By Manuel Guzmán
Manuel Guzmán is Professor of Biochemistry and Molecular Biology at Complutense University of Madrid, member of the Spanish Royal Academy of Pharmacy, and member of the Board of Directors of the International Association for Cannabinoid Medicines. His research focuses on the study of the mechanism of action and therapeutic properties of cannabinoids, especially in the nervous system. This work has given rise to more than one hundred publications in specialized international journals, as well as to several international patents on the possible therapeutic applications of cannabinoids as anticancer and neuroprotective drugs. He routinely collaborates with scientific reviewing and funding agencies.
The cells of any living organism are constantly exposed to countless stimuli, to which they respond by adapting how they function. However, few of these "decisions" that our cells make every second (through purely chemical processes and therefore "unconsciously", of course) are actually critical to them.
We say that living beings are born, grow, multiply, age and die. Something similar happens to each of our individual cells: they arise from a progenitor cell, grow and specialise by synthesising their necessary structural and functional components, then divide to give rise to daughter cells, age, and finally die. All these crucial "decisions" of a cell constitute what we know in a broad sense as "cell fate". So what do we know today about whether cannabinoids, through their specific receptors, can control these key processes that constitute "cell fate"?
Let's start at the beginning, i.e. at the earliest embryonic origin of any animal. Experimental data, obtained, among others, by the laboratories of Sudhansu Dey (Cincinnati), Mauro Maccarrone (L'Aquila) and Ekaitz Agirregoitia (Bilbao), show that CB1 and CB2 cannabinoid receptors are expressed in the gametes (egg and sperm), the zygote (the result of the fertilisation of the egg by the sperm) and the morula (a multicellular structure resulting from the first divisions of the zygote). In these cells, cannabinoid receptors could control, for example, gamete functionality as well as zygote division. The next embryonic stage, referred to as the blastula, then appears very early. To get an idea, the embryo is generally considered to have reached this stage when it has at least 64 cells (i.e. the result of 6 divisions of the zygote). Cannabinoid receptors are present in the cells that compose the two essential parts of the blastula: the inner cell mass, which will give rise to the foetus, and the trophoblast, the surface layer which will turn into the placenta. There is evidence that cannabinoid receptors control cell proliferation and survival in the blastula.
The cells in the inner mass of the blastula then generate the next embryonic stage, the gastrula, from which the three essential cell lineages of the future organism will emerge: the endoderm (generated from the innermost layer of the gastrula), the mesoderm (from the middle layer) and the ectoderm (from the outermost layer of the gastrula). This is the result of the cell differentiation process, whereby the unspecialised stem cells of the morula acquire specific structural and functional alterations that allow them to mature and thus become specialised. We know that cannabinoid receptor levels increase significantly during the formation of the gastrula and that these receptors control the development, differentiation and survival of at least some of its cells. In particular, there is evidence to support that cannabinoid receptors are involved in the formation of endodermal cells such as hepatocytes (liver cells); mesodermal cells such as leukocytes (white blood cells), adipocytes (fat cells) and osteocytes (bone cells); and ectodermal cells, such as keratinocytes (skin cells) and, most importantly, neurons and other cells of the nervous system.
The latter is the best known case of all, and the one for which there is the most robust experimental evidence, the result of the work of laboratories such as those of Tibor Harkany (Stockholm), Pat Doherty (London) and Ismael Galve-Roperh (Madrid), among others. Thus, cannabinoid receptors, especially CB1, regulate the process of proliferation of the cells originating from a specialised sub-region of the ectoderm, called the neuroectoderm, which will later generate the different structures that comprise the nervous tissue. The CB1 receptor also facilitates the differentiation and specialisation of these progenitor nerve cells into the main cell types that will later comprise the mature nervous system: neurons, astrocytes and oligodendrocytes. The CB1 receptor is also involved in the final maturation of neurons by controlling the process of extension of the axon (the main 'branch' of the neuron) and of dendrites (the 'small branches' of the neuron), as well as the establishment of the functional connections between neurons (synapses). This eventually allows neurons to communicate with their neighbouring cells (other neurons as well as astrocytes and oligodendrocytes) and thus establish the highly complex structural and functional framework that enables the coordinated functioning of an adult brain.
It should also be noted that in some animal species, albeit to a very limited extent in humans, a small number of neural stem cells remain in the adult brain, allowing the generation of new neurons to repair damaged nerve tissue or reorganise memory circuits. In fact, CB1 receptors also appear to regulate the proliferation, differentiation and maturation of these adult brain stem cells. Finally, studies performed in Guillermo Velasco's laboratory (Madrid) have also shown that the main cancer cells originating in the adult nervous system, which give rise to highly malignant tumours known as glioblastomas, express CB1 and CB2 receptors that control the proliferation, differentiation and survival of these cells.
Intriguingly, all these effects of cannabinoids on "cell fate" are highly dependent on a particular situation or context. For example, cannabinoids can produce proliferative and cell survival effects at low doses, while at high doses they often block proliferation and even cause cell death. It is also known that, at a certain dose, cannabinoids can kill tumour cells, while simultaneously protecting non-tumour cells against lethal stimuli. Moreover, while exposing a cell to a given dose of a cannabinoid for a short period of time may exert a particular effect, over longer periods cells become desensitised or tolerant to the cannabinoid, and the effect may therefore disappear. There is also evidence that, depending on the dose, cannabinoid receptors may interact differently with other receptors located on the cell's plasma membrane, which in turn may induce different responses from the cell. In other words, the expression "I am myself and my circumstances", coined by Spanish philosopher Ortega y Gasset, seems to apply not only to each of us as individuals, but also to each of the cells of which we are composed.
In conclusion, evidence from several scientific studies supports the idea that cannabinoids, through their receptors, can control "cell fate" at the prenatal, postnatal and adult stages of an animal's development. The most robust evidence comes specifically from research on the cells of the nervous system, especially neurons and their various progenitor and neighbouring cells. Many of these effects of cannabinoids are highly dependent on cellular context. Finally, it should be noted that, as with so many other aspects of cannabinoid and pathophysiology research, the vast majority of the findings summarised here about how cannabinoids affect "cell fate" come from experiments on mice and other small laboratory animals, so their possible application to humans remains unknown.
