Threshold levels of Flt3‐ligand are required for the generation and survival of lymphoid progenitors and B‐cell precursors

Dolence, Joseph J.; Gwin, Kimberly; Frank, Elena; Medina, Kay L.

doi:10.1002/eji.201040710

Cited by 19 publications

(40 citation statements)

References 42 publications

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“…Similar CFDA dilution in both vehicle-and indomethacin-treated DC progenitor cells indicates that PGE 2 does not regulate DC progenitor cell proliferation; rather, its primary effects are on progenitor cell survival. In support of this hypothesis, recent studies have also shown that Flt3 signaling can regulate progenitor cell survival without affecting proliferation 47,48 PGE 2 is a lipid messenger that regulates the expression of effector genes downstream of G protein-coupled receptors. PGE 2 signaling through EP receptors is known to directly promote survival of colon cancer cells and myocardium by up-regulation of STAT3 and survivin.…”

Section: Discussionmentioning

confidence: 90%

Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells

Singh

Hoggatt

et al. 2012

Blood

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Dendritic cell (DC) homeostasis, like all mature blood cells, is maintained via hierarchal generation from hematopoietic precursors; however, little is known about the regulatory mechanisms governing DC generation. Here, we show that prostaglandin E 2 (PGE 2 ) is required for optimal IntroductionDendritic cells (DCs) are specialized Ag-presenting immune cells that induce adaptive immune responses and maintain self-tolerance and are attractive targets for therapeutic manipulation of the immune system. 1,2 Two main DC subsets have been identified on the basis of their location, phenotype, and function: Ag-presenting classic DC (cDC) and type I IFN-producing plasmacytoid DC (pDC), 3,4 and are generated from Flt3-expressing hematopoietic progenitor cells in the BM. 5,6 Recent studies identified a common DC, monocyte and macrophage precursor designated as macrophage DC progenitor cell (MDP) 7,8 and a common DC progenitor (CDP) that is restricted to DC development. 9 MDPs differentiate to CDPs, which in turn give rise to cDCs and pDCs, but not monocytes, and finally to pre-cDCs, 10 a committed precursor of cDCs. 11,12 Unlike MDPs and CDPs that differentiate within the BM, pre-cDCs traffic to secondary lymphoid organs where they further differentiate into cDCs. 4,13 In addition, monocytes can also develop a DC phenotype under inflammatory conditions. 14,15 Flt3 (also known as Flk2 and CD135) is a receptor tyrosine kinase that is broadly expressed on early BM hematopoietic progenitor cells (HPCs), including DC progenitor cells. 5,9,16 Mice with a deficiency in Flt3 or Flt3 ligand (Flt3L) have reduced DC numbers, 13,17 whereas administration of Flt3L dramatically increases BM and peripheral DCs. 18 Although Flt3 signaling is crucial for DC generation from their progenitor cells at steady state, the normal physiologic mechanisms that control Flt3 expression and regulate Flt3L-dependent DC differentiation remain poorly understood.Prostaglandin E 2 (PGE 2 ) is the predominant metabolite of arachidonic acid metabolism produced through the sequential action of phospholipase A 2 , cyclooxygenases (COXs), and PGE synthase. 19,20 There are 2 functionally distinct COX enzyme isoforms, COX1 and COX2, that are encoded by different genes. 20 PGE 2 has been shown to modulate HPC differentiation, inhibiting CFU-GM 21-23 but promoting erythroid burst-forming unit and granulocyte, erythroid, megakaryocyte, and macrophage CFU. 24,25 The long-acting PGE 2 analog, 16,16-dimethyl-PGE 2 (dmPGE 2 ) was shown to increase HSC frequency and engraftment 26,27 and to enhance HSC survival, proliferation, and homing to the BM. 27 Thus, PGE 2 regulates self-renewal and differentiation of HSCs and HPCs, and its effects can differ, depending on hematopoietic cell type and stage of differentiation.The role of PGE 2 in DC maturation and migration under inflammatory conditions is well known. PGE 2 promotes the migration of monocyte-derived and Langerhans DCs, increases their expression of costimulatory molecules, and enhances their ability to stimulate T...

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Section: Discussionmentioning

confidence: 90%

Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells

Singh

Hoggatt

et al. 2012

Blood

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“…23 An early restriction in differentiation options parallels high expression of the Flt3 receptor. 19,24 Megakaryocyte and erythroid potentials markedly decline, and LSKs with high amounts of Flt3 are enriched for LMPP. 19,24 Therefore, we asked if quantitative differences in CD86 among Flt3 Hi LMPPs could predict differentiation potential.…”

Section: Cd86 ؊ Hscs Are Defective With Respect To Lymphopoiesis and mentioning

confidence: 99%

“…19,24 Megakaryocyte and erythroid potentials markedly decline, and LSKs with high amounts of Flt3 are enriched for LMPP. 19,24 Therefore, we asked if quantitative differences in CD86 among Flt3 Hi LMPPs could predict differentiation potential. The category was sorted into CD86 low and high subsets that were then placed in defined, serum-free, stromal cell-free cultures ( Figure 4B Figure 4).…”

Section: Cd86 ؊ Hscs Are Defective With Respect To Lymphopoiesis and mentioning

confidence: 99%

CD86 is expressed on murine hematopoietic stem cells and denotes lymphopoietic potential

Shimazu

Iida

Zhang

et al. 2012

Blood

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IntroductionA large body of information exists about molecular mechanisms involved in maintaining HSC integrity, and many studies have identified unique markers associated with differentiation. 1 However, several of these parameters differ between strains of mice or change dramatically according to developmental age, activation status, or inflammation. [2][3][4] This issue gained importance with the realization that HSCs are normally heterogeneous and that functionally distinct subsets can be resolved according to phenotypes. [5][6][7][8] As one example, we discovered that a unique population of lineage marker Ϫ Sca-1 ϩ c-Kit ϩ (LSK) CD150 ϩ CD48 Ϫ HSCs lacked CD86. 9 CD86 Ϫ HSCs accumulated in old mice as well as young mice repeatedly injected with lipopolysaccharide (LPS). At least some HSCs in those animals had low ability to self-renew and restore the adaptive immune system when transplanted. In addition, HSCs in the chronically stimulated animals were abnormally in cycle. 9 However, the relation between those phenomena and CD86 loss was unclear.B7-1 (CD80) and B7-2 (CD86) are type I transmembrane proteins that were originally identified as ligands for CD28/CTLA-4. 10 Murine CD80 and CD86 share ϳ 28% amino acid identity, but both are capable of using conserved binding sites to recognize either human or mouse CD28. Although this is important for T-cell activation, another ligand, CTLA-4 functions as an inhibitory receptor for immune responses. 11 CD86 is constitutively expressed on dendritic cells, B cells, and thymic epithelial cells. CD80 is only expressed by activated B and T cells. Several reports suggest that CD80 and CD86 have overlapping functions because double knockout (KO) mice have more severe defects in immune responses than single KOs. 12 However, one report suggests there are differential functions. 13 Given the importance of CD80/86 for T-cell activation, blocking Abs are valuable in establishing tolerance during BM transplantation. 14 Marrow stromal cells express the CD28 ligand in close proximity to B-lineage progenitors, and CD28 might slightly enhance B lymphopoiesis. 15 CD86 is expressed by many HSCs, 7,9 but gain or loss relative to hematopoiesis has not been explored. We now report that CD86 loss on stem and progenitor cells closely parallels their loss of lymphopoietic potential. It is a uniquely useful marker for appreciating functional heterogeneity among HSCs that are otherwise similar. MethodsMice C57BL/6 (CD45.2 alloantigen), CD86-deficient (CD86 Ϫ/Ϫ ), and B6-SJL/ Ly5.1 (CD45.1 alloantigen) mice were purchased from The Jackson Laboratory. C57BL/6 ϫ SJL/Ly5.1 F 1 (CD45.1 and CD45.2 alloantigens) and RAG1/GFP (recombinase activator gene 1/green fluorescent protein) knock-in mice were bred and maintained in the Laboratory Animal Resource Center at the Oklahoma Medical Research Foundation. PU.1 fl/fl and C/EBP␣ fl/fl mice were bred with Mx1 Cre mice to generate PU.1 fl/fl or C/EBP␣ fl/fl ϪMx1 Cre mice. Those and C/EBP␤KO mice were bred and maintained in Beth Israel Deaconess Medical C...

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“…Several cytokines, including IL-7 and Flt3-ligand, drive early B-cell proliferation and differentiation in vivo ; however, IL-7 is the only cytokine supplement added to the methylcellulose media to promote CFU-PreB colony formation [34–36]. Levels of IL-7Rα expressed on the cell surface of Hardy fractions A–D were not significantly different between Hspa9 +/− and Hspa9 +/+ mice as measured by flow cytometry (N=5/genotype) (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…This suggests that homeostatic regulation of B-cell numbers may account for in vivo compensation. IL-7 is the only supportive cytokine added to CFU-PreB media even though other cytokines such as Scf, Flt3-ligand and Cxcl12 regulate B-cell differentiation and proliferation in vivo [34–36]. Relying solely on the IL-7 signaling cascade in CFU-PreB culture conditions in the absence of these other cytokines may sensitize cells to subtle alterations in IL-7 signaling caused by heterozygous Hspa9 loss.…”

Section: Discussionmentioning

confidence: 99%

Reduced levels of Hspa9 attenuate Stat5 activation in mouse B cells

Krysiak¹,

Tibbitts²,

Shao³

et al. 2015

Experimental Hematology

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HSPA9 is located on chromosome 5q31.2 in humans, a region that is commonly deleted in patients with myeloid malignancies [del(5q)], including myelodysplastic syndromes (MDS). HSPA9 expression is reduced by 50% in patients with del(5q)-associated MDS, consistent with haploinsufficient levels. Zebrafish mutants and knockdown studies in human and mouse cells have implicated a role for HSPA9 in hematopoiesis. To comprehensively evaluate the effects of Hspa9 haploinsufficiency on hematopoiesis, we generated an Hspa9 knockout mouse model. While homozygous knockout of Hspa9 is embryonic lethal, mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop MDS. However, Hspa9+/− mice have a cell- intrinsic reduction in bone marrow CFU-PreB colony formation without alterations in the number of B-cell progenitors in vivo, consistent with a functional defect in Hspa9+/− B-cell progenitors. We further reduced Hspa9 expression (<50%) using RNAi and observe reduced B-cell progenitors in vivo, indicating that appropriate levels (≥50%) of Hspa9 are required for normal B- lymphopoiesis in vivo. Knockdown of Hspa9 in an IL-7 dependent mouse B-cell line reduced Stat5 phosphorylation following IL-7 receptor stimulation, supporting a role for Hspa9 in Stat5 signaling in B-cells. Collectively, these data implicate a role for Hspa9 in B-lymphopoiesis and Stat5 activation downstream of IL-7 signaling.

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Threshold levels of Flt3‐ligand are required for the generation and survival of lymphoid progenitors and B‐cell precursors

Cited by 19 publications

References 42 publications

Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells

Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells

CD86 is expressed on murine hematopoietic stem cells and denotes lymphopoietic potential

Reduced levels of Hspa9 attenuate Stat5 activation in mouse B cells

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