Mesenchymal stem cells (MSCs) are multipurpose cells found throughout the body that can develop into bone, cartilage, and fat cells. They also act as coordinators of tissue repair and immune regulation, making them one of the most studied cell types in regenerative medicine, with over 1,100 clinical trials registered as of late 2024.
How MSCs Are Defined
In 2006, the International Society for Cell and Gene Therapy established three minimum criteria a cell must meet to qualify as a mesenchymal stem cell. First, the cells must stick to plastic surfaces when grown in a lab, forming elongated, fiber-like shapes. Second, they must display a specific set of surface markers, small proteins on the cell’s outer membrane that act like identity tags. MSCs carry the markers CD73, CD90, and CD105 while lacking markers associated with blood-forming cells like CD34 and CD45. Third, when given the right chemical signals, they must be able to transform into at least three cell types: bone cells, cartilage cells, and fat cells. This “tri-lineage differentiation” is the hallmark test for confirming a cell population is truly mesenchymal.
Where MSCs Come From
MSCs have been isolated from nearly every tissue in the body, including bone marrow, fat, teeth, tendons, the liver, and even heart tissue. The two most commonly used sources in research and clinical work are bone marrow and adipose (fat) tissue. Bone marrow was the original source and remains the reference standard, but fat tissue yields MSCs in much larger quantities from a simpler collection procedure.
Neonatal tissues offer a third major source. Umbilical cord tissue and amniotic fluid both contain MSCs that are younger and more proliferative than adult-derived cells. Umbilical cord MSCs have a particular advantage for large-scale production and standardization, which matters when the goal is manufacturing consistent doses for hundreds of patients in a clinical trial.
What MSCs Can Become
The defining capability of MSCs is their ability to differentiate into bone-forming cells (osteocytes), cartilage cells (chondrocytes), and fat cells (adipocytes). This has been confirmed across multiple species, not just humans. In laboratory studies, MSCs from cattle, horses, and pigs all reliably transform into these three lineages when exposed to the appropriate growth conditions.
Under more specialized conditions, researchers have also coaxed MSCs toward other fates, including muscle cells, tendon cells, and cells resembling those found in skin. But the three core lineages remain the gold standard for identifying and validating MSC populations.
How MSCs Actually Help: Signaling Over Replacement
Early thinking assumed MSCs would work by physically replacing damaged cells. You inject them into a worn-out knee, and they become new cartilage. That does happen to a limited degree, but the larger story turns out to be more interesting. The primary therapeutic benefit of MSCs comes from what they secrete rather than what they become.
MSCs release a complex mix of signaling molecules, growth factors, and tiny membrane-bound packages called extracellular vesicles. These vesicles carry proteins and genetic instructions that influence surrounding cells. They can stimulate blood vessel formation, encourage local stem cells to multiply and differentiate, reduce inflammation, and limit scarring. In wound healing studies, extracellular vesicles derived from MSCs promoted skin cell growth, nerve regeneration, and new blood vessel development, sometimes more effectively than the MSCs themselves.
This discovery has shifted the field. Some researchers now focus on harvesting just the vesicles and secreted factors from MSCs, bypassing the need to transplant living cells entirely. This approach could reduce the risks associated with live-cell therapies while preserving the benefits.
Immune System Effects
One of the most valuable properties of MSCs is their ability to calm an overactive immune system. They do this through several mechanisms. MSCs display surface proteins that essentially tell attacking T-cells to stand down, halting their multiplication. They also release prostaglandin E2, a signaling molecule that converts inflammatory immune cells (M1 macrophages) into a repair-oriented state (M2 macrophages). On top of that, MSCs can prevent the premature death of neutrophils, a type of white blood cell, helping to protect tissues from collateral damage during inflammation.
This immunomodulatory profile is why MSCs are being tested for autoimmune and inflammatory conditions. Umbilical cord MSCs have shown potential in treating refractory lupus, while adipose-derived MSCs have reached the most advanced regulatory stage for Crohn’s disease among inflammatory bowel conditions.
Clinical Applications Being Tested
Osteoarthritis is one of the most active areas of MSC research. In a clinical trial using bone marrow MSCs transplanted into the knee, biopsies taken 42 weeks later showed tissue that resembled healthy hyaline cartilage, the smooth, glassy type that normally lines joints. A separate dose-escalation trial using fat-derived MSCs for severe knee osteoarthritis reported significant pain relief and improved function at six months with no serious adverse effects. A meta-analysis covering 36 randomized controlled trials and over 2,000 participants found consistent improvements in pain scores and functional outcomes across different MSC sources.
Beyond joints, MSCs are being studied in graft-versus-host disease (a dangerous complication of bone marrow transplants), liver failure, multiple sclerosis, and chronic kidney disease. In the United States, one MSC product, Ryoncil (remestemcel-L), developed by Mesoblast, appears on the FDA’s list of approved cellular therapy products.
Safety Profile
MSC therapies have a generally favorable safety record, but they are not without risks. The most commonly reported adverse events across clinical trials are blood clots (thromboembolism) and tissue fibrosis, where healthy tissue is gradually replaced by scar tissue. Fever is the most frequent side effect, occurring in roughly 10 to 22 percent of patients depending on the condition being treated and the MSC source used. In one study of progressive multiple sclerosis treated with bone marrow MSCs, fever occurred in 85 percent of patients.
For joint injections specifically, the most common complaint is mild swelling and increased pain at the injection site lasting 48 to 72 hours. In a large multicenter study of 2,372 patients receiving MSC injections for degenerative joint disease, serious events were rare. Seven cases of tumors were reported (0.3 percent of participants), though the study authors found no clear link between the tumors and the cell therapy. Serious neurological and vascular events each occurred in roughly 0.2 percent of patients.
The Consistency Problem
The biggest scientific hurdle facing MSC therapy is variability. MSCs from different donors, different tissues, and even different batches from the same donor can behave differently. A study examining 13 MSC samples from 10 healthy donors found measurable differences in gene expression driven by the donor’s individual biology. Factors like age, sex, health status, and genetic background all influence how well a given batch of MSCs proliferates, differentiates, and secretes therapeutic molecules.
This heterogeneity creates a practical problem: two patients receiving what appears to be the same treatment may get functionally different cell products. It also complicates clinical trials, where inconsistent results may reflect inconsistent starting material rather than a true failure of the therapy. Standardizing MSC production, possibly by favoring more uniform sources like umbilical cord tissue, is considered essential for moving the field from promising research into reliable, reproducible treatments.