Is an MSC a stem cell or a signaling cell?

Over the past few decades, stem cells have become synonymous with regenerative medicine. Stem cells are unspecialized cells that have the capacity for self-renewal and the ability to specialize into different adult cell types. With the dawn of stem cell therapies has come many misconceptions; the most prevalent misconception is that stem cell therapies involve embryonic stem cells. In fact, the majority of stem cell therapies are derived from adult stem cells that are harvested from the bone marrow or fat of adults. These treatments were initially based on the underlying principle that infused stem cells congregate at injured tissue sites, differentiate into the injured tissue type, and replace the injured tissue with new, healthy tissue.

Mesenchymal stem cells (MSCs)1 are an adult stem cell type that feature heavily in cell therapies. They are a multipotent cell that can specialize into mesenchymal tissue types (e.g. bone, cartilage, fat). When MSCs were discovered, they were branded as ‘stem cells’ because they exhibited in vitro multipotency capabilities. This discovery made them an attractive therapy option for clinicians. Since then, hundreds of cell therapy studies have been performed with living MSCs infusions. This paradigm has fueled the way regenerative medicine has designed and developed stem cell therapies for over a decade1.

But do MSCs work the way we originally thought?

The latest research suggests not. The original concept, that MSCs provided therapeutic benefit through differentiation, was based on their behavior in vitro. As more research has been done on MSC behavior in the body, a new paradigm is emerging. In recent years studies have found that MSCs actually function as pericytes or, put another way, cells that wrap around our blood vessels. This is corroborated by the fact that MSCs are readily found in the perivascular space of the tissues from which they are sourced. Additionally, the potency of MSCs does not come from their ability to differentiate into new cell types to create new tissue. Rather, their functionality stems from their signaling capabilities. MSCs, in fact, act in a localized manner, releasing cellular signals in the form of cytokines and growth factors. These signals biochemically target local cells and aid the body through the healing process. In short, MSC potency comes from their ability to signal repair in a patient’s own tissue1,2, rather than an ability to differentiate into various tissue types. A recent study demonstrated this by loading MSCs onto a scaffold and freeze-drying it, effectively rendering the cells non-viable, and then placing that scaffold/MSC construct into a cellular culture. The study found that these devitalized MSCs continued to release bioactive signals and were still able to influence the behavior of other cells3! Studies have found that MSC components retain a similar level of biochemical signaling as live MSCs3. This evidence is compelling and significant. It means that MSCs are not really functioning as traditional stem cells1, but rather as transducers of cellular signals. But that does not make them any less important for their therapeutic potential.


This sentiment was shared by the discoverer of MSCs, Arnold Caplan1. As more research has emerged since his discovery over 25 years ago, he has begun to lobby for a change in name for MSCs. He asserts that we must drop the ‘stem cell’ part of the name and change the MSC nomenclature to instead stand for ‘Medicinal Signaling Cells’1.

By changing our terminology, we can begin to change the way we think about MSCs and their therapeutic potential. Understanding and accepting the mechanism by which MSCs really function in the body allows us new possibilities for harnessing their capabilities. The possibility of being able to leverage MSCs, perhaps without the complicated and expensive process of live cell collection and infusion, creates a multitude of possibilities for new advancement in cell therapies and regenerative medicine. Thinking of MSCs as signaling cells paves the way for new, diverse, and exciting improvements in regenerative treatment options.

Historically, cellular therapies have looked to harness the differentiation potential of transplanted cells rather than the specific cellular components and signals the cells provide to the patient. But, the signaling components are the critical players in the mechanism by which MSCs provide a medicinal benefit to patients2. As regenerative medicine shifts from considering MSC therapy as a ‘stem cell therapy’ to considering it a ‘signaling therapy’, more treatment options will be available that can deliver the special mix of crucial signals provided by these cells. The future of cell therapies will shift to delivering defined cellular signals and molecular components, rather than just focusing on the cell types themselves. Regenerative medicine is on the verge of a new wave of treatment options that promise the delivery of known and characterized cellular components and molecular signals, like cytokines and growth factors, which can stimulate repair and aid in healing.