Format

Send to

Choose Destination
Cell Rep. 2017 May 23;19(8):1503-1511. doi: 10.1016/j.celrep.2017.04.074.

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

Author information

1
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK; Department of Haematology, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK; Stem Cell Institute, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK; Institute for Cancer Sciences, University of Glasgow, Glasgow, Lanarkshire G61 1BD, UK. Electronic address: kristina.kirschner@glasgow.ac.uk.
2
Epigenetics ISP, The Babraham Institute, Cambridge, Cambridgeshire CB22 3AT, UK; MRC Unit for Human Genetics, University of Edinburgh, Midlothian EH2 2XU, UK. Electronic address: tamir.chandra@igmm.ed.ac.uk.
3
The Wellcome Trust Sanger Institute, Cambridge, Cambridgeshire CB10 1SA, UK.
4
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK.
5
Epigenetics ISP, The Babraham Institute, Cambridge, Cambridgeshire CB22 3AT, UK; The Wellcome Trust Sanger Institute, Cambridge, Cambridgeshire CB10 1SA, UK. Electronic address: wolf.reik@babraham.ac.uk.
6
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK; Department of Haematology, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK; Stem Cell Institute, University of Cambridge, Cambridge, Cambridgeshire CB2 0XY, UK. Electronic address: arg100@cam.ac.uk.

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.

KEYWORDS:

JAK2; aging; cancer; cellular aging; genomics; hematology; leukemia; p53; scRNA-seq; stem cells

PMID:
28538171
PMCID:
PMC5457484
DOI:
10.1016/j.celrep.2017.04.074
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center