HSCs in the bone marrow
Humans may have ten times more hematopoietic stem cells (HSCs) than previously thought, according to research published in Nature.
Researchers developed a new approach for studying HSCs and found evidence suggesting that HSC numbers increase rapidly through childhood, reach a plateau by adolescence, and remain relatively constant throughout adulthood.
“We discovered that healthy adults have between 50,000 and 200,000 blood stem cells, which is about ten times more than previously thought,” said study author Peter Campbell, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.
“Whereas previous estimates of blood stem cell numbers were extrapolated from studies in mice, cats, or monkeys, this is the first time stem cell numbers have been directly quantified in humans. This new approach opens up avenues into studying stem cells in other human organs and how they change between health and disease, and as we age.”
For this study, Dr Campbell and his colleagues conducted whole-genome sequencing on hematopoietic stem and progenitor colonies from a healthy 59 year-old man. The team adapted a capture-recapture* method to “tag” stem cells and compare them to the population of blood cells.
Specifically, in the “capture” phase, the researchers isolated individual hematopoietic stem and progenitor cells from a bone marrow aspirate and peripheral blood draw from the male subject. The cells were expanded, and the researchers performed whole-genome sequencing on 198 colonies to identify somatic mutations.
In the “recapture” phase, the researchers isolated bulk populations of mature peripheral blood cells from the subject—granulocytes at three time points and B and T lymphocytes at one time point. The team then performed deep, targeted sequencing on these bulk populations.
“The mutations act like barcodes, each of which uniquely tags a stem cell and its descendants,” said study author Henry Lee-Six, of the Wellcome Trust Sanger Institute.
“We then looked for these mutations in the rest of the blood to see what fraction of blood cells carry the same barcodes, and, from this, we could estimate how many stem cells there were in total.”
The researchers’ results suggested the number of HSCs actively contributing to circulating granulocytes at any one time was in the range of 44,000 to 215,000.
The team also estimated that the time between successive self-renewal HSC divisions is likely in the range of 2 to 20 months.
Finally, the researchers observed signs of “rapid” HSC population expansion during early life, which reaches a relatively stable plateau by late childhood or early adolescence that continues into adulthood.
The team said this stability suggests that symmetric self-renewal divisions (when one HSC divides into two) are balanced by HSC death, senescence, and symmetric divisions into committed progenitors.
*Capture-recapture is commonly used in ecology to estimate a species’ population size. A portion of the population is captured, tagged, and released. Later, another portion is captured, and the number of tagged individuals within the sample is counted. Since the number of marked individuals within the second sample should be proportional to the number of marked individuals in the whole population, an estimate of the total population size can be obtained by dividing the number of marked individuals by the proportion of marked individuals in the second sample.