FLT3 receptor and ligand are dispensable for maintenance and posttransplantation expansion of mouse hematopoietic stem cells

Buza‐Vidas, Natalija; Cheng, Min; Duarte, Sara; Charoudeh, Hojjatollah Nozad; Jacobsen, Sten Eirik W.; Sitnicka, Ewa

doi:10.1182/blood-2008-08-174060

Cited by 31 publications

(32 citation statements)

References 43 publications

(66 reference statements)

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“…HSCs are also defined by the CD150 ϩ CD48 Ϫ CD41 Ϫ phenotype. 29 Consistent with the fact that in the mouse model FLT3 signaling is dispensable for repopulating HSCs 30 and with the higher enrichment in repopulating HSC in this population compared with the LSK population, 29 FLT3 expression on CD150 ϩ CD48 Ϫ CD41 Ϫ cells was nearly undetectable (supplemental Figure 1E). TGF-␤2 had a similar effect on the FLT3L/KL/TPO-supported proliferation and wt littermate LSK cell proliferation in response to FLT3L, the combination of KL/TPO, or IL3.…”

Section: Resultssupporting

confidence: 60%

“…Consistent with this expression pattern, Prdm16 is critical for the establishment and maintenance of the HSC pool during development and after transplantation. 21,22 Because allelic variation in Prdm16 only appears to affect signaling by FLT3/FLT3L, which has been shown to be dispensable for HSC renewal, 30 deletion of Prdm16 does not model the effect of a single amino acid change in PRDM16, as observed in DBA/2 and C57BL/6 mice.…”

Section: Coding Variation In Prdm16 Determines Regulation Of Responsimentioning

confidence: 97%

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Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-β2 and FLT3 in hematopoiesis

Avagyan

Aguiló

Kamezaki

et al. 2011

Blood

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Hematopoiesis is the process whereby BM HSCs renew to maintain their number or to differentiate into committed progenitors to generate all blood cells. One approach to gain mechanistic insight into this complex process is the investigation of quantitative genetic variation in hematopoietic function among inbred mouse strains. We previously showed that TGF-␤2 is a genetically determined positive regulator of hematopoiesis. In the presence of unknown nonprotein serum factors TGF-␤2, but not TGF-␤1 or -␤3, enhances progenitor proliferation in vitro, an effect that is subject to mouse straindependent variation mapping to a locus on chr.4, Tb2r1. TGF-␤2-deficient mice show hematopoietic defects, demonstrating the physiologic role of this cytokine. Here, we show that TGF-␤2 specifically and predominantly cell autonomously enhances signaling by FLT3 in vitro and in vivo. A coding polymorphism in Prdm16 IntroductionHSCs can self-renew and give rise to all the cells of the blood and the immune system. As they differentiate, HSCs progressively lose their self-renewal capacity and generate lineage-restricted multipotential progenitor (MPP) cells that in turn give rise to mature cells. 1,2 Among inbred mouse strains there is extensive genetically determined variation in the hematopoietic stem and progenitor cell (HSPC) compartment. Traits that vary continuously across genetically different persons are determined by the contribution of multiple loci and are called quantitative trait loci (QTLs). Within the hematopoietic system, QTLs have been mapped that affect HSPC number, cycling activity, cytokine responsiveness, mobilization, aging, and gene expression. [3][4][5][6][7][8][9][10][11][12][13] Although phenotypic consequences of individual polymorphism may be subtle, the identification of genes underlying QTLs is a powerful approach to show novel regulatory mechanisms. [14][15][16] Furthermore, because many genes or pathways that show quantitative genetic variation in the mouse model also do so in humans, 16 this approach allows insight into human genetic variation in a more targeted fashion than is currently possible in genome-wide association studies. Although multiple suggestive "hematopoietic" QTLs have been mapped, only 1 of the underlying genes been identified thus far, latexin, which is involved in the negative regulation of stem cell pool size. 13,14 We have shown that signaling by one isoform of TGF-␤, TGF-␤2, is subject to quantitative genetic variation in HSPCs. 17 Although TGF-␤s either inhibit HSPC growth in vitro or have no effect on them in vivo, 18 we have previously shown that TGF-␤2 is a positive regulator of HSPCs. Studies in Tgfb2-deficient mice showed lower frequency, cycling activity, and in vitro proliferative capacity of HSPCs and showed decreased serial repopulating capacity of HSCs compared with wild-type (wt) littermates. In vitro, TGF-␤2 has a biphasic dose response on the proliferation of purified HSPCs, defined as lineage Ϫ Sca1 ϩ Kit ϩ or LSK cells. Its effect is stimulatory at concentrations...

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Section: Resultssupporting

confidence: 60%

Section: Coding Variation In Prdm16 Determines Regulation Of Responsimentioning

confidence: 97%

Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-β2 and FLT3 in hematopoiesis

Avagyan

Aguiló

Kamezaki

et al. 2011

Blood

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“…3,4 The existence of adult and fetal GMlymphoid-restricted mouse MPPs has been confirmed through alternative approaches, 2,[5][6][7][8] and recently a similar progenitor was also identified in human hematopoiesis. 9,10 The restriction of mouse LMPPs to the fraction of LIN Ϫ SCA1 ϩ KIT ϩ (LSK) cells with high cell-surface FMS-like tyrosine kinase receptor 3 (FLT3) expression and of long-term self-renewing HSCs to LSK cells lacking detectable cell-surface FLT3 expression [11][12][13] raises the question as to what stage of lineage commitment FLT3 (protein) and Flt3 (mRNA) expression is initiated. Notably, the expression of FLT3 in human hematopoiesis appears to initiate already in multipotent stem or progenitor cells with sustained MkE potential, 14,15 differing from the apparent expression pattern in multipotent progenitors in mice.…”

Section: Introductionmentioning

confidence: 99%

FLT3 expression initiates in fully multipotent mouse hematopoietic progenitor cells

Buza‐Vidas

Woll

Hultquist

et al. 2011

Blood

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“…6 In addition, FL is important for lymphocyte (B-cell and T-cell) development, but not for differentiation into myeloid lineages. [7][8][9] In contrast to the more limited expression of flt3 on hematopoietic cells, FL mRNA has been found in various hematopoietic and non-hematopoietic tissues. 10 Alone, or in combination with other growth factors, FL stimulates the proliferation of highly enriched human and murine HSC in vitro and leads to expansion and mobilization of progenitor cells in animals and humans in vitro.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic stem and progenitor cells are differentially mobilized depending on the duration of Flt3-ligand administration

Kruijf¹,

Hagoort²,

Velders³

et al. 2010

Haematologica

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BackgroundFlt3-ligand is a cytokine that induces relatively slow mobilization of hematopoietic cells in animals and humans in vivo. This provides a time-frame to study hematopoietic stem and progenitor cell migration kinetics in detail. Design and MethodsMice were injected with Flt3-ligand (10 μg/day, intraperitoneally) for 3, 5, 7 and 10 days. Mobilization of hematopoietic stem and progenitor cells was studied using colony-formingunit granulocyte/monocyte and cobblestone-area-forming-cell assays. The radioprotective capacity of mobilized peripheral blood mononuclear cells was studied by transplantation of 1.5¥106 Flt3-ligand-mobilized peripheral blood mononuclear cells into lethally irradiated (9.5 Gy) recipients. ResultsHematopoietic progenitor cell mobilization was detected from day 3 onwards and prolonged administration of Flt3-ligand produced a steady increase in mobilized progenitor cells. Compared to Flt3-ligand administration for 5 days, the administration of Flt3-ligand for 10 days led to a 5.5-fold increase in cobblestone-area-forming cells at week 4 and a 5.0-fold increase at week 5. Furthermore, transplantation of peripheral blood mononuclear cells mobilized by 5 days of Flt3-ligand administration did not radioprotect lethally irradiated recipients, whereas peripheral blood mononuclear cells mobilized by 10 days of Flt3-Ligand administration did provide 100% radioprotection of the recipients with significant multilineage donor chimerism. Compared to the administration of Flt3-ligand or interleukin-8 alone, co-administration of interleukin-8 and Flt3-ligand led to synergistic enhancement of hematopoietic stem and progenitor cell mobilization on days 3 and 5. ConclusionsThese results indicate that hematopoietic stem and progenitor cells show different mobilization kinetics in response to Flt3-ligand, resulting in preferential mobilization of hematopoietic progenitor cells at day 5, followed by hematopoietic stem cell mobilization at day 10.Key words: stem cell mobilization, Flt3-ligand, IL-8, animal models. Flt3-ligand administration. Haematologica 2010;95:1061-1067. doi:10.3324/haematol.2009 Citation: de Kruijf E-JFM, Hagoort H, Velders GA, Fibbe WE, and van Pel M. Hematopoietic stem and progenitor cells are differentially mobilized depending on the duration of

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FLT3 receptor and ligand are dispensable for maintenance and posttransplantation expansion of mouse hematopoietic stem cells

Cited by 31 publications

References 43 publications

Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-β2 and FLT3 in hematopoiesis

Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-β2 and FLT3 in hematopoiesis

FLT3 expression initiates in fully multipotent mouse hematopoietic progenitor cells

Hematopoietic stem and progenitor cells are differentially mobilized depending on the duration of Flt3-ligand administration

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