First generation stem cell therapies, such as forms of mesenchymal stem cell therapy, have underperformed in comparison to the original hopes for the scope of benefits to patients. Treatments fairly reliably reduce chronic inflammation in aged or lastingly injured individuals, but boosted regenerative capacity and functional improvement are uncommon, unreliable, and unpredictable. Effects vary widely from individual to individual and clinic to clinic.
One view on why this is the case is that not enough has been done to make the injected cells optimally effective. Even minor differences in protocol when culturing stem cells can produce widely divergent outcomes, such as quite different degrees of cellular senescence, or other cell behaviors. Thus therapies might be meaningfully improved by, for example, using senolytic strategies to clear senescent cells from stem cell cultures. Further, it is possible work towards triggering specific beneficial cell behaviors prior to injection via the use of signal molecules. Not enough work has yet taken place to truly judge whether or not this view is correct, but it seems plausible that there is scope for improvement.
It is almost impossible to catalogue all of the therapeutic investigations conducted and ongoing using mesenchymal stem cells (MSCs). However, the excitement in this burgeoning field has been somewhat dampened by some less than stellar clinical trial results and persistent variability of effect due to production practicalities and correlative, rather than causative, potency assays.
During these studies an immense amount of data has been generated regarding stem cell biology and possible mechanism of action in diseases, including the physiological niche where various stem cells are sourced, cell-cell contact-dependent mechanisms and a rich secretome containing small molecules, proteins, organelles and even full membrane bound bodies. Indeed, much of this data has been accumulated regardless of whether the overall subsequent clinical trials themselves were successful. These have prompted a multitude of strategies that could putatively be included in the cell manufacturing process to improve outcomes in patients.
In this review we will look at current and future strategies that might overcome limitations in efficacy. Many of these take their inspiration from stem cell niche and the mechanism of MSC action in response to the injury microenvironment, or from previous gene therapy work which can now benefit from the added longevity and targeting ability of a live cell vector. We will also explore the nascent field of extracellular vesicle therapy and how we are already seeing enhancement protocols for this exciting new drug. These enhanced MSCs will lead the way in more difficult to treat diseases and restore potency where donors or manufacturing practicalities lead to diminished MSC effect.