Abstract
Age-related decline in the generation of T cells is associated with two primary lymphoid organs, the bone marrow (BM) and thymus. Both organs contain lympho-hematopoietic progenitor/stem cells (LPCs) and non-hematopoietic stromal/niche cells. Murine model showed this decline is not due to reduced quantities of LPCs, nor autonomous defects in LPCs, but rather defects in their niche cells. However, this viewpoint is challenged by the fact that aged BM progenitors have a myeloid skew. By grafting young wild-type (WT) BM progenitors into aged IL-7R-/- hosts, which possess WT-equivalent niches although LPCs are defect, we demonstrated that these young BM progenitors also exhibited a myeloid skew. We, further, demonstrated that aged BM progenitors, recruited by a grafted fetal thymus in the in vivo microenvironment, were able to compete with their young counterparts, although the in vitro manipulated old BM cells were not able to do so in conventional BM transplantation. Both LPCs and their niche cells inevitably get old with increasing organismal age, but aging in niche cells occurred much earlier than in LPCs by an observation in thymic T-lymphopoiesis. Therefore, the aging induced decline in competence to generate T cells is primarily dependent on status of the progenitor niche cells in the BM and thymus.
Highlights
The progressive degeneration and functional decline of cells, tissues, and organs that accompany aging are unavoidable
We asked whether aged bone marrow (BM) progenitors recruited in vivo by a grafted fetal thymus are able to compete with their young counterparts, because when we examined in vivo repopulation in the fetal thymus with aged lympho‐hematopoietic progenitor/stem cells (LPCs) over 1 to 4 weeks in a kidney capsule transplantation (KCT) model and in a time-course manner [1, 34], we found that LPCs from old BM were able to generate the same number of thymocytes (Fig. 2A) with similar differentiation profiles as young BM progenitor did (Fig. 2B)
In the BM and thymus, lympho-hematopoietic and nonhematopoietic cellular compartments tightly regulate competence for T-cell generation, while aging clearly induces defects in this competence [36]. It is still controversial whether the defect originates in the LPC/hematopoietic stem cells (HSCs) itself or in the supportive microenvironment
Summary
The progressive degeneration and functional decline of cells, tissues, and organs that accompany aging are unavoidable. The most rigorous studies on aging have been conducted on the T-lymphoid immune organs, primarily comprising the reservoir for hematopoietic stem cells (HSCs) – the bone marrow (BM), and the immature T-cell cradle and educators – the thymus gland. These organs are all comprised of two main cellular components of different origins: lympho-hematopoietic — immature and mature T cells and non-lympho-hematopoietic — stromal or niche cells. It is important to clarify this clinically relevant issue so that selection of the right target(s) and development of proper strategies to rejuvenate the aged immune system can be implemented. Such an approach will hopefully delay and/or treat the onset of age-related immune deficient diseases
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