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Population dynamics of normal human blood inferred from somatic mutations

2018; Nature Portfolio; Volume: 561; Issue: 7724 Linguagem: Inglês

10.1038/s41586-018-0497-0

1476-4687

Henry Lee-Six, Nina Friesgaard Øbro, Mairi Shepherd, Sebastian Großmann, Kevin J. Dawson, Miriam Belmonte, Robert J. Osborne, Brian J.P. Huntly, Iñigo Martincorena, Elizabeth Anderson, Laura P. O’Neill, Michael R. Stratton, Elisa Laurenti, Anthony R. Green, David G. Kent, Peter J. Campbell,

Hematopoietic Stem Cell Transplantation

Haematopoietic stem cells drive blood production, but their population size and lifetime dynamics have not been quantified directly in humans. Here we identified 129,582 spontaneous, genome-wide somatic mutations in 140 single-cell-derived haematopoietic stem and progenitor colonies from a healthy 59-year-old man and applied population-genetics approaches to reconstruct clonal dynamics. Cell divisions from early embryogenesis were evident in the phylogenetic tree; all blood cells were derived from a common ancestor that preceded gastrulation. The size of the stem cell population grew steadily in early life, reaching a stable plateau by adolescence. We estimate the numbers of haematopoietic stem cells that are actively making white blood cells at any one time to be in the range of 50,000–200,000. We observed adult haematopoietic stem cell clones that generate multilineage outputs, including granulocytes and B lymphocytes. Harnessing naturally occurring mutations to report the clonal architecture of an organ enables the high-resolution reconstruction of somatic cell dynamics in humans. Analysis of blood from a healthy human show that haematopoietic stem cells increase rapidly in numbers through early life, reaching a stable plateau in adulthood, and contribute to myeloid and B lymphocyte populations throughout life.