Myeloid-biased hematopoietic stem cells have extensive self-renewal capacity but generate diminished lymphoid progeny with impaired IL-7 responsiveness

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Abstract
The adult hematopoietic stem cell (HSC) compartment contains a substantial population of lineage-biased (Lin-bi) HSCs. Lin-bi HSCs generate cells of all hematopoietic lineages, albeit with skewed ratios of lymphoid to myeloid cells. The biased ratios are stable through serial transplantation, demonstrating that lineage bias is an inherent function of the HSCs. To define the mechanisms that cause lineage bias, the developmental potential of myeloid-biased (My-bi) HSCs was characterized. In serial transplantation experiments, My-bi HSCs contributed significantly longer to repopulation than other types of HSCs. The long lifespan indicates that My-bi HSCs are important for the persistence of HSC function throughout life. My-bi HSCs produce normal levels of myeloid precursors but reduced levels of precursors for the T- and B- lymphocyte lineages. Gene array analysis suggested that the lymphoid progeny of My-bi HSCs express lowered levels of interleukin-7 (IL-7) receptor. Indeed, the progeny derived from My-bi HSCs failed to respond to IL-7 in vitro. Thus, My-bi HSCs are programmed for diminished lymphopoiesis through a mechanism that involves a blunted response of its progeny to the central lymphokine IL-7. The data demonstrate that epigenetic regulation on the level of the HSCs can directly affect the number, composition, and function of the mature progeny.