G2 arrest primes hematopoietic stem cells for megakaryopoiesis
Corey M. Garyn,
Oriol Bover,
John W. Murray,
Jing Ma,
Karen Salas-Briceno,
Susan R. Ross,
Hans-Willem Snoeck
Affiliations
Corey M. Garyn
Columbia Center for Human Development/Center for Stem Cell Therapies, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Department of Genetics and Development, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Oriol Bover
Columbia Center for Human Development/Center for Stem Cell Therapies, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
John W. Murray
Columbia Center for Human Development/Center for Stem Cell Therapies, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Jing Ma
Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA
Karen Salas-Briceno
Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA
Susan R. Ross
Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA
Hans-Willem Snoeck
Columbia Center for Human Development/Center for Stem Cell Therapies, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Department of Microbiology and Immunology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Corresponding author
Summary: In contrast to most hematopoietic lineages, megakaryocytes (MKs) can derive rapidly and directly from hematopoietic stem cells (HSCs). The underlying mechanism is unclear, however. Here, we show that DNA damage induces MK markers in HSCs and that G2 arrest, an integral part of the DNA damage response, suffices for MK priming followed by irreversible MK differentiation in HSCs, but not in progenitors. We also show that replication stress causes DNA damage in HSCs and is at least in part due to uracil misincorporation in vitro and in vivo. Consistent with this notion, thymidine attenuated DNA damage, improved HSC maintenance, and reduced the generation of CD41+ MK-committed HSCs. Replication stress and concomitant MK differentiation is therefore one of the barriers to HSC maintenance. DNA damage-induced MK priming may allow rapid generation of a lineage essential to immediate organismal survival, while also removing damaged cells from the HSC pool.
