Proliferation drives aging-related functional decline in a subpopulation of the hematopoietic stem cell compartment

Kirschner, K. et al. (2017) Proliferation drives aging-related functional decline in a subpopulation of the hematopoietic stem cell compartment. Cell Reports, 19(8), pp. 1503-1511. (doi: 10.1016/j.celrep.2017.04.074) (PMID:28538171) (PMCID:PMC5457484)

Abstract

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.

• Item Type: Articles
• Additional Information: The laboratory of Wolf Reik is supported by the BBSRC (BB/K010867/1), the Wellcome Trust (095645/Z/ 11/Z), EU BLUEPRINT, and EpiGeneSys. Work in the A.R.G. lab is supported by Bloodwise (grant ref. 13003), the Wellcome Trust (grant ref. 104710/Z/14/Z), the Medical Research Council, the Kay Kendall Leukaemia Fund, the Cambridge NIHR Biomedical Research Center, the Cambridge Experimental Cancer Medicine Centre, the Leukemia and Lymphoma Society of America (grant ref. 07037), and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute. K.K. is supported by a Wellcome Trust ISSF Fellowship (grant 105641/Z/14/ Z). The M.H. lab is supported by a Wellcome Trust core grant to the WTSI. T.C. is supported by a Chancellor’s Fellowship held at the University of Edinburgh.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kirschner, Dr Kristina
• Authors: Kirschner, K., Chandra, T., Kiselev, V., Flores-Santa Cruz, D., Macaulay, I. C., Park, H. J., Li, J., Kent, D. G., Kumar, R., Pask, D. C., Hamilton, T. L., Hemberg, M., Reik, W., and Green, A. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Life Sciences
• Journal Name: Cell Reports
• Publisher: Elsevier (Cell Press)
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Published Online: 23 May 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Cell Reports 19(8): 1503-1511
• Publisher Policy: Reproduced under a Creative Commons License