers at the University of California San Diego (UCSD) have found that two of the most frequently administered stem cell therapies, which are often used interchangeably, actually contain completely different types of cells. For their studies the team analyzed cell populations of autologous bone marrow aspirate concentrate (BMAC) and adipose-derived stromal vascular fraction (ADSVF) collected from the same subjects. Their results, they suggest, challenge the current “one-cell-cures-all” paradigm in orthopedic stem cell therapeutics and highlight the need for more informed and rigorous characterization of injectable stem cell therapies before they are marketed for use in patients.
First author Severin Ruoss, PhD, and colleagues reported on their findings in Science Advances, in a paper titled “Comparative single-cell transcriptional and proteomic atlas of clinical-grade injectable mesenchymal source tissues.” The investigators have made their datasets available through an interactive web tool.
Bone marrow aspirate concentrate (BMAC) and adipose-derived stromal vascular fraction (ADSVF) are the most marketed stem cell therapies to treat a variety of conditions in the general population and elite athletes,” the team wrote. These two therapies have many similarities: both are injectable therapies derived from a patient’s own cells—bone marrow in BMAC and adipose tissue (fat) in ADSVF—and they are both thought to contain mesenchymal stem/stromal cells (MSCs), cells that can differentiate into muscle, bone and other connective tissues.
Because of their similarities, the two therapies are frequently marketed as interchangeable “stem cell therapies” and are used to treat a range of musculoskeletal and skin conditions, particularly in professional athletes. However, little research to date has attempted to characterize the composition and underlying biology of these two therapies.
So, while the global stem cell market was valued at $11.9 billion in 2021, the authors continued, a lack of information has prevented rigorous clinical investigations into the ideal dosages for these therapies and, according to the researchers, has “… facilitated anecdata and misinformation.”
They noted “The mesenchymal stromal cell (MSC) has been proposed as the key active ingredient of both BMAC and ADSVF cell preparations and has been, maybe misleadingly, marketed as a ‘stem cell’ … Both tissues have been used interchangeably clinically even though their detailed composition, heterogeneity, and mechanisms of action have neither been rigorously inventoried nor compared.” Knowing this information, they suggested, would allow scientists and clinicians to have some reference standards to start characterizing samples on the basis of ingredients that they think are important. “… detailed analysis and clarification of cell and protein doses in these widely used injectables are urgent and critical to advance and to justify precision regenerative medicine and to combat current anecdata and misinformation.”
To help fill this gap in knowledge the researchers analyzed 62 BMAC cell populations and 57 ADSVF populations derived from the same individuals, to create a cellular atlas that details what types of cells are present in each therapy, what genes are active in these cells, and what proteins are present. “… we analyzed single-cell transcriptomes, proteomes, and flow cytometry profiles from paired clinical-grade BMAC and ADSVF,” they explained.
Their resulting single-cell transcriptional and proteomic atlas revealed that MSC concentrations in BMAC formulations were extremely low, and that overall, there were no comparable “stem cell” types in both therapies. In fact, the two treatments had very different compositions; BMAC was composed mainly of red and white blood cells, and ADSVF was composed mainly of connective tissue cells. Their data, they pointed out, “… suggest that cell preparations derived from the most popular mesenchymal depots, BMAC and ADSVF, are predominantly a T cell/monocyte/erythroblast and a fibroblastic/endothelial cell injection, respectively.”
In addition, many proteins associated with regenerative function were either absent or found in extremely low concentrations in both therapies, calling their mechanisms of action and overall efficacy into question. The results did provide data of surface markers that the team suggested may enable isolation and investigation of cell (sub)populations. “Furthermore, the proteome atlas highlights inter-tissue and interpatient heterogeneity of injected proteins with potentially regenerative or immunomodulatory capacities.”
In addition to providing a rich resource for researchers, the findings suggest that the active ingredients in biologic therapies like BMAC and ADSVF need to be defined more thoroughly. They also suggest that the field as a whole should move toward more standardized cell therapies, in which clinically necessary doses of the cell and protein concentrations have been carefully quantified.
As the authors stated in their report, “… there are no transcriptionally comparable stem cells present in both clinically prepared injectates, nor do they appear to be related to culture-expanded MSCs, meaning that new guidelines and clinical gold standards are needed to define and quantify clinical-grade MSCs, ASCs, and other potentially therapeutic cells … more human data are needed to establish in vivo function upon injection and to elucidate which patient population or tissue state would benefit from transplantation.”
The datasets analyzed can interactively be explored via a web tool at muscle.ucsd.edu/BMACandADSVF.
