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

K Kirschner; T Chandra; V Kiselev; D Flores-Santa Cruz; IC Macaulay; HJ Park; J Li; DG Kent; R Kumar; DC Pask; TL Hamilton; M Hemberg; W Reik; AR Green

doi:10.1016/j.celrep.2017.04.074

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

K Kirschner, T Chandra, V Kiselev, D Flores-Santa Cruz, IC Macaulay, HJ Park, J Li, DG Kent, R Kumar, DC Pask, TL Hamilton, M Hemberg, W Reik, AR Green

Biology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1503-1511
Number of pages	9
Journal	Cell reports
Volume	19
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2017.04.074
Publication status	Published - 23 May 2017

Bibliographical note

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10.1016/j.celrep.2017.04.074

1-s2.0-S2211124717306034-main
© 2017 The Author(s).
Final published version, 2.97 MBLicence: CC BY

https://www.ncbi.nlm.nih.gov/pubmed/28538171

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Kirschner, K., Chandra, T., Kiselev, V., Flores-Santa Cruz, D., Macaulay, IC., Park, HJ., Li, J., Kent, DG., Kumar, R., Pask, DC., Hamilton, TL., Hemberg, M., Reik, W., & Green, AR. (2017). Proliferation Drives Aging-Related Functional Decline in a Subpopulation of the Hematopoietic Stem Cell Compartment. Cell reports, 19(8), 1503-1511. https://doi.org/10.1016/j.celrep.2017.04.074

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

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.",

author = "K Kirschner and T Chandra and V Kiselev and {Flores-Santa Cruz}, D and IC Macaulay and HJ Park and J Li and DG Kent and R Kumar and DC Pask and TL Hamilton and M Hemberg and W Reik and AR Green",

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Kirschner, K, Chandra, T, Kiselev, V, Flores-Santa Cruz, D, Macaulay, IC, Park, HJ, Li, J, Kent, DG, Kumar, R, Pask, DC, Hamilton, TL, Hemberg, M, Reik, W & Green, AR 2017, 'Proliferation Drives Aging-Related Functional Decline in a Subpopulation of the Hematopoietic Stem Cell Compartment.', Cell reports, vol. 19, no. 8, pp. 1503-1511. https://doi.org/10.1016/j.celrep.2017.04.074

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T1 - Proliferation Drives Aging-Related Functional Decline in a Subpopulation of the Hematopoietic Stem Cell Compartment.

AU - Kirschner, K

AU - Chandra, T

AU - Kiselev, V

AU - Flores-Santa Cruz, D

AU - Macaulay, IC

AU - Park, HJ

AU - Li, J

AU - Kent, DG

AU - Kumar, R

AU - Pask, DC

AU - Hamilton, TL

AU - Hemberg, M

AU - Reik, W

AU - Green, AR

PY - 2017/5/23

Y1 - 2017/5/23

N2 - 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.

AB - 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.

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DO - 10.1016/j.celrep.2017.04.074

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EP - 1511

JO - Cell reports

JF - Cell reports

SN - 2211-1247

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