Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli Are Altered with Age
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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.
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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.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [23]
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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
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 25
- Issue
- 11
- Pages
- 2992-3005.e5
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6424521
- 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
- gold
- doi.org
- Licence
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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