Endothelial cells form the lining of all of our body’s blood vessels, from the tiniest capillaries to the largest arteries. When blood vessels are damaged due to trauma, atherosclerosis, or some other reason, our body has to repair them and form new, healthy vessels. Regenerative medicine includes ways to help with this process, and a new study from the University of Illinois at Chicago found a way to persuade pluripotent stem cells to mature into endothelial cells a little faster.
Undifferentiated stem cells, like those that eventually mature into endothelial cells in the lining of blood vessels, rely on carbon as an energy source to grow and build cellular structures. An important source of carbon for stem cells is an amino acid called glutamine. For this reason, the University of Illinois at Chicago College of Medicine focused on the role of glutamine in stem cell differentiation, in a study recently published in Cell Reports.
First, they saw that glutamine metabolism happens very quickly in populations of undifferentiated stem cells. However, when stem cells begin to differentiate into mature cell types, glutamine metabolism drops significantly.
What would happen if we prevented stem cells from metabolizing glutamine? The researchers pondered. They decided to find out. When they withheld glutamine from stem cells, three things happened: levels of a regulatory molecule called OCT4 drastically dropped, levels of reactive oxygen species elevated, and the stem cells began to differentiate.
They found that OCT4, a molecule which is largely in control of whether stem cells differentiate or not, is particularly vulnerable to degradation by reactive oxygen species. When glutamine disappears as a carbon source for stem cells, reactive oxygen species build up in the cell, degrading OCT4. Without OCT4 there to inhibit the genes for differentiation and maturation and to activate the genes for pluripotency, the stem cells were free to differentiate into different cell types, like endothelial cells in the lining of blood vessels.
Withholding glutamine is now a real possibility for adding to the “differentiation cocktails” researchers use to nudge stem cells to mature. Also included in these mixtures are growth factors and other chemicals known to produce a certain cell type. From their research of glutamine withholding, the team from the University of Illinois at Chicago know that twice as many endothelial cells are produced when stem cells don’t have glutamine as a carbon source. Additionally, they saw that the mature cells produced from this process were of a “higher quality” and more efficiently organized themselves into blood vessels.
This new method has limits, though, since high levels of reactive oxygen species can damage cells, a condition commonly called oxidative stress.
“We need to help stem cells adapt to the metabolic environment and demands of the mature organs,” said Dr. Jalees Rehman, leader of the study. Is glutamine the future of regenerative medicine and blood vessel formation? Only time will tell.
Sources: University of Illinois at Chicago
, The Journal of Physiology
, Royal Society of Chemistry
, Molecular Biology of the Cell, 4th Edition