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Identification of a bone marrow precursor of the earliest thymocytes in adult mouse.

ABSTRACT: The thymus requires continuous replenishment of progenitors from the bone marrow (BM) to sustain T cell development. However, it remains unclear which hematopoietic progenitors downstream from hematopoietic stem cells in the BM home to the thymus in adult mice. In this work, we demonstrate that although multiple BM populations have intrinsic T lineage differentiation potential, a small subset of multipotent progenitors (MPPs) expressing CCR9 preferentially homes to the thymus. These CCR9(+) MPPs are phenotypically similar to the most immature early T lineage progenitors (ETPs) in the thymus and are present in the peripheral blood. Similar to ETPs, CCR9(+) MPPs undergo Notch signaling, as indicated by higher expression of Notch1 and downstream target Hes1 genes compared with other MPP subsets. Furthermore, CCR9(+) MPPs possess differentiation potential similar to that of ETPs, with very limited granulocyte/macrophage differentiation potential, but they can differentiate into T, B, and dendritic cells. These characteristics implicate CCR9(+) MPPs as the BM precursors of the earliest thymic progenitors. In addition, our data suggest that before transition from BM to thymus, MPPs are lymphoid-specified and primed for T lineage differentiation.

SUBMITTER: Lai AY

PROVIDER: S-EPMC1851047 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Identification of a bone marrow precursor of the earliest thymocytes in adult mouse.

Lai Anne Y AY Kondo Motonari M

Proceedings of the National Academy of Sciences of the United States of America 20070402 15

The thymus requires continuous replenishment of progenitors from the bone marrow (BM) to sustain T cell development. However, it remains unclear which hematopoietic progenitors downstream from hematopoietic stem cells in the BM home to the thymus in adult mice. In this work, we demonstrate that although multiple BM populations have intrinsic T lineage differentiation potential, a small subset of multipotent progenitors (MPPs) expressing CCR9 preferentially homes to the thymus. These CCR9(+) MPPs ...[more]

PMID: 17404232

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Project description:Mitochondrial metabolism is a tightly regulated process that plays a central role throughout the lifespan of hematopoietic cells. Herein, we analyze the consequences of the mitochondrial oxidative phosphorylation (OXPHOS)/metabolism disorder associated with the cell-specific hematopoietic ablation of apoptosis-inducing factor (AIF). AIF-null (AIF-/Y ) mice developed pancytopenia that was associated with hypocellular bone marrow (BM) and thymus atrophy. Although myeloid cells were relatively spared, the B-cell and erythroid lineages were altered with increased frequencies of precursor B cells, pro-erythroblasts I, and basophilic erythroblasts II. T-cell populations were dramatically reduced with a thymopoiesis blockade at a double negative (DN) immature state, with DN1 accumulation and delayed DN2/DN3 and DN3/DN4 transitions. In BM cells, the OXPHOS/metabolism dysfunction provoked by the loss of AIF was counterbalanced by the augmentation of the mitochondrial biogenesis and a shift towards anaerobic glycolysis. Nevertheless, in a caspase-independent process, the resulting excess of reactive oxygen species compromised the viability of the hematopoietic stem cells (HSC) and progenitors. This led to the progressive exhaustion of the HSC pool, a reduced capacity of the BM progenitors to differentiate into colonies in methylcellulose assays, and the absence of cell-autonomous HSC repopulating potential in vivo. In contrast to BM cells, AIF-/Y thymocytes compensated for the OXPHOS breakdown by enhancing fatty acid β-oxidation. By over-expressing CPT1, ACADL and PDK4, three key enzymes facilitating fatty acid β-oxidation (e.g., palmitic acid assimilation), the AIF-/Y thymocytes retrieved the ATP levels of the AIF +/Y cells. As a consequence, it was possible to significantly reestablish AIF-/Y thymopoiesis in vivo by feeding the animals with a high-fat diet complemented with an antioxidant. Overall, our data reveal that the mitochondrial signals regulated by AIF are critical to hematopoietic decision-making. Emerging as a link between mitochondrial metabolism and hematopoietic cell fate, AIF-mediated OXPHOS regulation represents a target for the development of new immunomodulatory therapeutics.

Dataset Information

Identification of a bone marrow precursor of the earliest thymocytes in adult mouse.

Publications

Identification of a bone marrow precursor of the earliest thymocytes in adult mouse.

Similar Datasets

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