Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli Are Altered with Age
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1-s2.0-S2211124718318321-main.pdf
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Author(s)
Mann, Mati
Mehta, Arnav
de Boer, Carl G.
Kowalczyk, Monika S.
Lee, Kevin
Haldeman, Pearce
Rogel, Noga
Knecht, Abigail R.
Farouq, Daneyal
Regev, Aviv
Date Issued
December 2018
Journal
Cell Reports
Publisher
Elsevier
Citation
Mann, Mati et al. “Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli Are Altered with Age.” Cell Reports 25, 11 (December 2018): 2992–3005 © 2018 The Author(s)
Version
Final published version
Abstract
Long-term hematopoietic stem cells (LT-HSCs) maintain hematopoietic output throughout an animal's lifespan. However, with age, the balance is disrupted, and LT-HSCs produce a myeloid-biased output, resulting in poor immune responses to infectious challenge and the development of myeloid leukemias. Here, we show that young and aged LT-HSCs respond differently to inflammatory stress, such that aged LT-HSCs produce a cell-intrinsic, myeloid-biased expression program. Using single-cell RNA sequencing (scRNA-seq), we identify a myeloid-biased subset within the LT-HSC population (mLT-HSCs) that is prevalent among aged LT-HSCs. We identify CD61 as a marker of mLT-HSCs and show that CD61-high LT-HSCs are uniquely primed to respond to acute inflammatory challenge. We predict that several transcription factors regulate the mLT-HSCs gene program and show that Klf5, Ikzf1, and Stat3 play an important role in age-related inflammatory myeloid bias. We have therefore identified and isolated an LT-HSC subset that regulates myeloid versus lymphoid balance under inflammatory challenge and with age. Mann et al. show an age-dependent inflammatory response of hematopoietic stem cells (HSCs) and unveil a CD61-high subpopulation primed for inflammatory response. This CD61-high subpopulation is more prevalent in aged mice and has a cell-intrinsic myeloid-biased potential, which is regulated in part by Ikzf1, Klf5, and Stat3 transcription factors.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1016/j.celrep.2018.11.056
