Discovery and tissue sources
The mesenchymal stem cell was not discovered in a search for a therapy. In the 1960s and 70s the Soviet scientist Alexander Friedenstein noticed that a small, rare fraction of bone-marrow cells would stick to plastic culture dishes, grow into colonies, and, under the right conditions, turn into bone and cartilage. These were plainly not the blood-forming (hematopoietic) stem cells everyone was studying at the time. They were something else: a stromal, connective-tissue-forming population.
Two decades later, Arnold Caplan formalized and popularized the term "mesenchymal stem cell" for this population, framing it as a multipotent progenitor capable of becoming the tissues of the musculoskeletal system: bone, cartilage, tendon, ligament, muscle, marrow stroma, and fat.[1] That framing shaped a generation of research and the entire commercial regenerative-medicine field that followed. The laboratory capacity underlying it was characterized systematically in 1999, when Pittenger and colleagues showed that culture-expanded human marrow cells could be directed into bone, cartilage, or fat lineages under defined conditions.[8]
Since then, cells with the same defining behavior have been isolated from tissues beyond bone marrow: adipose (fat) tissue, umbilical cord (Wharton's jelly), placenta, dental pulp, and synovium, among others. In practical terms, cells meeting this description can be recovered from most connective tissues. Cord-derived cells have drawn particular clinical interest because Wharton's jelly is a young, non-invasively obtained tissue that yields cells with high proliferative capacity and a favorable immune profile.[9] TrueCell's protocols in México use Wharton's jelly umbilical-cord MSCs from screened donor tissue; the cell sourcing article covers donor screening and release testing, and the treatments overview covers how the cells are administered. The physiological role of these cells, and what they can reliably be expected to do once injected, is a more difficult question than the name suggests.
- In one sentence
- A mesenchymal stem cell is a plastic-adherent, self-renewing stromal cell that can differentiate into bone, cartilage, and fat in the laboratory; its main therapeutic action, however, appears to be signaling to other cells rather than replacing them.
The ISCT minimal criteria
Because "MSC" was being applied inconsistently across hundreds of labs, in 2006 the International Society for Cellular Therapy (ISCT) published a set of minimal criteria. They remain the reference standard for what may legitimately be called a mesenchymal stromal cell.[2] There are three:
- Plastic adherence. Under standard culture conditions the cells must adhere to tissue-culture plastic. This was Friedenstein's original observation and now serves as a gatekeeping test.
- A specific surface-marker profile. At least 95% of the population must express CD105, CD73, and CD90, while lacking (≤2%) the hematopoietic and immune markers CD45, CD34, CD14/CD11b, CD79α/CD19, and HLA-DR. This is what separates them from blood and immune cells.
- Trilineage differentiation. The cells must be able to become osteoblasts (bone), adipocytes (fat), and chondroblasts (cartilage) when pushed to in vitro.
It is worth being precise about what this definition does and does not establish. It sets a floor for identity and reproducibility so that two labs mean the same thing by "MSC." It says nothing, on its own, about potency, clinical effect, or which secreted factors a given batch produces. Two preparations can both satisfy the ISCT criteria and still behave quite differently in a patient, a point the field has spent the last decade taking seriously.[10]
The criteria also describe a bulk population rather than a uniform one. Within cultures that meet them, researchers have described rarer subpopulations, including the multilineage-differentiating stress-enduring (Muse) cells, which are reported to survive stress, differentiate across germ layers, and home to injured tissue without forming teratomas in animal models.[11] Work on these subpopulations is early and largely preclinical; the Muse cell article reviews what has and has not been shown.
The paracrine hypothesis
The original hypothesis was straightforward: injected MSCs travel to damaged tissue, engraft, and differentiate into replacement cells, such as new cartilage for a degenerated joint or new neurons for a damaged nerve. For most indications, this is not what the evidence shows.
When researchers tracked labeled cells after injection, they found that the great majority do not durably engraft. Many are cleared within days, and a large fraction of intravenously delivered cells are trapped in the lungs on first pass. Functional benefit is nonetheless observed. This discrepancy reshaped the field's understanding of the mechanism. How much of that first-pass loss applies to a given protocol depends on the cell dose and the route of administration. Where the cells go instead, and how the effect outlives them, is covered in biodistribution and clearance of infused cells.[3] Biodistribution studies place the majority of intravenously infused cells in the pulmonary capillary bed within minutes, with clearance over the following hours to days and only a small fraction reaching other organs.[12]
The cells appear to act less as replacement tissue and more as a transient source of secreted signals that alter the behavior of the cells already present.
This is the paracrine hypothesis: the therapeutic effect is driven mainly by what the cells secrete, not by what they become. That secretome is a complex mixture of growth factors, cytokines, and extracellular vesicles (exosomes) that can dampen inflammation, promote local blood-vessel formation, reduce programmed cell death in stressed tissue, and recruit the body's own resident repair cells.[4] Caplan and Correa described the injected MSC as functioning as an injury drugstore, dispensing site-specific factors in response to the local environment it lands in.[4]
This distinction has direct implications for what a realistic outcome looks like. If the mechanism were cell replacement, one would expect visible tissue regrowth on imaging. If the mechanism is signaling, the expected outcome is a shift in the tissue environment (less inflammation, better function, slower degradation), which is the pattern the better clinical trials report.
Immunomodulatory mechanisms
Perhaps the most clinically consequential property of MSCs is their effect on immunity. In inflamed tissue they release mediators, among them prostaglandin E2, indoleamine 2,3-dioxygenase (IDO), TGF-β, and nitric oxide, that suppress the proliferation of activated T cells, dampen inflammatory macrophages, and shift the local immune response toward tolerance and resolution rather than chronic activation.[5]
Two features make this practically important. First, the effect is conditional: MSCs are largely inert until "licensed" by an inflammatory environment, which is part of why they are generally well tolerated. Second, their own low immunogenicity, meaning modest HLA class II expression and a lack of the co-stimulatory signals that normally trigger rejection, is what makes allogeneic (donor-derived) therapy feasible at all. It is the reason a well-screened umbilical-cord cell line can be given to an unrelated recipient without tissue matching, the model most modern clinics use.
This immunomodulatory capacity is also why MSCs are studied well beyond orthopedics: in graft-versus-host disease, autoimmune conditions, and inflammatory organ injury. The same immunomodulatory rationale underlies the trials in autoimmune neurological disease, including the randomized work in multiple sclerosis, where infusions have been well tolerated but have not yet shown a consistent effect on the primary imaging endpoints. The mechanism under study in an inflamed joint is, in principle, the same one being tested against systemic inflammation.
The nomenclature debate
The most prominent criticism of the terminology comes from the researcher who coined it. In 2017 Arnold Caplan published a paper titled "Mesenchymal Stem Cells: Time to Change the Name!"[6] His argument was that the phrase "stem cell" implies the cells routinely differentiate into replacement tissue in the body, which, as the tracking studies showed, is mostly not how they help. In his view the word oversells the mechanism and fuels marketing claims the science does not support.
Caplan proposed renaming them "medicinal signaling cells," keeping the initials MSC while relocating the emphasis to where the evidence actually points: signaling. The ISCT, for its part, has recommended reserving "mesenchymal stromal cell" (not stem cell) for the bulk, unfractionated populations used clinically, restricting "stem cell" to preparations where genuine stem-cell activity has been demonstrated.[7]
The terminology matters for patients because the name sets the expectation. "Stem cell therapy" invites the belief that damaged tissue will be regrown. The honest, evidence-based expectation is different and more modest: a well-characterized dose of signaling cells can, in the right candidate, meaningfully reduce inflammation and improve function, and in doing so defer surgery and improve quality of life. That is a real benefit, but it is smaller than the label sometimes implies, and a responsible clinic should state this plainly.
If you want to see how this mechanism translates into a specific condition, the companion pieces on arthritis and neuropathy walk through the trial evidence, candidacy, and realistic timelines. For where these cells come from and why cord tissue is favored, see the article on cell sourcing. A rare pluripotent subset of the same population, Muse cells, is reviewed in a separate article. The MSC and Muse protocols TrueCell delivers are listed for Cancún and Tijuana.
Common questions
Where do mesenchymal stem cells actually come from?
Cells meeting the ISCT definition can be isolated from bone marrow, adipose tissue, umbilical cord (Wharton's jelly), placenta, dental pulp, and synovium. Marrow was the original source, and cord tissue is now the most common source in allogeneic clinical protocols because the tissue is obtained non-invasively after a planned delivery and the cells expand well in culture. Preparations from different tissues satisfy the same identity criteria but are not interchangeable, and direct head-to-head clinical comparisons remain limited.
Do these cells turn into new cartilage, nerve, or other tissue?
They can be pushed into bone, cartilage, and fat lineages in the laboratory, which is part of how they are identified. In the body, tracking studies show that most injected cells are cleared within days and do not durably engraft, so measurable benefit is attributed mainly to the factors they secrete rather than to tissue replacement. A realistic expectation is a change in the local inflammatory environment and in function, not visible regrowth of tissue on imaging.
What do mesenchymal stem cells do in the body?
The best-supported answer is signaling. After injection, most MSCs are cleared within days, and their measurable effects, reduced inflammation, altered immune cell behavior, and support for local repair, are attributed to the growth factors, cytokines, and extracellular vesicles they secrete rather than to the cells becoming new tissue. This is the paracrine hypothesis described above, and it is why dosing, cell viability, and delivery route matter more than the word "stem" implies.
Why do researchers argue about what these cells are called?
The term "stem cell" implies routine differentiation into replacement tissue, which is not what the biodistribution and tracking data support for most indications. Arnold Caplan, who popularized the original name, has argued for "medicinal signaling cells," while the ISCT recommends "mesenchymal stromal cell" for the bulk populations used clinically and reserves "stem cell" for preparations where stem-cell activity has been demonstrated. The disagreement is about accuracy of description, not about whether the cells have measurable biological activity.