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Published December 11, 2018 | Supplemental Material + Accepted Version + Submitted + Published
Journal Article Open

Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli are Altered with Age


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.

Additional Information

© 2018 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Received 10 June 2018, Revised 5 October 2018, Accepted 13 November 2018, Available online 11 December 2018. This work was supported by the Sackler Foundation (D.B.), the Howard Hughes Medical Institute (A.R.), the Klaman Cell Observatory at the Broad Institute (A.R.), the Human Frontiers Science Foundation (M.M.), the National Research Service Award (CA183220, to A.M.), the UCLA/Caltech Medical Scientist Training Program (A.M.), the Canadian Institutes for Health Research (C.G.d.B.), the Charles A. King Trust Postdoctoral Research Fellowship Program, Bank of America, N.A., Co-Trustee, and the Simeon J. Fortin Charitable Foundation, Bank of America, N.A. (M.S.K.). Author Contributions: M.M., A.M., and D.B. designed the study with assistance from C.G.d.B. and M.S.K. M.M. conducted the experimental work with assistance from A.M., K.L., and P.H. M.S.K., N.R., A.R.K., D.F., M.M., A.M., P.H., and K.L. conducted bulk and scRNA-seq and sample perpetrations. C.G.d.B. performed the bioinformatics analysis. M.M., A.M., A.R., and D.B. wrote the manuscript with contributions from C.G.d.B. and M.S.K. The authors declare no competing interests.

Attached Files

Published - 1-s2.0-S2211124718318321-main.pdf

Accepted Version - nihms-1004634.pdf

Submitted - 163402.full.pdf

Supplemental Material - 1-s2.0-S2211124718318321-mmc1.pdf

Supplemental Material - 1-s2.0-S2211124718318321-mmc2.xlsx

Supplemental Material - 1-s2.0-S2211124718318321-mmc3.xlsx

Supplemental Material - 1-s2.0-S2211124718318321-mmc4.xlsx

Supplemental Material - 1-s2.0-S2211124718318321-mmc5.xlsx

Supplemental Material - 1-s2.0-S2211124718318321-mmc6.xlsx


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