Low Rate of Protein Synthesis in Stem Cells Critical to Their Function

For the first time, protein synthesis has been studied in somatic stem cells. It turns out that in hematopoietic stem cells (HSCs), low rates of protein synthesis may be essential for maintaining metabolic homeostasis. This result, the work of scientists centered at UT Southwestern Medical Center, could lead to insights about all kinds of cells, not just stem cells. That is, rates of protein synthesis could be determined for various kinds of cells, and comparisons of these rates could serve as indicators of cellular function and health, even longevity.

According to Dr. Sean Morrison, director of the Children's Research Institute, Professor of Pediatrics, and the Mary McDermott Cook Chair in Pediatric Genetics at UT Southwestern Medical Center, “This finding not only tells us something new about stem cell regulation, but opens up the ability to study differences in protein synthesis between many kinds of cells in the body. We believe there is an undiscovered world of biology that allows different kinds of cells to synthesize protein at different rates and in different ways, and that those differences are important for cellular survival.”

Dr. Morrison and his colleagues published their work March 9 in Nature, in an article entitled “Haematopoietic stem cells require a highly regulated protein synthesis rate.” The article argues that protein synthesis is not only fundamental to how stem cells are regulated, but also is critical to their regenerative potential.

At Harvard Medical School, in the laboratory of co-author Adrian Salic, the antibiotic puromycin was modified in a way that made it possible to visualize and quantify the amount of protein synthesized by individual cells within the body. Dr. Robert A.J. Signer, a postdoctoral research fellow in Dr. Morrison's laboratory and first author of the study, realized that this reagent could be adapted to measure new protein synthesis by stem cells and other cells in the blood-forming system.

Using this reagent, the researchers were able to discover that different types of blood cells produce vastly different amounts of protein per hour. “We found that the amount of protein synthesized per hour in HSCs in vivo was lower than in most other haematopoietic cells,” the authors wrote in their study, “even if we controlled for differences in cell cycle status or forced HSCs to undergo self-renewing divisions.” Also, in mouse models, the researchers tried altering the rate of protein synthesis—decreasing it by interfering with ribosome function, or increasing it by deleting a tumor supressor gene. In either case, HSC function was impaired.

In the discussion section of their article, the authors speculated that low rates of protein synthesis may be essential for maintaining metabolic homeostasis in HSCs and potentially in other kinds of somatic stem cells. “Changes in protein synthesis may cause undesirable changes in the quality and/or content of the proteome, such as due to misfolding,” they continued. “There may also be changes in the translation of certain subsets of transcripts (potentially including key HSC regulators) when protein synthesis increases, similar to what occurs in cancer cells.”