Proliferation Drives Aging-Related Functional Decline in a Subpopulation of the Hematopoietic Stem Cell Compartment

Kristina Kirschner; Tamir Chandra; Vladimir Kiselev; David Flores-Santa Cruz; Iain C. Macaulay; Hyun Jun Park; Juan Li; David G. Kent; Rupa Kumar; Dean C. Pask; Tina L. Hamilton; Martin Hemberg; Wolf Reik; Anthony R. Green

doi:10.1016/j.celrep.2017.04.074

Cell Reports (May 2017)

Proliferation Drives Aging-Related Functional Decline in a Subpopulation of the Hematopoietic Stem Cell Compartment

Kristina Kirschner,
Tamir Chandra,
Vladimir Kiselev,
David Flores-Santa Cruz,
Iain C. Macaulay,
Hyun Jun Park,
Juan Li,
David G. Kent,
Rupa Kumar,
Dean C. Pask,
Tina L. Hamilton,
Martin Hemberg,
Wolf Reik,
Anthony R. Green

Affiliations

Kristina Kirschner: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK
Tamir Chandra: Epigenetics ISP, The Babraham Institute, Cambridge, Cambridgeshire CB22 3AT, UK
Vladimir Kiselev: The Wellcome Trust Sanger Institute, Cambridge, Cambridgeshire CB10 1SA, UK
David Flores-Santa Cruz: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK
Iain C. Macaulay: The Wellcome Trust Sanger Institute, Cambridge, Cambridgeshire CB10 1SA, UK
Hyun Jun Park: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK
Juan Li: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK
David G. Kent: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK
Rupa Kumar: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK
Dean C. Pask: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK
Tina L. Hamilton: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK
Martin Hemberg: The Wellcome Trust Sanger Institute, Cambridge, Cambridgeshire CB10 1SA, UK
Wolf Reik: Epigenetics ISP, The Babraham Institute, Cambridge, Cambridgeshire CB22 3AT, UK
Anthony R. Green: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK

DOI: https://doi.org/10.1016/j.celrep.2017.04.074
Journal volume & issue: Vol. 19, no. 8
pp. 1503 – 1511

Abstract

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Aging of the hematopoietic stem cell (HSC) compartment is characterized by lineage bias and reduced stem cell function, the molecular basis of which is largely unknown. Using single-cell transcriptomics, we identified a distinct subpopulation of old HSCs carrying a p53 signature indicative of stem cell decline alongside pro-proliferative JAK/STAT signaling. To investigate the relationship between JAK/STAT and p53 signaling, we challenged HSCs with a constitutively active form of JAK2 (V617F) and observed an expansion of the p53-positive subpopulation in old mice. Our results reveal cellular heterogeneity in the onset of HSC aging and implicate a role for JAK2V617F-driven proliferation in the p53-mediated functional decline of old HSCs.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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