Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli Are Altered with Age
Author(s)Mann, Mati; Mehta, Arnav; de Boer, Carl G.; Kowalczyk, Monika S.; Lee, Kevin; Haldeman, Pearce; Rogel, Noga; Knecht, Abigail R.; Farouq, Daneyal; Regev, Aviv; Baltimore, David; ... Show more Show less
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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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biology
Mann, Mati et al. “Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli Are Altered with Age.” Cell Reports 25, 11 (December 2018): 2992–3005 © 2018 The Author(s)
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