Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli Are Altered with Age
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
Affiliations
Mati Mann
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Corresponding author
Arnav Mehta
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
Carl G. de Boer
Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA
Monika S. Kowalczyk
Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA
Kevin Lee
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
Pearce Haldeman
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
Noga Rogel
Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA
Abigail R. Knecht
Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA
Daneyal Farouq
Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA
Aviv Regev
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; Corresponding author
David Baltimore
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Corresponding author
Summary: 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. : Mann et al. show an age-dependent inflammatory response of hematopoietic stem cells (HSCs) and unveil a CD61-high subpopulation primed for inflammatory response. This CD61-high subpopulation is more prevalent in aged mice and has a cell-intrinsic myeloid-biased potential, which is regulated in part by Ikzf1, Klf5, and Stat3 transcription factors. Keywords: hematopoietic stem cells, stem cell aging, inflammation, single-cell RNA sequencing
