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Hematopoiesis
The lifespan quantitative trait locus gene Securin controls hematopoietic progenitor cell function
Andreas Brown,1 Desiree Schuetz,1 Yang Han,2 Deidre Daria,3
Kalpana J. Nattamai,3 Karina Eiwen,1 Vadim Sakk,1 Johannes Pospiech,1 Thomas Saller,1 Gary van Zant,4 Wolfgang Wagner2 and Hartmut Geiger1,3
1Institute of Molecular Medicine and Stem Cell Aging, Ulm University, Ulm, Germany; 2Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, Aachen, Germany; 3Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH, USA and 4University of Kentucky College of Medicine, UK Medical Center, Lexington, KY, USA
ABSTRACT
The percentage of murine hematopoietic stem and progenitor cells, which present with a loss of function upon treatment with the geno- toxic agent hydroxyurea, is inversely correlated to the mean lifespan of inbred mice, including the long-lived C57BL/6 and short-lived DBA/2 strains. Quantitative trait locus mapping in BXD recombinant inbred strains identified a region spanning 12.5 cM on the proximal part of chromosome 11 linked to both the percentage of dysfunctional hematopoietic stem and progenitor cells as well as regulation of lifespan. By generating and analyz- ing reciprocal congenic mice for this locus, we demonstrate that this region indeed determines the sensitivity of hematopoietic stem and progenitor cells to hydroxyurea. These cells do not present, as previously anticipated, with differences in cell cycle distribution; neither do they present with changes in the frequency of cells undergoing apoptosis, senescence, replica- tion stalling and re-initiation activity, excluding the possibility that varia- tions in proliferation, replication or viability underlie the distinct response of these cells from the congenic and parental strains. An epigenetic aging clock in blood cells was accelerated in C57BL/6 mice congenic for the DBA/2 version of the locus. We verified pituitary tumor-transforming gene- 1 (Pttg1)/Securin as the quantitative trait gene regulating the differential response of hematopoietic stem and progenitor cells to hydroxyurea treat- ment and which might therefore be linked to the regulation of lifespan.
Introduction
We previously reported a correlation between the frequency of hematopoietic stem and progenitor cells (HSPC) from a set of inbred mouse strains with impaired progenitor cell function upon treatment with hydroxyurea (HU) and the mean lifes- pan of these mice. The set of inbred strains also included C57BL/6 (B6) (low fre- quency of HSPC dysfunctional in response to HU, long lifespan) and DBA/2 (D2) (high frequency of HSPC dysfunctional in response to HU, short lifespan). In these experiments, the in vitro cobblestone area forming cell (CAFC) assay was used to determine the number of functional HSPC before and after treatment with HU. Given that HU kills proliferating cells via the induction of DNA strand breaks that arise from stalled replication forks after depletion of the nucleotide pool, this find- ing was interpreted as a significantly higher percentage of HSPC from D2 versus B6 in S-phase, and subsequently that elevated levels of HSPC proliferation could be negatively linked to lifespan.1-3 Using BXD recombinant inbred (RI) mice, which are genetic chimeras based on B6 and D2, subsequently a quantitative trait locus (QTL) was mapped to chromosome 11 linked to the frequency of HSPC susceptible to HU. Interestingly, the same locus showed also a linkage to the mean lifespan with- in the BXD RI set of mice, transforming the reported phenotypic correlation into a genetic connection, implying a common underlying gene and thus mechanism for
Ferrata Storti Foundation
Haematologica 2020 Volume 105(2):317-324
Correspondence:
HARTMUT GEIGER
hartmut.geiger@cchmc.org
Received: November 25, 2018. Accepted: May 9, 2019. Pre-published: May 9, 2019.
doi:10.3324/haematol.2018.213009
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/2/317
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