Stem cell research has generated countless waves of enthusiasm and controversy throughout the decades. Now and then news emerges of promising new stem cell techniques, only to be followed by negative or mediocre clinical results. Potential applications have included treating heart disease, eye lesions, diabetes, stroke, spinal cord injury, dementia, neurological degeneration and cancer, but to this day only bone marrow transplants have proved feasible.
The technical problems are manifold, ranging from extraction, culturing and implantation challenges, to safety issues and donor rejection. Perhaps the most prohibitive aspect of all is the deep lack of understanding of how stem cells are actually regulated.
This problem is well illustrated by the surprising finding that endocannabinoids could very well play a decisive role in cell maturation and differentiation.
Two recent preclinical studies (2014, 2016) concluded that cannabidiol (CBD) strongly regulates the proliferation, migration and neurogenesis of mesenchymal stem cells (MCSs). These adult stem cells are able to differentiate into the main types of precursor cells and have demonstrated anti-inflammatory, immune, metabolic and self-renewal properties. As of now, there are over 500 ongoing or concluded clinical trials based on MSCs.
At the turn of the century, researchers found MSCs present in the mouth cavity. Besides being easier to collect, these cells also showed some stronger properties compared to MSCs from other tissues. In light of this knowledge, Dr. Emanuela Mazzon and colleagues became interested in finding out whether oral MCSs were also responsive to CBD.
MCSs were collected from the gums of five healthy patients and incubated with CBD for 24 hours. Analysis of cell proliferation and viability revealed that an optimal concentration of CBD was set at 5 μM, with higher dosages being increasingly toxic.
The researchers then analyzed changes in the genetic expression of cells treated with 5 μM CBD, compared to controls. The analysis showed that almost 6000 genes had been modulated by CBD, with a near 50/50 split in terms of being over-activated or inhibited.
Interestingly, several of the genes with altered expression are known to be involved in neurodevelopmental processes, including the proliferation of cells that precede new neurons, neurogenesis itself, and more coarse regulation of the nervous system. On the other hand, several of the inhibited genes are associated with the formation of other types of cells such as glial cells, bone tissues and blood vessels.
To test the ability of CBD to promote the differentiation of MSCs into neuronal precursor cells, the authors labeled the latter with a colorful marker and proceeded to quantify them. As can be observed in the figure below, CBD was strongly associated with an increase in neural precursor cells after 2 and 4 days of incubation, compared to the control (DMSO). The relative decrease from the 4th day is explained by the further differentiation of those cells into fully fledged neurons.
In sum, these results suggest a strong regulatory role of CBD in the differentiation of stem cells into neurons. Further in vivo studies are required to assess the therapeutic potential of combining MSCs with CBD in animal models of neuronal diseases.
The original study by Dr. Mazzon and colleagues can be found in the Journal of Cellular Biochemistry.
Featured image via Виталий Смолыгин.