Reductive isolation from bone marrow and blood implicates common lymphoid progenitors as the major source of thymopoiesis

Stanford Institute of Stem Cell Biology and Regenerative Medicine, CA, USA.
Blood (Impact Factor: 10.45). 11/2008; 113(4):807-15. DOI: 10.1182/blood-2008-08-173682
Source: PubMed


Ongoing thymopoiesis requires continual seeding from progenitors that reside within the bone marrow (BM), but the identity of the most proximate prethymocytes has remained controversial. Here we take a comprehensive approach to prospectively identify the major source of thymocyte progenitors that reside within the BM and blood, and find that all thymocyte progenitor activity resides within a rare Flk2(+)CD27(+) population. The BM Flk2(+)CD27(+) subset is predominantly composed of common lymphoid progenitors (CLPs) and multipotent progenitors. Of these 2 populations, only CLPs reconstitute thymopoiesis rapidly after intravenous injection. In contrast, multipotent progenitor-derived cells reconstitute the thymus with delayed kinetics only after they have reseeded the BM, self-renewed, and generated CLPs. These results identify CLPs as the major source of thymocyte progenitors within the BM.

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    • "Multiple bone marrow-derived hematopoietic precursor populations that belong mainly to the MPP or the CLP subsets are able to enter the thymus (Saran et al., 2010; Serwold et al., 2009), where they represent the population of early thymic progenitors (ETP), the initial source for the development of T cells. At this developmental stage the ETP still retain beside the T cell developmental potential also the capability to develop into B cells, macrophages, granulocytes, dendritic cells, and NK cells. "

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    • "The frequency of TNPs in BM was approximately half of the frequency of CLPs, while in blood the frequency of TNPs was comparable with that of CD90+ precursors (Figure 1B). Based on calculations made by us and others to determine absolute numbers of MPPs and CLPs in BM and blood we estimate that the observed frequencies of TNP correspond to 18,000 cells per femur and 50 cells per mL of blood [2], [3], [16]. It remains to be established though, whether TNPs constitute a homogeneous population. "
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    ABSTRACT: T cell development depends on continuous recruitment of progenitors from bone marrow (BM) to the thymus via peripheral blood. However, both phenotype and functional characteristics of physiological T cell precursors remain ill-defined. Here, we characterized a putative CD135(+)CD27(+) T cell progenitor population, which lacked expression of CD127, CD90, and high levels of CD117 and was therefore termed triple negative precursor (TNP). TNPs were present in both BM and blood and displayed robust T lineage potential, but virtually no myeloid or B lineage potential, in vitro. However, TNPs did not efficiently generate T lineage progeny after intravenous or intrathymic transfer, suggesting that a physiological thymic microenvironment does not optimally support T cell differentiation from TNPs. Thus, we propose that physiological T cell precursors are confined to populations expressing either CD127, CD90, or high levels of CD117 in addition to CD135 and CD27 and that TNPs may have other physiological functions.
    Preview · Article · Feb 2012 · PLoS ONE
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    • "Furthermore, MPP have been shown by numerous laboratories to be responsible for a more extended thymopoiesis than CLP [12] [13] [19] [20] [21] [22]. Nevertheless, recent reports have raised new questions as they implicated CLPs as the only immediate source of ETPs, with MPPs allowing an extended thymopoiesis because of their renewal in the BM before further differentiation into CLPs [23] [24]. Thus, further experiments are necessary to elucidate the stages directly linking HSC in the bone marrow to a T cell-committed progenitor in the thymus. "
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    ABSTRACT: The thymus forms as an alymphoid thymic primordium with T cell differentiation requiring the seeding of this anlage. This review will focus on the characteristics of the hematopoietic progenitors which colonize the thymus and their subsequent commitment/differentiation, both in mice and men. Within the thymus, the interplay between Notch1 and IL-7 signals is crucial for the orchestration of T cell development, but the precise requirements for these factors in murine and human thympoeisis are not synonymous. Recent advances in our understanding of the mechanisms regulating precursor entry and their maintenance in the thymus will also be presented.
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