In vitro analysis of age‐related changes in the developmental potential of bone marrow thymocyte progenitors

Abstract

Mechanisms underlying the age-related decrease in the developmental capacity of thymocyte progenitors from the bone marrow (BM) were analyzed, focussing on interaction of these cells with the thymic microenvironment. We employed the experimental model in which mixtures of young and old mouse BM cells, congenic for the Thy-1 marker, were seeded onto fetal thymus (FT) explains depleted of self lymphocytes and the levels of Thy-1+ cells developing from each of the two donor types were measured. When cells from young and old BM donors were seeded simultaneously, in saturating quantities, a higher level of T cells developed from the young donors. To find out whether there were originally more thymocyte progenitors in the young BM, we carried out the competitive colonization under limiting dilution conditions and found that the advantage of the young had diminished under these conditions, thus suggesting that the age-related changes could not be related solely to quantitative differences. We then incubated the FT sequentially with old donor cells for 24 h, followed by young for an additional 48 h and found that the advantage of the young progenitors was eliminated. We thus established that the initial stage of colonization of the FT was important in determining the outcome of the subsequent development. The kinetics of simultaneous competition within the FT, however, revealed that the advantage of the young BM-derived cells became significant only from day 7 in organ culture, thus suggesting that sequential divisions of these cells were at a higher level than those of the old. Recolonization of FT explants by young or old BM-derived thymocytes obtained from the first colonization of the FT stroma showed a reduced, but still significant advantage for the young BM-derived cells over the old. Thus, we concluded that the old BM thymocyte progenitors manifested a qualitative disadvantage which became apparent during competitive colonization of the FT.

The Effects of Age, Thymectomy, and HIV Infection on α and β TCR Excision Circles in Naive T Cells

“…We could alternatively have made the more classical assumption, and explain decreased thymus production by decreasing the influx, , of progenitor cells (16,40,41). In that model the TREC content of TCR␣␤ ϩ and TCR␤ ϩ thymocytes, and the overall sj/ ␤-TREC ratio would be completely independent of age, because cells on average complete the same number of divisions in the thymus.…”

Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging

“…7 In support of the former, it has been suggested that decreased thymopoietic capacity is caused by the quantitative and/or qualitative alteration of progenitors with aging. [8][9][10][11] However, other investigators have reported that the number of immature CD44 ϩ CD25 Ϫ CD3 Ϫ CD4 Ϫ CD8 Ϫ ("triple-negative," TN) thymocytes is not significantly changed with aging. 12 Instead, increased apoptosis of immature thymocytes caused by insufficient amounts of the stroma-derived cytokine IL-7 reduces the number of thymocytes at subsequent stages of thymic differentiation, and IL-7 treatment normalizes thymopoiesis.…”

Multiple prethymic defects underlie age-related loss of T progenitor competence

“…16,17 Studies using fetal thymic organ culture showed that aged BM is less efficient at reconstituting thymic lobes compared with young BM in competitive conditions. 18 It is possible that these data reflect reduced MPP frequency in aged BM, since MPPs can rapidly develop into thymocytes. However, because these studies did not assess purified populations, they did not distinguish between defects within individual hematopoietic progenitor cells versus age-related changes in frequencies of hematopoietic progenitor populations in the BM preparations.…”