Unlocking stem cell potential…
Updated: Feb 15, 2021
Author: Sonali Salvi
Stem cells or progenitor cells are specialised cells that have the ability to either self-renew or differentiate into a particular cell type. The brain has two different kinds of stem cells, one differentiates to form a neuron, hence called a neural stem cell and the other differentiates to give rise to an oligodendrocyte (OL), called oligodendrocyte progenitor cell (OPC).
For the purpose of this article, I would like to focus on OPCs and OLs and to that aim, let me start by narrating a short story.
A long time ago, precisely in 1921, a young scientist named Pio del Rio Hortega, used his newly discovered staining method to make an observation - OLs are responsible for generating myelin, a fatty matrix that surrounds the axons of neurons (1) and is important for a bunch of things. But we shall get to this later. This discovery, as all great discoveries go, did not receive much attention until the 1960s when several scientists using the electron microscope pointed out the functional relationship between OLs, myelin and ensheathed axons (2). Today, scientists all over the world have filled the treasure trove of oligodendroglia knowledge to an extent which allows us to glimpse their potential for regenerative therapy.
The importance of OLs and myelin:
We know for a fact that the myelin ensheathment of axons facilitates conduction of electrical signals generated by a neuron. But how do we know OLs and myelin are important for survival and optimum functioning of the brain? I am rather sure that everyone of us have at least heard of or know someone suffering from a crippling disease named MS, short for Multiple Sclerosis. It is a disease that has made its presence known worldwide, to at least 2.5 million people. It is the death of OLs, the myelin producing cells in the brain, that causes MS. The death of OLs induces a considerable loss of myelin and this in turn leads to death of neurons which causes behavioural deficits, and eventually death of the organism (3). I would also like to point that apart from MS, there are several other diseases/conditions where an organism experiences OL death and loss of myelin (4). Behaviourally, loss of myelin is known to negatively affect motor function and lead to cognitive decline. Interestingly however, recent studies have correlated an increase in the number of OLs to behavioural improvements (5).
Factoring all this in, don’t you think that if there was a way to increase the number of endogenous OPCs and OLs, it just might make the demyelinating diseases more manageable!?
A few years ago, the Calegari lab at Technical University Dresden pioneered a paradigm shift in stem cell research showing that it is possible to lengthen one phase of the cell cycle (G1 phase) by increasing the expression of a specific protein complex (Cdk4/cyclinD1 aka 4D complex) in the neural stem cells. This ultimately triggers expansion of the neural stem cells in vivo, thereby increasing the number of neurons generated in the brain (Fig. A). My masterplan aka PhD project involves applying this knowledge and tools for the first of its kind expansion of endogenous OPCs and OLs in preclinical animal models of MS (Fig. B). This will allow me to investigate whether 4D complex-driven increase in OPC proliferation allows for a quicker recovery, or even rescues the deficits, following demyelination.
Stay tuned for the next chapter!
1. Rio, Pd. Son homologables la glia de escasas radiaciones y la celula de Schwann Trab. Lab. Histol. Patol. 1922 vol. 16 (1922).
2. Bunge, R. P. Glial cells and the central myelin sheath. Physiological reviews vol. 48 197–251 (1968).
3. Dobson, R. & Giovannoni, G. Multiple sclerosis – a review. European Journal of Neurology vol. 26 27–40 (2019).
4. Love, S. Demyelinating diseases. Journal of Clinical Pathology vol. 59 1151–1159 (2006).
5. Steadman, P. E. et al. Disruption of Oligodendrogenesis Impairs Memory Consolidation in Adult Mice. Neuron 105, 150-164.e6 (2020).
6. Lange, C., Huttner, W. B. & Calegari, F. Cdk4/CyclinD1 Overexpression in Neural Stem Cells Shortens G1, Delays Neurogenesis, and Promotes the Generation and Expansion of Basal Progenitors. Cell Stem Cell 5, 320–331 (2009).