Chronic Inflammation Harms Hematopoietic Stem Cells

Hematopoietic stem cells reside in bone marrow and are responsible for producing blood cells, including immune cells. Recent research illustrates one way in which chronic inflammation, important in the progression of degenerative aging, can harm this stem cell population. Since chronic inflammation rises due to immune system dysfunction in aging, mechanisms of this nature may be an important component of negative feedback loops that arise in later stages of aging, in which damaged systems interact to further degrade one another.

IL-1 is a cytokine long understood to be an essential signal the immune system uses to recruit and activate inflammatory cells needed to protect from and repair acute occurrences of infection or injury. However, elevated levels of IL-1 are a feature of chronic inflammation, as is commonly seen in aging, and with a number of disease conditions including obesity and type 2 diabetes, which are associated with Western diet and lifestyle. "Inflammation evolved to function for very short periods of time, marshaling resources to fight infections and repair damaged tissue. However, over long periods of time, these conditions become very toxic. If you're working under a constant state of emergency, you become stressed and less effective. I think of blood stem cells in the same way."

While blood-forming stem cells, also termed hematopoietic stem cells (or HSCs), are usually dormant in the bone marrow, "waking" occasionally to maintain proper blood levels in healthy individuals. HSCs are sensitive to the amount of IL-1 they encounter, and go to work creating "first responder" myeloid cells needed to fight what they recognize as a crisis of infection or injury. If the IL-1 signal doesn't end, HSCs continue making these cells but at the expense of their ability to regenerate themselves and correctly build the rest of the blood system. "They're receiving a signal telling them they need to keep building myeloid cells and as a result they don't make the other blood cells you need. You can end up with too few red blood cells, reducing the body's ability to deliver oxygen to cells. Or we see decreased production of new lymphoid cells, leaving the system potentially immunodeficient. These are all common features of chronically inflamed and even aged blood systems."

Another major question was whether these effects are reversible, in other words, once an HSC has "learned" to overproduce myeloid cells, can it just as readily unlearn this function? To test the durability of the IL-1 insult to HSCs following chronic inflammation, researchers treated mice for 20 days with IL-1 and then took it away for several weeks to see if the HSCs recovered. "Our data suggest that it is possible to turn back the clock and reverse the effects of chronic inflammation on blood stem cells, perhaps using therapies already available in the clinic to block inflammatory signals such as IL-1. Of course, we don't yet know on a human scale how long it takes a stem cell to 'remember' these insults. It may be that after a longer period of exposure to IL-1, these changes become more fixed." Overall, the study demonstrates for the first time that blood stem cells adapt to meet what they recognize as the body's needs, and that chronic inflammation can act like a thumb on the scale, implying a need that does not really exist.



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