Identification of very early lymphoid precursors in bone marrow and their regulation by estrogen

Medina, Kay L.; Garrett, Karla P.; Thompson, Linda F.; Rossi, Maria Isabel D.; Payne, Kimberly J.; Kincade, Paul W.

doi:10.1038/90659

Cited by 210 publications

(196 citation statements)

References 56 publications

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“…A variety of evidence suggests that prolymphocytes in the Lin Ϫ c-kit low fraction of bone marrow are more differentiated than early lymphoid progenitors (ELP) in the Lin Ϫ c-kit high category (33,(35)(36)(37). For example, prolymphocytes efficiently give rise to CD19 ϩ B lineage cells in less than 1 wk, and the fraction has a greatly reduced incidence of myeloid progenitors.…”

Section: Adiponectin Inhibits B Lymphopoiesis Only When Stromal Cellsmentioning

confidence: 99%

Adiponectin, a Fat Cell Product, Influences the Earliest Lymphocyte Precursors in Bone Marrow Cultures by Activation of the Cyclooxygenase-Prostaglandin Pathway in Stromal Cells

Yokota

Meka

Kouro

et al. 2003

The Journal of Immunology

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130

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Adiponectin, an adipocyte-derived hormone, is attracting considerable interest as a potential drug for diabetes and obesity. Originally cloned from human s.c. fat, the protein is also found in bone marrow fat cells and has an inhibitory effect on adipocyte differentiation. The aim of the present study is to explore possible influences on lymphohematopoiesis. Recombinant adiponectin strongly inhibited B lymphopoiesis in long-term bone marrow cultures, but only when stromal cells were present and only when cultures were initiated with the earliest category of lymphocyte precursors. Cyclooxygenase inhibitors abrogated the response of early lymphoid progenitors to adiponectin in stromal cell-containing cultures. Furthermore, PGE2, a major product of cyclooxygenase-2 activity, had a direct inhibitory influence on purified hematopoietic cells, suggesting a possible mechanism of adiponectin action in culture. In contrast to lymphopoiesis, myelopoiesis was slightly enhanced in adiponectin-treated bone marrow cultures, and even when cultures were initiated with single lymphomyeloid progenitors. Finally, human B lymphopoiesis was also sensitive to adiponectin in stromal cell cocultures. These results suggest that adiponectin can negatively and selectively influence lymphopoiesis through induction of PG synthesis. They also indicate ways that adipocytes in bone marrow can contribute to regulation of blood cell formation.

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Section: Adiponectin Inhibits B Lymphopoiesis Only When Stromal Cellsmentioning

confidence: 99%

Adiponectin, a Fat Cell Product, Influences the Earliest Lymphocyte Precursors in Bone Marrow Cultures by Activation of the Cyclooxygenase-Prostaglandin Pathway in Stromal Cells

Yokota

Meka

Kouro

et al. 2003

The Journal of Immunology

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130

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“…Intracellular staining was performed as described by Medina et al (2001). Bone marrow pro-B/pre-B cells were enriched by negative selection using biotinylated anti-Gr-1, Mac-1, Ter119, CD3 , and IgM antibodies, strepavidin-conjugated magnetic beads and MACS columns (Militenyi Biotec).…”

Section: Intracellular Staining and Cell-cycle Analysis With 7-aadmentioning

confidence: 99%

IRF-4,8 orchestrate the pre-B-to-B transition in lymphocyte development

Lu¹,

Medina²,

Lancki³

et al. 2003

Genes Dev.

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240

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IRF-4,8 are two specialized members of the interferon regulatory factor (IRF) family that have been implicated in regulating immunoglobulin (Ig) light-chain gene transcription during B-lymphocyte development (Pongubala et al. 1992;Eisenbeis et al. 1995;Shaffer et al. 1997;Brass et al. 1999; Muljo and Schlissel 2002). They are more highly related to one another than to other IRFs and are selectively expressed in the lymphoid and myeloid lineages of the immune system (for review, see Taniguchi et al. 2001). IRF-4,8 bind very weakly to DNA-containing IRF sites, but are recruited to their binding sites via interactions with other transcription factors. In particular, the related Ets family transcription factors PU.1 and Spi-B have been shown to recruit IRF-4 or IRF-8 to Ets-IRF composite elements (EICE) in Ig 3Ј and enhancers (Pongubala et al. 1992;Eisenbeis et al. 1995;Brass et al. 1999;Escalante et al. 2002). These heterodimeric protein complexes have been implicated in the control of Ig light-chain gene transcription. PU.1 is required for early B-cell development and Spi-B is important for B-cell activation (Scott et al. 1994;Su et al. 1997). It remains to be determined whether PU.1/Spi-B regulate Ig light-chain gene expression during the pre-B-to-B transition. IRF-4 −/− mutant mice exhibit profound defects in B-and T-cell activation that are manifested in the failure to mount antibody, cytotoxic, or antitumor responses (Mittrucker et al. 1997;Rengarajan et al. 2002). IRF-8 −/− mutant mice are impaired in macrophage development, highly susceptible to viral infections, and manifest a chronic myelogenous leukemia-like syndrome (Holtschke et al. 1996). Loss of either IRF-4 or IRF-8 does not block the generation of B lymphocytes. Given their structural relatedness and similar molecular properties, we sought to examine whether they function redundantly to regulate Ig lightchain gene expression and the pre-B-to-B transition. (Fig. 1A). Strikingly, the double mutant mice lacked sIgM + peripheral B lymphocytes (Fig. 1B). In contrast, splenic T lymphocytes, (CD4 + or CD8 + ) were present in the double mutant mice, albeit with reduced numbers (Fig. 1C). We note that loss of IRF-4 and IRF-8 does not impair T-cell development in the thymus (data not shown). We next examined B-cell generation in the bone marrow. Immature IgM + B cells were absent in the IRF-4,8 −/− bone marrow (Fig. 1D). These results establish that the combined loss of IRF-4,8 causes a lineage-specific block to B-cell development. It should be noted that as is the case for IRF-8 −/− mice, there was an increase in the numbers of myeloid cells Fig. 2A). The levels of HSA expression on the mutant B220 + , CD43 + , BP-1 + , B-lineage cells were particularly high, suggesting that they represent transitional pre-B cells, which are a subset of fraction C cells in the nomenclature of Hardy et al. (1991). The disproportionate increase in the percentage fraction C cells in the IRF-4,8 −/− bone marrow ( Fig. 2A) was also reflected in a substantial increase in their a...

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“…17,18 Investigating human B-cell differentiation is hampered both by the low proliferation rate of human pro-B cells 8,19 and the small number of markers recognizing early-B cells, as opposed to those available in mice (B220, CD43, CD24, c-Kit, AA4.1). [20][21][22] Furthermore, reproducible conditions to grow human B-cell progenitors in vitro have been described only recently. High numbers of CD34 Ϫ CD19 ϩ CD10 ϩ sIgM Ϫ pre-B cells that express Pax-5, -like, and transcripts are obtained 23 in cocultures of cord bloodderived CD34 ϩ cells on murine feeders.…”

Section: Introductionmentioning

confidence: 99%

In vitro identification of human pro-B cells that give rise to macrophages, natural killer cells, and T cells

Reynaud

Lefort

Manié

et al. 2003

Blood

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IntroductionEarly stages of human B-cell development can be identified by the expression of cytoplasmic and cell-surface markers and the ordered rearrangements of the V, D, and J gene segments that encode the variable domain of the immunoglobulin heavy-chain (IgH) locus. 1 Thus, D3J H rearrangements in pro-B cells precede the V3DJ H rearrangement in pre-B cells. The earliest B-cell precursors that carry a complete VDJ H rearrangement have been identified by their intracellular expression of a chain without light (L) chain. These pre-B cells express the CD10 and CD19 antigens and the chain associated with a surrogate light chain coded by the 5/14.1 and VpreB genes. 2 More primitive pro-B cells recognized by their expression of CD34, CD19, and CD10 antigens carry a DJ H rearrangement, which can be transcribed. More recently, CD19 Ϫ cells have been isolated from fresh bone marrow, which expresses the B-cell receptor (BCR)-associated molecule CD79a or Vpre-B proteins and a DJ H rearrangement. [3][4][5][6] This suggests that the B-cell program can be activated prior to the expression of the CD19 antigen and VDJ H rearrangement. How multipotent stem cells progressively restrict their potential to a B-cell fate has been best studied in mice deleted of key control genes, such as E2A, EBF, Absence of the first 2 arrest B-cell differentiation prior to the DJ H rearrangement, whereas typical B220 ϩ c-Kit ϩ pro-B cells, which have initiated DJ H rearrangement and express Rag-1, Rag-2, TdT, 5, VpreB, E2A, and EBF, can be isolated from the bone marrow of Pax-5 Ϫ/Ϫ mice. Despite their pro-B phenotype, these cells can differentiate into macrophages, osteoclasts, dendritic cells, natural killer (NK) cells, T cells, granulocytic cells and erythroid cells in vitro and in vivo, when exposed to the appropriate conditions. 10,11 On the basis of these observations, it has been proposed that the B-cell program is first activated in a "multipotent" cell and that the function of Pax-5 is to repress the myeloid and T-cell genes and restrict cells to a B-cell fate. 12,13 Even though this 2-step pattern has not been demonstrated using primary cells or wild-type mice, a close proximity exists between B-lymphoid, macrophages, and osteoclast lineages in healthy mice, [14][15][16] perhaps controlled by the relative levels of Pu.1 and Pax-5. 17,18 Investigating human B-cell differentiation is hampered both by the low proliferation rate of human pro-B cells 8,19 and the small number of markers recognizing early-B cells, as opposed to those available in mice (B220, CD43, CD24, c-Kit, AA4.1). [20][21][22] Furthermore, reproducible conditions to grow human B-cell progenitors in vitro have been described only recently. High numbers of CD34 Ϫ CD19 ϩ CD10 ϩ sIgM Ϫ pre-B cells that express Pax-5, -like, and transcripts are obtained 23 in cocultures of cord bloodderived CD34 ϩ cells on murine feeders. [23][24][25][26][27][28] Human B-cell differentiation can also be obtained in vivo in NOD-SCID (nonobese diabetic severe combined immunodeficient) mice inj...

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Identification of very early lymphoid precursors in bone marrow and their regulation by estrogen

Cited by 210 publications

References 56 publications

Adiponectin, a Fat Cell Product, Influences the Earliest Lymphocyte Precursors in Bone Marrow Cultures by Activation of the Cyclooxygenase-Prostaglandin Pathway in Stromal Cells

Adiponectin, a Fat Cell Product, Influences the Earliest Lymphocyte Precursors in Bone Marrow Cultures by Activation of the Cyclooxygenase-Prostaglandin Pathway in Stromal Cells

IRF-4,8 orchestrate the pre-B-to-B transition in lymphocyte development

In vitro identification of human pro-B cells that give rise to macrophages, natural killer cells, and T cells

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