Loss of stem cell diversity in blood ageing revealed

A new method for tracking the lineage and type of different blood cells in humans has shown how ageing changes the make-up of blood.

Blood has a reservoir of stem cells that in young adults can replenish up to 200 billion new red, white or platelet cells every day. By tracking epigenetic changes across generations of cells, researchers at the Barcelona Institute of Science and Technology, Spain, showed that – over time – a select few blood stem cells outcompete others in the reservoir and eventually dominate blood cell production. They observed the same effect in both mouse and human cells.

'The change from diversity to dominance isn't random but clock-like. By age 50, you can already see it starting, and after 60 it becomes almost inevitable,' said Indranil Singh, co-first author of the study, which was published in Nature.

Previously, tracking the lineage of blood cells from their original stem cell required making genetic changes to label cells, and was not appropriate for use in humans. The new method looked at the natural epigenetic patterns of DNA methylation: chemical tags are added by enzymes to DNA to tell cells which genes are switched on or off.

'This simple on-off information can be transformed into a natural barcode, one that each stem cell passes on to its descendants,' said Dr Michael Scherer, co-first author. 'Five years ago, I wouldn't have thought this possible at single-cell resolution, across tens of thousands of cells. It's been a huge leap forward in technology.'

The study showed that the dominant clones favoured producing myeloid cells, which are immune cells linked to chronic inflammation. It also replicated findings from a previous study, which used a more limited lineage tracing approach, that some clones expressed 'driver' mutations linked to clonal haematopoiesis, which can trigger faster cell multiplication (see BioNews 1146). While this dominance-over-diversity switch might relate to the age-related risk of diseases like heart disease, stroke, and cancer, the authors suggested it could be part of normal ageing, as some clones had no known mutations at all.

The researchers' next step is to identify which clones are problematic and which are healthy, using the new method which they have named 'EPI-Clone'. Past studies in mice showed that selectively removing myeloid-biased stem cells can restore a younger profile of blood stem cells, boosting the production of infection-fighting lymphocytes and improving immune responses. The team hope that it could unlock precision prevention approaches to age-related disease.

'We have only shown what's possible,' said co-corresponding author Dr Alejo Rodriguez-Fraticelli. 'Now the goal is to refine EPI-Clone so it can boost clinical research efforts.'