Abstract

One factor responsible for poor hematopoietic health-span is overproduction of myeloid lineage cells at the expense of lymphoid cells, which is associated with increased risk of myeloid leukemia and reduced immune responsiveness with aging. This lineage imbalance is caused by declining ability of hematopoietic stem cells (HSC) to regenerate and sustain proper lineage-balanced production of mature hematopoietic cells. We identify the hematopoietic decline to become significant in C57BL/6 mice as young as 8 months old, suggesting that by middle age the initiation events of myeloid overproduction have already begun to occur. Placing young (2mo) long-term hematopoietic stem cells (LT-HSC) into a 2mo or middle-aged (9-12mo) bone marrow (BM) microenvironment is sufficient to induce myeloid-biased cell production (2mo into 2mo: 12.3% myeloid ± SEM (n= 3) vs. 2mo into 9-12mo: 26.5% myeloid ± SEM (n= 11) ** P < 0.01), clearly implicating components of the bone marrow microenvironment in the age-related overproduction of myeloid cells. Data utilizing RNA-Seq and ELISA analysis identify a decrease in insulin-like growth factor (IGF)-1 expression as candidate signaling factor produced by cells in the middle- aged microenvironment that drive myeloid-biased hematopoiesis from HSC. LT-HSC expression of IGF-1 signaling receptor, IGF1R, is increased with age identifying that the balance of IGF signaling is altered in the bone marrow microenvironment. In vitro studies show that the stimulation of the middle-aged (12-14mo) Lin-/c-kit+/Sca-1+(LSK) population by IGF-1 leads to decreased myeloid production, rescuing the aging phenotype (12-14mo: 126.7 CFU vs. 12-14mo + IGF1: 79.9 CFU ± SEM *** P < 0.001 by one-way ANOVA ± SEM of n= 3 replicates). Phospho-flow analysis of middle-aged LT-HSC from mice indicate increased IGF1R and AKT signaling response to IGF-1 stimulation suggesting the decrease of IGF-1 bioavailability in the bone marrow microenvironment seen during aging is influencing LT-HSC function and lineage output. Our ongoing studies aim to define how aging-induced alterations in the BM microenvironment initiate myeloid lineage-biased hematopoiesis from HSC and how this is mediated through IGF signaling. Understanding these mechanisms may enable new therapeutic approaches to improve hematopoietic health-span.

Disclosures

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.