Continuous mitotic activity of primitive hematopoietic stem cells in adult mice

• Published in: The Journal of experimental medicine Vol. 217; no. 6
• Main Authors: Morcos, Mina N F, Zerjatke, Thomas, Glauche, Ingmar, Munz, Clara M, Ge, Yan, Petzold, Andreas, Reinhardt, Susanne, Dahl, Andreas, Anstee, Natasha S, Bogeska, Ruzhica, Milsom, Michael D, Säwén, Petter, Wan, Haixia, Bryder, David, Roers, Axel, Gerbaulet, Alexander
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 01.06.2020
• Subjects: Aging - physiology; Animals; cd34; Clinical Medicine; dynamics; exchange; Fluorescence; Gene Expression Regulation; gene-expression; Hematologi; Hematology; Hematopoiesis; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; heterogeneity; Histones - metabolism; history; Immunologi inom det medicinska området; Immunology; Immunology in the medical area; Kinetics; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Mice, Inbred C57BL; Mitosis; Models, Biological; proliferation; Proteolysis; Recombinant Fusion Proteins - metabolism; Research & Experimental Medicine; self-renewal; Stem Cells & Regeneration
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20191284

The proliferative activity of aging hematopoietic stem cells (HSCs) is controversially discussed. Inducible fluorescent histone 2B fusion protein (H2B-FP) transgenic mice are important tools for tracking the mitotic history of murine HSCs in label dilution experiments. A recent study proposed that primitive HSCs symmetrically divide only four times to then enter permanent quiescence. We observed that background fluorescence due to leaky H2B-FP expression, occurring in all H2B-FP transgenes independent of label induction, accumulated with age in HSCs with high repopulation potential. We argue that this background had been misinterpreted as stable retention of induced label. We found cell division-independent half-lives of H2B-FPs to be short, which had led to overestimation of HSC divisional activity. Our data do not support abrupt entry of HSCs into permanent quiescence or sudden loss of regeneration potential after four divisions, but show that primitive HSCs of adult mice continue to cycle rarely.