Age-related functional changes in hematopoietic microenvironment

The hematopoietic microenvironment composed of stromal cells strictly regulates hematopoietic stem cells and hematopoietic progenitor cells by producing positive- and negative-regulators to supply mature hematopoietic cells to the periphery throughout its entire lifetime. However, hematopoiesis attenuates with aging. Extensive studies have revealed cell-intrinsic deterioration of hematopoietic cells with aging, but the responsibility of the age-associated deterioration of stromal cells has not yet been fully elucidated. Senescence-accelerated mice (SAMP1) exhibited premature senescence-like stromal cell impairment after 30 weeks of age. Thus, this model mouse is a useful tool for clarifying the role of stromal cells during the development of senescence-associated defects in hematopoiesis. It is well known that B lymphopoiesis at steady-state is attenuated with aging, whereas myelopoiesis remains unaffected. At steady-state, SAMP1 mice exhibit simultaneous down-regulation of positive- and negative-regulators of B lymphopoiesis in the bone marrow during premature aging, resulting in suppressive homeostasis in B cell development. While both regulators are down-regulated, the relative cytokine levels are barely maintained at a steady-state. Once SAMP1 mice are in a perturbed condition induced by myeloablation or inflammation, the latent deterioration of stromal cell function becomes apparent in aged mice: they exhibit dysregulation of positive and negative regulators produced by stromal cells, resulting in decreased supportive activity for not only B lymphopoiesis, but also for the hematopoiesis of other lineages, such as myelopoiesis, erythropoiesis and mast cell development. These results suggest that the age-associated deterioration of hematopoiesis may be due not only to hematopoietic cell-intrinsic deterioration, but also to hematopoietic cell-extrinsic deterioration, such as stromal cell deterioration.