Impaired Ability of Bone Marrow Stromal Cells to Support B-Lymphopoiesis With Age

Abstract

B-lymphopoiesis decreases with age. We studied how aging affects bone marrow stromal cells, because they provide the growth factors and cell contacts required for B-lymphopoiesis. No differences were noted in the cell-surface phenotype of young and old primary-cultured stromal cells. Fluorescence-activated cell sorter-purified stromal cells from old mice were deficient in the ability to support the proliferation of interleukin-7 (IL-7)–specific B-lymphoid cell lines. The kinetics of this response indicated that IL-7 was not immediately available from stromal cells of either age and was further delayed on aged stromal cells. The levels of IL-7 protein within stromal cells were equivalent between young and old animals, suggesting that the production of IL-7 was not altered by aging. Negligible amounts of IL-7 were found either freely secreted or in the extracellular matrix of cultures of young and old marrow. Contact between the lymphoid cells and the primary stromal cells was required for detectable proliferation, suggesting that cell contact was required for the release of IL-7. We propose that stromal cells regulate B-lymphopoiesis by limiting the amount of IL-7 available to the developing precursors. Therefore, we conclude that the age-related decrease in the function of bone marrow stromal cells is related to the impaired release of IL-7.

Aging and Options to Halt Declining Immunity to Virus Infections

“…Although total B cell counts remain relatively stable in the adult population, a reduced output of naive B cells from the bone marrow (BM) has been reported in mouse and human studies (226)(227)(228)(229). Decreased production of IL-7 by stromal cells in the BM, reduces the size of the B cell progenitor population and affects B lymphopoiesis (230)(231)(232). The function of hematopoietic stem cells (HSCs) declines with age and shifts toward the generation of non-lymphoid cells, therefore reducing the source of B cell progenitors.…”

Immune senescence: significance of the stromal microenvironment

“…The development of B cells is critically dependent upon the stromal environment within the BM [34], and although maturation of B cells resides within a different compartment, which is associated with HSC differentiation, given the agerelated changes within the BM niche [15], the defects of B cell function in the aged could nevertheless be attributed, in part, to the aged microenvironment. Previous studies have shown that primary culture of stromal cells from old and not young fail to support B cell development, due possibly to a defect in the secretion of interleukin (IL)-7, a key cytokine for B cell maturation, from ageing stromal cells [35]. Adoptive transfer experiments suggest that the aged BM stroma may reduce the recombinase activity in B cell progenitors which leads to the inability to undergo gene rearrangement, resulting in a decrease in B cell differentiation [36].…”

Adaptive immunity and atherosclerosis: aging at its crossroads

“…In addition to an aging-associated decrease in self renewal of HSCs in the bone marrow, a reduction in the differentiation of progenitor B cells, precursor B cells and immature B cells has for instance been correlated to the presence of aged bone marrow stroma in aged mouse models ( 73 , 130 ). This impaired differentiation can be partially attributed to a reduced capacity of the murine progenitor B cells to respond to stromal derived IL-7 on which they depend for their survival ( 131 , 132 ). Similar to T cells, a reduction in B cell precursors in lymphoid organs could conceivably impact the diversity of the BCR repertoire.…”