Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli are Altered with Age [article]

Mati Mann, Arnav Mehta, Carl de Boer, Monika S. Kowalczyk, Kevin Lee, Noga Rogel, Abigail R. Knecht, Daneyal Farouq, Aviv Regev, David Baltimore
2017 biorxiv/medrxiv   pre-print
Long-term hematopoietic stem cells (LT-HSCs) maintain hematopoietic output throughout an animal's lifespan. With age, however, they produce a myeloid-biased output that may lead to 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-seq, we identify a myeloid-biased
more » ... myeloid-biased subset within the LT-HSC population (mLT-HSCs) that is much more common amongst aged LT-HSCs and is uniquely primed to respond to acute inflammatory challenge. We predict several transcription factors to regulate differentially expressed genes between mLT-HSCs and other LT-HSC subsets. Among these, we show that Klf5, Ikzf1 and Stat3 play important roles in age-related inflammatory myeloid bias. These factors may regulate myeloid versus lymphoid balance with age, and can potentially mitigate the long-term deleterious effects of inflammation that lead to hematopoietic pathologies.
doi:10.1101/163402 fatcat:fx5zamz4hbal5jxw2mo4iuepiy