Lead image: A single chess piece left standing. In this study, researchers found blood production could be sustained by a single stem cell, without any of the variations usually associated with clonal haematopoiesis.
Blood is made from a small, special population of stem cells. As we age, our ability to produce healthy blood cells can gradually decline. At the same time, a phenomenon called clonal haematopoiesis frequently emerges. By age 70, about 20% of people will have clonal haematopoiesis—this is when a few stem cells dominate blood production. Historically, clonal haematopoiesis research has focused on mutations acquired during life that give stem cells an advantage; in this context, it can be a predictor of an increased risk of blood cancer, immune disorders, and mortality.
Now, this new research, led by Professors KJ Patel and Thomas Höfer, reveals a different way that we can develop clonal haematopoiesis.
The team found that formaldehyde - a chemical naturally produced in our bodies - can damage DNA and steadily reduce the number of blood stem cells over time. Rather than a few advantaged cells taking over, stem cells are simply lost, leaving only a handful behind to sustain blood production.
Using an animal model without protection against formaldehyde damage, the team showed that fewer blood stem cells were formed early in life, and those that did form were gradually depleted. However, despite vanishingly small numbers of stem cells, blood production continued for months.
To understand how the mice could keep making blood, the team used an unbiased computational method called SCIFER, which tracks how cell populations change over time by using mutations that the cells carry as natural “barcodes.” This revealed that, in aged animals, all blood was being produced by a single original cell, without any of the usual mutations associated with clonal haematopoiesis.
The researchers then applied the same technique to samples from children with Fanconi anaemia, who are unable to properly repair DNA damage caused by formaldehyde. They saw the same striking pattern in one child, with blood production being driven by a single stem cell, again without mutations known to give cells a competitive advantage.
Co-first author Ashley Kamimae-Lanning said:
This extreme form of clonal haematopoiesis has only been described once before in a 115-year-old woman. What naturally takes place over a century in a healthy person can take less than a decade in Fanconi anaemia. For people who live long enough, clonal haematopoiesis may be inevitable due to depletion of stem cells.
The findings suggest that stem cell loss, driven by natural, everyday DNA damage, plays an important role in ageing and disease. Jill Brown, co-first author, said:
We describe a new way by which clonal haematopoiesis can develop. It shifts the focus from how certain cells gain advantages to how the loss of cells reshapes a population.
Read the full paper in Cell Stem Cell: Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis