All stem cells are not created equal, a new study finds. Two distinct kinds of self-renewing blood cells have been spotted in mice, muddying a simplistic view of stem cell categories.
Knowing how these different types of stem cells behave may help scientists better understand and treat blood diseases.
“The definition of a stem cell, as you look closer, gets more complicated,” comments stem cell researcher Timm Schroeder of the German Research Center for Environmental Health’s Institute of Stem Cell Research in Neuherberg. The new study, appearing March 5 in Cell Stem Cell, adds to a growing body of evidence that “black and white characterizations might not be right,” says Schroeder, who was not involved with the study.
In the blood, millions of diverse cells die every second. To keep up with this loss, stem cells continually divide to create the correct balance of cell types, which include oxygen-carrying red blood cells and a menagerie of immune cells.
“For the longest time, people always thought there was one single type of blood stem cell in the bone marrow that continually replenished the blood system throughout the life of a person,” says study coauthor Grant Challen of Baylor College of Medicine in Houston. Recent studies have hinted that blood stem cells have distinct behaviors, but no one had been able to pinpoint the different kinds of cells. “We’re the first group to actually identify them using different markers,” Challen says.
Challen and colleagues used a special dye to stain stem cells removed from mouse bone marrow. Some stem cells expelled the dye at different rates, which, along with other well-known stem cell markers, allowed the researchers to sort these cells into two classes. This dye difference told researchers that the stem cells looked different, but not whether the cells acted differently, too.
Researchers next transplanted several hundred of these presorted types into mice lacking blood stem cells. Over the next few weeks and months, the researchers monitored what kinds of blood cells were produced by the stem cells. While each type of stem cell was able to produce every kind of blood cell, the team found a clear difference in productivity: One type of stem cell produced many more red blood cells than immune cells and vice versa. These strong biases for producing different kinds of cells were evident even when the researchers injected a single stem cell into a mouse and watched as the stem cell repopulated the entire blood system.
Earlier studies had shown that stem cells could have vastly different behaviors, Schroeder says, but researchers didn’t know whether that was because individual cells were unpredictable or because they were truly different types. These new results, he says, “show they’re not that unpredictable — some contribute more and some contribute less.”
What’s more, as the mice aged, the relative amounts of these stem cell types shifted. As mice got older, the stem cells that create more red blood cells made up a larger proportion of all stem cells, beating out the immune-cell–biased stem cells.
This age-related change, if it holds true in humans, may be related to some of the blood diseases and cancers that increase with age, Challen says. “We believe that this phenomenon we discovered — that myeloid stem cells become increased over time — may be related to some of the myeloid proliferative diseases associated with the elderly.” The concurrent decline in immune-cell–producing stem cells might be important for weakened immune systems too, he says.
In additional experiments, Challen and colleagues found that a protein called TGF-β1 spurs red blood cell–producing stem cells to divide and at the same time represses division of their immune cell–producing counterparts. The discovery solves a conundrum in the field, Challen says. Different reports had found conflicting roles for TGF-β1, sometimes finding it causes cell proliferation and sometimes concluding the opposite. “This effect is because people are using all of the stem cells,” Challen says, instead of separating them into subtypes. The different actions of TGF-β1 may allow fine-tuning of the ratio of different stem cell subtypes, the authors write in their paper.
Finding fine-scale differences between blood stem cells may be a prelude of what’s to come in other stem cell fields. “The blood stem cell is by far the most characterized stem cell in the body,” Challen says. “I think that once those fields catch up to blood stem cells, this may pan out to be true for other organs as well.”
And the case is far from closed on blood stem cells, Challen adds. More detailed experiments and better separation methods will enable scientists to make even further distinctions, he says. “I think even what we’ve given is a somewhat simplistic view.”