PT  - JOURNAL ARTICLE
AU  - Mati Mann
AU  - Arnav Mehta
AU  - Carl de Boer
AU  - Monika S. Kowalczyk
AU  - Kevin Lee
AU  - Noga Rogel
AU  - Abigail R. Knecht
AU  - Daneyal Farouq
AU  - Aviv Regev
AU  - David Baltimore
TI  - Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli are Altered with Age
AID  - 10.1101/163402
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 163402
4099  - http://biorxiv.org/content/early/2017/11/14/163402.short
4100  - http://biorxiv.org/content/early/2017/11/14/163402.full
AB  - 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 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.LT-HSCs from young and aged mice have differential responses to acute inflammatory challenge.HSPCs directly sense inflammatory stimuli in vitro and have a robust transcriptional response.Aged LT-HSCs demonstrate a cell-intrinsic myeloid bias during inflammatory challenge.Single-cell RNA-seq unmasked the existence of two subsets within the LT-HSC population that was apparent upon stimulation but not steady-state. One of the LT-HSC subsets is more prevalent in young and the other in aged mice.Klf5, Ikzf1 and Stat3 regulate age‐ and inflammation-related LT-HSC myeloid-bias.One sentence summary Murine hematopoietic stem cells display transcriptional heterogeneity that is quantitatively altered with age and leads to the age-dependent myeloid bias evident after inflammatory challenge.