Cited by 188Hematopoietic Stem Cell TransplantationAcute Myeloid Leukemia ResearchMesenchymal stem cell research

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

Open access
Mann, Mati, Mehta, Arnav, de Boer, Carl G., Kowalczyk, Monika S., Lee, Kevin, Haldeman, Pearce, Rogel, Noga, Knecht, Abigail R. +3 more·2018·Cell Reports

Published version of a preprint

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.

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  • In blood, lineage tracing, single-cell RNA-seq and large-scale clonal analysis studies indicate that old HSCs generate fewer lymphoid cells and are skewed towards the myeloid lineage.

    “In blood, lineage tracing, single-cell RNA-seq and large-scale clonal analysis studies all indicate that old HSCs generate fewer lymphoid cells and are skewed towards the myeloid lineage23–26.”

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Authors
Mann, M., Mehta, A., de Boer, C. G., Kowalczyk, M. S., Lee, K., Haldeman, P., Rogel, N., Knecht, A. R., Farouq, D., Regev, A., & Baltimore, D.
Affiliations
  • California Institute of Technology (US)
  • Broad Institute (US)
Corresponding author
  • Mann, Mati
  • Regev, Aviv
  • Baltimore, David
Venue
Cell Reports
Publisher
Elsevier BV
Published
2018-12
Volume
25
Issue
11
Pages
2992-3005.e5
ISSN
2211-1247 (ISSN-L)
OpenAlex
W2952842332
Cited by
188
References
80
Citations by year
2026: 15 · 2025: 25 · 2024: 26 · 2023: 28 · 2022: 34 · 2021: 21 · 2020: 19 · 2019: 20
FWCI
10.76
Type
journal article
Language
en
Open access
Locations
  • Cell Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Bank of America
  • Frontiers Foundation
  • Canadian Institutes of Health Research
  • Raymond and Beverly Sackler Foundation
  • Simeon J. Fortin Charitable Foundation
  • Charles A. King Trust
  • Broad Institute
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
long-term hematopoietic stem cells, aging, myeloid bias, inflammation, CD61, KLF5, IKZF1, STAT3, myeloid leukemia, transcription factors, single-cell RNA sequencing
MeSH terms
Aging, Animals, Hematopoietic Stem Cells, Inflammation, Ligands, Mice, Inbred C57BL, Models, Biological, Transcription, Genetic, Biomarkers, Myeloid Cells, Toll-Like Receptors

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