You are hereJune 18, 2018
Cell umbrella protects stem cells from DNA damage
Tissue-specific stem cells have the crucial role of maintaining and replenishing all the specialized cells that make up a given tissue or system, so it is essential that their functions are preserved throughout an organism’s life. These adult stem cells therefore reside in dedicated microenvironments called stem cell niches, which help to regulate and protect the stem cells. In a paper in Nature, Friedrich Kapp, M.D., who at the time of the study was at the Harvard Stem Cell Institute, and colleagues investigated factors that affect the locations of niches for hematopoietic stem and progenitor cells (HSPCs), which give rise to all blood-cell lineages.
Their findings provide insights into the evolutionary drivers of niche location.
Stem cell niches have several commonalities, regardless of the type of tissue stem cell they sustain. They provide structural support, enable access to molecular signals from either local or remote sources, produce proteins that help tether stem cells to the location and help to regulate stem cell metabolism. Cues from the niche also restrict unnecessary stem cell divisions, presumably both to prevent stem cell exhaustion (in which stem cells lose the ability to regenerate cell lineages) and to minimize the number of genetic mutations that arise during DNA replication, maintaining the fidelity of the genome.
Most information that researchers have about the HSPC niche has been gained from mouse studies. These analyses have revealed that, during development, there are several different sites at which blood lineages are generated: in mice, HSPCs and their niches move, depending on the developmental stage. Moreover, studies of adult HSPC populations in flies, and in zebrafish and other vertebrates, have revealed different niche locations in different species — the bone marrow in birds and mammals, the kidney in fish and the liver in frogs, for example.
A theory published almost 40 years ago states that HSPC niches in terrestrial animals evolved at sites that minimize damage from ionizing radiation, with the assumption that water would have provided aquatic organisms with protection from damaging ultraviolet light. Dr. Kapp’s team set out to examine whether the need to minimize damage might influence HSPC-niche location in the model organism zebrafish, which tends to inhabit clear bodies of water that offer little UV protection. During embryonic stages, zebrafish are largely transparent, making them well suited to live imaging using fluorescently labeled cells. However, the authors found that visualization of the HSPC population was consistently obscured by pigmented cells called melanocytes.
The researchers used genetic engineering to generate zebrafish lacking melanocytes and found that HSPCs developed normally, indicating that the pigmented cells are not essential for HSPC maintenance. However, this finding raised the question of what, if any, role the melanocyte population has in relation to HSPCs. Dr. Kapp and his colleagues performed a series of clever experiments to investigate. They genetically engineered fish to lack melanocyte pigmentation and showed that UV radiation caused higher levels of DNA damage in these fish than in controls, as well as an increase in HSPC death.
Next, they anesthetized pigmented fish, causing them to flip onto their backs. This removed the protection provided by the physical location of the melanocytes — again, the HSPCs were rapidly damaged by UV. Thus, melanocytes protect HSPCs by generating a physical opaque shield against UV irradiation (see Fig. 1, below).
Figure 1. Image courtesy of Dr. F. Kapp.
The research team next showed that this melanocyte “umbrella” is present in other species of fish as well as in frogs, in which melanocytes shield the HSPC niche in tadpoles before the cells migrate to the bone marrow during development. Fish without melanocytes in this location might have had a selective disadvantage during evolutio, because their HSPCs would not have been protected by the umbrella and would have been exposed to UV damage. This would have led to decreased numbers of HSPCs, and daily exposure to UV would probably have been lethal.
These findings raise the question of whether aquatic organisms have evolved so that other crucial, vulnerable cells are also physically shielded — either by melanocytes or by other carefully positioned cells — to prevent UV-induced damage. It will be interesting to determine how many other tissue-specific stem cells have appropriated this type of physical protection in fish.
It remains to be seen whether HSPCs home to locations protected by melanocytes, or whether melanocytes can be recruited or stimulated to proliferate by signals from blood stem cell niches. Another question is why HSPCs seek out a different niche in terrestrial vertebrates. HSPCs regularly leave their niches and circulate in the blood, whereas other adult stem cells, although capable of movement, tend to be more static.
Indeed, Dr. Kapp and his team highlighted this mobility in adult Rana frogs, in which the location of HSPCs switches depending on the season — perhaps driven by changing exposure to UV. This mobility could give HSPCs an increased capacity to seek out alternative sites that can better protect them from damage. Bone would completely encapsulate the stem cells, providing a shield from all angles. There might also be other benefits to a niche in the bone marrow, such as lower oxygen levels, which could provide protection from other forms of DNA damage.
Fish have evolved the ability to mitigate UV-induced DNA damage through light-dependent DNA repair. The fact that, despite this ability, HSPCs seem to be under evolutionary pressure to seek additional protection highlights the importance of maintaining the fidelity of tissue stem cells. Physical protection might be of particular value in the hematopoietic system, because blood cells have a high turnover rate. If HSPCs are unable to re-establish blood-cell populations, the organism would be likely to die from anemia or infection.
Finally, it might be predicted that other tissue-specific stem cells that have less migratory potential than HSPCs would be more prone to damage, because they would be less able to move to protective niches. By gaining insight into the evolutionary steps taken to protect hematopoietic stem cells, we might be able to develop strategies to protect these cell types, refining their current niches to better maintain stem cell potential in longer-lived organisms, including humans.