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

Mann, Mati and Mehta, Arnav and de Boer, Carl G. and Kowalczyk, Monika S. and Lee, Kevin and Haldeman, Pearce and Rogel, Noga and Knecht, Abigail R. and Farouq, Daneyal and Regev, Aviv and Baltimore, David (2018) Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli are Altered with Age. Cell Reports, 25 (11). pp. 2992-3005. ISSN 2211-1247. PMCID PMC6424521. http://resolver.caltech.edu/CaltechAUTHORS:20180122-131324532

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.celrep.2018.11.056DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424521PubMed CentralArticle
https://doi.org/10.1101/163402DOIDiscussion Paper
ORCID:
AuthorORCID
Regev, Aviv0000-0003-3293-3158
Baltimore, David0000-0001-8723-8190
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.
Funders:
Funding AgencyGrant Number
Raymond and Beverly Sackler FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Broad Institute of MIT and HarvardUNSPECIFIED
Human Frontier Science ProgramUNSPECIFIED
NIH Predoctoral FellowshipCA183220
UCLA/Caltech Medical Scientist Training ProgramUNSPECIFIED
Canadian Institutes of Health Research (CIHR)UNSPECIFIED
Charles A. King TrustUNSPECIFIED
Simeon J. Fortin Charitable FoundationUNSPECIFIED
PubMed Central ID:PMC6424521
Record Number:CaltechAUTHORS:20180122-131324532
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20180122-131324532
Official Citation:Mati Mann, Arnav Mehta, Carl G. de Boer, Monika S. Kowalczyk, Kevin Lee, Pearce Haldeman, Noga Rogel, Abigail R. Knecht, Daneyal Farouq, Aviv Regev, David Baltimore, Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli Are Altered with Age, Cell Reports, Volume 25, Issue 11, 2018, Pages 2992-3005.e5, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2018.11.056. (http://www.sciencedirect.com/science/article/pii/S2211124718318321)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:84459
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:23 Jan 2018 14:21
Last Modified:21 Mar 2019 15:41

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