by Mick Aulakh
The protein p53 regulates haematopoietic stem cell quiescence; a new labelling technique lets researchers watch cells divide.
Every day, haematopoietic stem cells replenish the blood system, but they only make as much blood as the body needs. Although much is known about how haematopoietic stem cells move through both self-renewal and differentiation to become many blood types, far less is understood about what keeps the cells in a nondividing state. Now, researchers led by Stephen Nimer at the Memorial Sloan-Kettering Cancer Center in New York have elucidated a key role for p53 in the regulation of haematopoietic stem cell quiescence.
As part of a stress response, the protein p53 facilitates senescence, apoptosis and cell-cycle arrest in virtually all cell types2. Nimer and colleagues found that p53-deficient mice had more haematopoietic stem (HS) cells and that the cells were less quiescent than those in wild-type mice. They studied the phenomenon in mice lacking the transcription factor MEF/ELF4, which is known to regulate HS cell division, and found that p53 was essential for maintaining quiescence.
Further work showed that two p53 target genes, Gfi-1 and Necdin, helped keep HS cells from entering the cell cycle, both in wild-type and MEF-null HS cells. Establishing the role of p53 in controlling when HS cells start to divide may lead to therapeutic strategies for targeting quiescent cancer cells.
To be sure, there's still much to be understood in knowing how p53 encourages quiescence, but HS cells exhibit much more complex behaviour than just dividing or not. Their ability to divide at different rates is also of interest.
A group led by Hanno Hock of Massachusetts General Hospital has a new technique for discerning HS cell proliferation patterns3. These researchers challenged the conventional wisdom that stem cell cycling could be identified using labels that are diluted as cells divide. They generated a mouse strain that showed transient, transgenic expression of a histone 2B–green fluorescent protein (H2B-GFP), which was rapidly incorporated into virtually all HS cells. They then analyzed H2B-GFP expression in combination with established surface markers for progenitors and HS cells, including lineage markers, c-Kit, Sca-1, CD48 and CD150. Proliferation rates of defined populations were then compared with their retention of H2B-GFP over designated time points ending at 72 weeks.
Most labelled HS cells proliferated at the expected rate of once every two weeks; however, roughly 20% of the cells seemed to divide much more slowly — once every 100 days or longer. These cells were also found to have the greatest H2B-GFP retention. Further experimentation with stem cell transplants, conducted using labelled HS cells, revealed that these slower-cycling cells were more likely to survive and engraft than their lesser H2B-GFP-retaining counterparts.
Much HS cell research has a heavy focus on the cells' ability to divide rapidly — either in malignant, excessive growth in leukaemia or in the drive for rapid proliferation to rebuild depleted blood supplies. However, these two studies indicate that researching the slower cells may be just as enlightening.
Source: Nature