Alexander Friedenstein showed that the fibroblastic cells he described in bone marrow in 1966 (see The what, when and why of mesenchymal stromal cells) form robust colonies on cell culture surfaces (Friedenstein et al. 1970). Five years later, we find for the first time the term mesenchymal stem cells to describe these cells based on their apparent ability to differentiate into several cell types (Collet & Des Biens 1975).
In the following decade, research groups described mechanisms of MSC differentiation (Sparks & Scott 1986) and clarified their interaction with hematopoietic components of marrow. Yet, it wasn’t until the 90’s that work by Arnold Caplan boosted the visibility of MSCs as therapeutic tools (Caplan 1991).
Pushing therapeutic power
Initially, Caplan’s research explored #orthopedic applications of MSCs based on their copious secretion of extracellular matrix, which led to the founding of Osiris Therapeutics, perhaps the first MSC company.
On the heels of this commercial launch came the elucidation of other important MSC features – support of hematopoiesis (Majumdar et al. 2000), evidence of T-cell activity suppression (Klyushnenkova et al. 2005), and a definitive publication on their multilineage potential (Pittenger et al. 1999). MSCs were used for heart muscle therapy (Toma et al. 2002), cartilage fibrin regeneration, revascularization and more, often with promising results in pre-clinical models.
The stem cell race tears a chasm
This growth in knowledge set the stage for a race to find “the best stem cell” with superiority claimed for candidates from various tissues.
In the midst of this competition emerged a rather fascinating intellectual divide around MSCs. The original concept of their therapeutic potential was that when introduced into diseased tissue, they differentiate according to local stimuli and replace diseased cells. This “spare parts” thinking was perhaps informed by a seemingly obvious connection in early orthopedic work: injected MSCs appear to rebuild menisci and rescue knees (Murphy et al. 2003).
Subsequent probing, however, revealed that implanted cells were sometimes present only temporarily at the implantation site and that MSCs secrete copious quantities of bioactive factors with sometimes well-understood regenerative properties. Thus, MSCs may now be viewed as transient, localized pharmaceutical factories.
A new paradigm for MSC therapies
These findings have shifted therapeutic strategies with MSCs away from claims of stemness and towards their use as chaperones that secrete bioactive factors to initiate regenerative mechanisms. This rationale goes a long way in buttressing the description of MSCs as active pharmaceutical ingredients, the core of every drug development program.
Christian van den Bos