Age-related Changes in the Regulation of Hematopoiesis

Abstract

The hematopoietic microenvironment is composed of heterogeneous mesenchymal cells, such as osteoblasts, epithelial cells, fibroblastoid cells, adipocytes and macrophages, which are referred to as stromal cells. Stromal cells regulate hematopoietic stem cell (HSC) by producing positive- and negative-regulators to supply mature hematopoietic cells for the lifetime. It is well known that B lymphopoiesis in the bone marrow (BM) is attenuated with aging, whereas myelopoiesis is not affected. One standing issue is whether age-associated defects in B lymphopoiesis reflect intrinsic defects and/or extrinsic defects of the cells, such as stromal cell defects. Although extensive studies have revealed that age-associated intrinsic defects occur in B cell development, the age-associated stromal cell defects have not been fully elucidated. Since B lymphopoiesis in the BM is more dependent on stromal cells than the other lineages, B lymphopoiesis is a good model to investigate the effect of aging on stromal cells. Senescence accelerated mice (SAMP1) exhibit premature senescence-like stromal cell impairment after 30 weeks of age. Thus, this model mouse is a useful tool to clarify the role of stromal cells during the development of senescence-associated defects in B lymphopoiesis. In the steady state, SAMP1 mice exhibit simultaneous down-regulation of positive- and negative-regulators of B lymphopoiesis in the BM during premature aging, resulting in suppressive homeostasis of B cell development. While both regulators are down-regulated, the relative cytokine levels are barely maintained in the steady-state. Under perturbed conditions induced by 5-fluorouracil or irradiation, aged SAMP1 mice exhibit prolonged dysregulation of cytokine production, resulting in a further diminution of B lymphopoiesis. These results suggest that, in part, age-related deterioration of B cell development may be due to functional impairment of stromal cells, which induces vicious suppressive homeostasis of B cell development. Taken together, age-associated changes in hematopoiesis seem to be due not only to intrinsic-defects but also to extrinsic defects of hematopoietic cells.