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Adults Have 10 Times More Blood Stem Cells Than Previously Estimated

NEW YORK (GenomeWeb) – Adult humans have between 50,000 and 200,000 hematopoietic stem cells that are actively making blood cells in their bodies, a new study has found. This estimate — which is based on the number of somatic mutations researchers found — is about 10 times higher than previous approximations.

Hematopoietic stem cells differentiate into myeloid, T, and B cells to replenish the body's blood cells. But despite the use of hematopoietic stem cells as a therapy for diseases such as leukemia, their exact number and dynamics have been unclear.

A team of UK researchers used the somatic mutations that crop up in cells over their lifetimes to develop a population phylogenetic tree for blood cells they isolated from a human adult. As they reported in Nature today, the researchers uncovered nearly 130,000 somatic mutations across the cells they isolated, which they used to build their phylogenetic tree. Then, taking a page from ecological research, they used a capture-recapture approach based on those mutations to estimate the number of blood stem cells that person has.

"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," co-senior author Peter Campbell from the Wellcome Sanger Institute said in a statement.

The researchers collected bone marrow aspirate and peripheral blood from a healthy 59-year-old man and isolated single hematopoietic stem and progenitor cells. After growing these up in single-cell liquid cultures or colony-forming cell assays, the researchers sequenced 198 colonies to about 15X depth. After excluding polyclonal colonies, the researchers derived 140 colonies from 89 immunophenotypic hematopoietic stem cells, 38 megakaryocyte–erythrocyte pro- genitors, eight granulocyte–macrophage progenitors, and five common myeloid progenitors.

Mutation burden was similar across the colonies, the researchers reported, with a mean 1,023 substitutions and 20 small insertion or deletion events. Using the total 129,582 somatic substitutions they uncovered, the researchers constructed a phylogenetic tree. As the number of somatic mutations in a normal blood cell increases with age, they noted these mutations could be used as a sort of molecular clock to trace the cells' ancestors.

The investigators identified two mutations that distinguished the colonies: one mutation was found in 52 colonies and one in 88. Each colony had one or the other mutation and none had both. These mutations, the researchers noted, were also present in a buccal swab they obtained from the subject, which suggested that these two mutations cropped up in the first cell division of the fertilized egg.

The researchers also found that there was a rapid expansion of hematopoietic stem cell populations early in this individual's life, reaching a plateau by late childhood or early adolescence.

In the second part of the study, the team used an approach akin to the capture-recapture experiments used in ecology to estimate the numbers of blood stem cells. The researchers collected samples from the same research participant as before at three time points to perform deep targeted sequencing on these bulk populations to identify the somatic mutations they identified in the first part of their experiment.

"The mutations act like barcodes, each of which uniquely tags a stem cell and its descendants," said first author Henry Lee­Six from the Wellcome 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."

In all, they estimated that adult humans have between 50,000 and 200,000 hematopoietic stem cells.

"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," Campbell added.