Previous posts from Angela and Michelle will have alerted readers to the importance of where a stem cell resides in the body. The stem cell niche is a complicated environment and one of the most challenging things for blood stem cell biologists to decipher is how “dormant” stem cells manage their energy in such an environment.
Last month, Cell Stem Cell published two articles that begin to offer some insight into the bioenergetics of these rare populations of stem and progenitor cells in the blood system. It has been suggested by several leading groups that the niche where stem cells find themselves has a much lower amount of oxygen available for consumption. Typically, cells will use oxygen to generate energy (e.g.: adenosine tri-phosphate, or ATP) via specialised organelles inside the cells known as mitochondria. Stem cells have been shown to possess fewer mitochondria, leading to the suggestion that they may produce their energy via the other, less productive method of converting sugar into ATP, namely, fermentation.
The first study was a herculean effort of cell isolation and metabolite profiling by Takubo et al., using one million highly purified mouse stem cells to see if the balance between aerobic (oxygen mediated) and anaerobic (non-oxygen mediated) respiration was different in stem cells. Analysis of these profiles showed that, compared to more mature cells in the blood system, the most primitive stem cells produced a metabolite profile highly consistent with stem cells using anaerobic respiration for their energy needs.
The switch to anaerobic respiration might seem strange as it produces less total energy per molecule of sugar; however, aerobic respiration is known to produce reactive oxygen species that lead to DNA-damage. The tolerance to DNA-damage in cells that do not divide often is not completely understood, but the switch to anaerobic respiration could be a good method of protecting the integrity of the genome.
Importantly, the second study shows that the more specialized progeny of stem cells require a switch to aerobic respiration to keep up with the energy demands of differentiation. By blocking aerobic respiration, Yu et al. show that stem cell divisions remain intact, but production of mature blood cells comes to a catastrophic halt. This creates a very interesting paradigm of the different processes operating in stem, progenitor and more mature cells and begs the question of what other metabolic pathways might be altered between these cell types. Understanding these intricacies will potentially allow us to decouple cell division from cell fate choice and identify which components might be altered to help expand stem cell numbers without compromising their productive capacity.
Takubo K., Nagamatsu G., Kobayashi C., Nakamura-Ishizu A., Kobayashi H., Ikeda E., Goda N., Rahimi Y., Johnson R. & Soga T. & (2013). Regulation of Glycolysis by Pdk Functions as a Metabolic Checkpoint for Cell Cycle Quiescence in Hematopoietic Stem Cells, Cell Stem Cell, 12 (1) 49-61. DOI: 10.1016/j.stem.2012.10.011
Yu W.M., Liu X., Shen J., Jovanovic O., Pohl E., Gerson S., Finkel T., Broxmeyer H. & Qu C.K. (2013). Metabolic Regulation by the Mitochondrial Phosphatase PTPMT1 Is Required for Hematopoietic Stem Cell Differentiation, Cell Stem Cell, 12 (1) 62-74. DOI: 10.1016/j.stem.2012.11.022