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

Autor:	Mann M; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: mati@calech.edu., Mehta A; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; David Geffen School of Medicine, UCLA, Los Angeles, CA 90025, USA., de Boer CG; Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA., Kowalczyk MS; Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA., Lee K; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Haldeman P; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Rogel N; Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA., Knecht AR; Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA., Farouq D; Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA., Regev A; Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Koch Institute of Integrative Cancer Biology, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02140, USA. Electronic address: aregev@broadinstitute.org., Baltimore D; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: baltimo@caltech.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2018 Dec 11; Vol. 25 (11), pp. 2992-3005.e5.
DOI:	10.1016/j.celrep.2018.11.056
Abstrakt:	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. (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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