FLT3 expression initiates in fully multipotent mouse hematopoietic progenitor cells

Buza‐Vidas, Natalija; Woll, Petter S.; Hultquist, Anne; Duarte, Sara; Lutteropp, Michael; Bouriez-Jones, Tiphaine; Ferry, Helen; Luc, Sidinh; Jacobsen, Sten Eirik W.

doi:10.1182/blood-2010-10-316232

Cited by 64 publications

(75 citation statements)

References 26 publications

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“…1,6,7,16,[18][19][20] A recent IL7R-Cre fate mapping study provided particularly convincing evidence for a shared T/B cell differentiation path and clear separation of myeloid and lymphoid lineages, 6,19 as proposed upon isolation of CLP and CMP. 14,21 Our own data, as well as the results from Buza-Vidas et al, 13 also support this model, as all myeloid-committed cells have similar Flk2-Cre-mediated floxing efficiencies that are lower than those of lymphoid-committed cells. These studies also show that the contribution of putative Flk2 + myeloid restricted progenitors, proT cells or "lymphoid-biased" MPP 10,11,22,23 to the total GM output is either minimal or includes equivalent MegE production.…”

Section: Introductionsupporting

confidence: 73%

Mapping differentiation pathways from hematopoietic stem cells using Flk2/Flt3 lineage tracing

2012

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G enetic fate-mapping approaches provide a unique opportunity to assess differentiation pathways under physiological conditions. We have recently employed a lineage tracing approach to define hematopoietic differentiation pathways in relation to expression of the tyrosine kinase receptor Flk2.1 Based on our examination of reporter activity across all stem, progenitor and mature populations in our Flk2-Cre lineage model, we concluded that all mature blood lineages are derived through a Flk2 + intermediate, both at steady-state and under stress conditions. Here, we reexamine in depth our initial conclusions and perform additional experiments to test alternative options of lineage specification. Our data unequivocally support the conclusion that onset of Flk2 expression results in loss of self-renewal but preservation of multilineage differentiation potential. We discuss the implications of these data for defining stem cell identity and lineage potential among hematopoietic populations.

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Section: Introductionsupporting

confidence: 73%

Mapping differentiation pathways from hematopoietic stem cells using Flk2/Flt3 lineage tracing

2012

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“…[9][10][11][12] DCs develop from HSCs in the BM and are derived from both myeloid and lymphoid progenitors ( Figure 1). [13][14][15][16] This has been demonstrated in both mouse and human studies, in which all DC subsets can be generated from either a common lymphoid progenitor or common myeloid progenitor. 6,[17][18][19] The hematopoietic growth factor fms-like tyrosine kinase 3 ligand (Flt3L) plays a central role in steady-state DC development; this is evidenced by the majority of DC precursors being Flt3 ϩ (CD135 ϩ ) and culture with Flt3L resulting in all major DC subsets.…”

Section: Hematopoiesis and Immunobiologymentioning

confidence: 91%

Dendritic cells and regulation of graft-versus-host disease and graft-versus-leukemia activity

Stenger

Turnquist

Mapara

et al. 2012

Blood

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IntroductionHematopoietic stem cell transplantation (HSCT) remains the only curative therapy for many high-risk malignant hematologic diseases, as well as numerous life-threatening genetic and hematologic disorders. However, despite peritransplant prophylaxis, HSCT is frequently complicated by GVHD, which leads to significant morbidity and mortality. The risk of GVHD limits the broader application of HSCT where it has the potential to cure autoimmune diseases, facilitate transplant tolerance, and correct immunologic deficiencies, including HIV infection. 1 Conventional immunosuppressants remain the mainstay of treatment for GVHD, yet they frequently fail and carry a significant risk for infection. 2,3 It is therefore of significant interest to identify new, effective, and safe prophylactic and therapeutic approaches, particularly those that maintain the critical graft-versus-leukemia (GVL) effect of HSCT. In this review, we consider advances that have been made in understanding the role of dendritic cells (DCs) in GVHD and address the challenge of monitoring, targeting, and exploiting these cells to improve therapeutic outcomes.Our understanding of the pathogenesis of GVHD has advanced significantly over the past 45 years, since Billingham proposed that GVHD is the result of immunocompetent donor cells recognizing recipient antigens (Ags) in an immunocompromised host unable to reject donor cells. 4 The principal immunocompetent donor effector cells are T cells, and the vigor of the immune response is driven by differences in MHC and minor histocompatibility antigens (miHA). Furthermore, the crucial role of Ag-presenting cells (APCs), in particular uniquely well-equipped donor and recipient DCs, has begun to be elucidated, not only in GVHD, but also in the GVL effect of HSCT. DC hematopoiesis and immunobiologyDCs are rare, heterogeneous bone marrow (BM)-derived professional APCs, first characterized in mouse spleen by Steinman and Cohn,5 that are distributed ubiquitously in blood, lymphoid, and peripheral tissues, especially at portals of entry. They arise from hematopoietic stem cells through specialized progenitor subsets 6 and are important in innate and adaptive immune function and in determining the balance between immunity and tolerance. In the normal steady state, DCs reside in "immature" or "semimature" states in the periphery where they constantly take up and process self-Ags and maintain self-tolerance. 7 Immunostimulatory DCs have undergone maturation after recognition of exogenous and endogenous alarmins/danger signals by Toll-like receptors (TLRs). 8 These signals include pathogen-associated molecular patterns in the form of microbial products and danger-associated molecular patterns, such as products of damaged or dying cells (eg, highmobility group protein B1 or DNA). DCs are also matured by CD40 ligation and by proinflammatory cytokines that can induce DC maturation ex vivo, independent of CD40 ligation. Maturation is associated with up-regulation of cell surface MHC gene products, costimulatory ...

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“…Furthermore, they are in accordance with recent data demonstrating that platelets and erythrocytes originate from Flt3-expressing progenitors. [40][41][42] …”

Section: Discussionmentioning

confidence: 99%

In vivo evidence for an instructive role of fms-like tyrosine kinase-3 (FLT3) ligand in hematopoietic development

et al. 2014

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© F e r r a t a S t o r t i F o u n d a t i o nshown to be crucial in sustaining adult B-cell lymphopoiesis. 21 However, ablation of the FLT3/FLT3L axis alone did not result in a complete block in the generation of any hematopoietic lineage, suggesting that FLT3L might exert its crucial role in hematopoiesis through interactions with other cytokines, such as interleukin-7 (IL-7) or stem cell factor. 19,22,23 To elucidate the specific action of FLT3L on hematopoiesis in vivo, FLT3L has been administered, with the results confirming the important role of FLT3L in DC generation. 24 We have previously shown that apart from DC, FLT3L injection leads to transient expansion of a FLT3 + progenitor population with lymphoid and myeloid potential. 25 In order to evaluate the role of FLT3L in the development of different hematopoietic lineages, in this study we investigated the effects of sustained over-expression of FLT3L in a transgenic mouse model. Our study confirms the positive role of FLTL in DC development and highlights the importance of this cytokine in the survival and expansion of lymphoid and myeloid progenitors. Furthermore, our data provide evidence for an instructive role of FLT3L in hematopoietic development. Methods MiceAll mice used in this study were bred and maintained in our animal facility under pathogen-free conditions and all animal experiments were performed in accordance with institutional guidelines (permission numbers 1887 and 1888). Immunization to induce a Tdependent antibody response and FLT3L treatment of mice were carried out as previously described. 25 Cell culturesST2, OP9 and OP9 stromal cells expressing Notch ligand Deltalike 1 (OP9DL1) were maintained in IMDM supplemented with 5 x 10 -5 M β-mercaptoethanol, 1 mM glutamine, 0.03% w/v Primatone (Quest Naarden, the Netherlands), 100 U/mL penicillin, 100 μg/mL streptomycin and 5% fetal bovine serum. Co-cultures of stromal cells with sorted progenitor cells were performed as previously described 25 (and Online Supplementary Materials and Methods). Platelet countsBlood was drawn from the tail vein of mice and incubated with 1% ammonium oxalate for 10 min at room temperature. Following incubation, live cells were counted in a Neubauer hemocytometer. ImmunofluorescenceSpleens were snap-frozen and embedded in OCT-compound (Sakura, Zoetermeer, the Netherlands), and 5 μm sections were prepared. Sections were fixed in acetone for 10 min, air-dried for 60 min and subsequently stained with fluorescein isothiocyanatelabeled anti-CD90, phycoerythrin-labeled anti-IgM and allophycocyanin-labeled anti-CD11c antibodies for 30 min. Results Splenomegaly and lymphadenopathy in FLT3L transgenic miceTo investigate the effect of prolonged FLT3L overexpression, we generated mice expressing the human FLT3L gene under the control of the β-actin promoter (hereafter referred to as FLT3L-Tg mice). FLT3L levels in the blood were in the range of 500-1000 ng/mL, as assesed by enzyme-linked immunosorbent assay using an antihuman FLT3L antibody developed in our ...

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FLT3 expression initiates in fully multipotent mouse hematopoietic progenitor cells

Cited by 64 publications

References 26 publications

Mapping differentiation pathways from hematopoietic stem cells using Flk2/Flt3 lineage tracing

Mapping differentiation pathways from hematopoietic stem cells using Flk2/Flt3 lineage tracing

Dendritic cells and regulation of graft-versus-host disease and graft-versus-leukemia activity

In vivo evidence for an instructive role of fms-like tyrosine kinase-3 (FLT3) ligand in hematopoietic development

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