The contribution of the Tie2<sup>+</sup> lineage to primitive and definitive hematopoietic cells

Tang, Yun‐Chi; Harrington, Anne; Yang, Xuehui; Friesel, Robert; Liaw, Lucy

doi:10.1002/dvg.20654

Cited by 147 publications

(138 citation statements)

References 17 publications

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“…(28)(29)(30) We therefore examined whether the reduced TRAP activity in Tie2-Dkk1 TG mice is associated with inhibition of osteoclast differentiation from progenitor cells. To accomplish this, we first examined in vitro differentiation of osteoclast.…”

Section: Resultsmentioning

confidence: 99%

“…The Tie2 promoter and enhancer are commonly used in mouse models to direct transgene expression to endothelial cells. (28,31,32) Indeed, we have previously demonstrated Tie2-driven overexpression of Dkk in endothelial cells. (17) Although Tie2 is expressed in all endothelial cells, (27) there is also evidence that it is expressed in various hematopoietic cells and adult bone marrow.…”

Section: Discussionmentioning

confidence: 95%

“…(17) Although Tie2 is expressed in all endothelial cells, (27) there is also evidence that it is expressed in various hematopoietic cells and adult bone marrow. (28)(29)(30) Therefore, it is possible that Dkk expression driven by Tie2 would be expected to be across the whole embryo in endothelial as well as other cells from early in development. However, we found that Dkk1 (and Dkk2) have no effects on cartilage tissue morphogenesis in the embryo, and only a significant consequence of the overexpression of Dkk1 driven by Tie2 is observed when bone is being formed.…”

Section: Discussionmentioning

confidence: 99%

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Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

Oh¹,

Ryu²,

Jeon³

et al. 2012

Journal of Bone and Mineral Research

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Developing cartilage serves as a template for long-bone development during endochondral ossification. Although the coupling of cartilage and bone development with angiogenesis is an important regulatory step for endochondral ossification, the molecular mechanisms are poorly understood. One possible mechanism involves the action of Dickkopf (DKK), which is a family of soluble canonical Wnt antagonists with four members (DKK1-4). We initially observed opposite expression patterns of Dkk1 and Dkk2 during angiogenesis and chondrocyte differentiation: downregulation of Dkk1 and upregulation of Dkk2. We examined the in vivo role of Dkk1 and Dkk2 in linking cartilage/bone development and angiogenesis by generating transgenic (TG) mice that specifically express Dkk1 or Dkk2 in chondrocytes, hypertrophic chondrocytes, or endothelial cells. Despite specific expression pattern during cartilage development, chondrocyte-and hypertrophic chondrocyte-specific Dkk1 and Dkk2 TG mice showed normal developmental phenotypes. However, Dkk1 misexpression in endothelial cells resulted in defects of endochondral ossification and reduced skeletal size. The defects are caused by the inhibition of angiogenesis in developing bone and subsequent inhibition of apoptosis of hypertrophic chondrocytes and cartilage resorption. ß

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

Oh¹,

Ryu²,

Jeon³

et al. 2012

Journal of Bone and Mineral Research

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“…47 The Tie2 promoter is active in endothelial and hematopoietic lineages from E7.5 onwards, 48 and almost all primitive hematopoietic cells can be traced to Tie2 þ cells. N1ICD and Tie2 have a similar expression pattern in YS blood islands.…”

Section: Discussionmentioning

confidence: 99%

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

et al. 2014

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Loss-of-function studies have demonstrated the essential role of Notch in definitive embryonic mouse hematopoiesis. We report here the consequences of Notch gain-of-function in mouse embryo hematopoiesis, achieved by constitutive expression of Notch1 intracellular domain (N1ICD) in angiopoietin receptor tyrosine kinase receptor-2 (Tie2)-derived enhanced green fluorescence protein (EGFP þ ) hematovascular progenitors. At E9.5, N1ICD expression led to the absence of the dorsal aorta hematopoietic clusters and of definitive hematopoiesis. The EGFP þ transient multipotent progenitors, purified from E9.5 to 10.5 Tie2-Cre;N1ICD yolk sac (YS) cells, had strongly reduced hematopoietic potential, whereas they had increased numbers of hemogenic endothelial cells. Late erythroid cell differentiation stages and mature myeloid cells (Gr1 þ , MPO þ ) were also strongly decreased. In contrast, EGFP þ erythro-myeloid progenitors, immature and intermediate differentiation stages of YS erythroid and myeloid cell lineages, were expanded. Tie2-Cre;N1ICD YS had reduced numbers of CD41 þ þ megakaryocytes, and these produced reduced below-normal numbers of immature colonies in vitro and their terminal differentiation was blocked. Cells from Tie2-Cre;N1ICD YS had a higher proliferation rate and lower apoptosis than wild-type (WT) YS cells. Quantitative gene expression analysis of FACS-purified EGFP þ YS progenitors revealed upregulation of Notch1-related genes and alterations in genes involved in hematopoietic differentiation. These results represent the first in vivo evidence of a role for Notch signaling in YS transient definitive hematopoiesis. Our results show that constitutive Notch1 activation in Tie2 þ cells hampers YS hematopoiesis of E9.5 embryos and demonstrate that Notch signaling regulates this process by balancing the proliferation and differentiation dynamics of lineage-restricted intermediate progenitors.

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“…17 More importantly, Tie1 is expressed by a small proportion (≈20%) of BMD hematopoietic cell lineages 21 (as opposed to other constitutive endothelial-specific Cre models, such as Tie2Cre, which is reportedly expressed in ≈80%). 28 We examined β3-integrin expression in BMDCs from both Cre models. Although we saw no changes in β3-integrin in BMDCs of OHT-treated Pdgfb-iCreER T2 -positive animals, Tie1Cre-positive animals showed a loss of β3-integrin expression in CD45 + cells (CD45 is a PAN marker for hematopoietic cells, including hematopoietic progenitor/ stem cells but excluding erythrocytes and platelets; Online Figure IIB).…”

Section: Resultsmentioning

confidence: 99%

Acute Depletion of Endothelial β3-Integrin Transiently Inhibits Tumor Growth and Angiogenesis in Mice

Steri

Ellison

Gontarczyk

et al. 2014

Circulation Research

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Rationale:The dramatic upregulation of αvβ3-integrin that occurs in the vasculature during tumor growth has long suggested that the endothelial expression of this molecule is an ideal target for antiangiogenic therapy to treat cancer. This discovery led to the development of small-molecule inhibitors directed against αvβ3-integrin that are currently in clinical trials. In 2002, we reported that β3-integrin−knockout mice exhibit enhanced tumor growth and angiogenesis. However, as β3-integrin is expressed by a wide variety of cells, endothelial cell-specific contributions to tumor angiogenesis are muddied by the use of a global knockout of β3-integrin function.Objective: Our aim was to examine the endothelial-specific contribution β3-integrin makes to tumor growth and angiogenesis. Methods and Results:We have crossed β3-integrin-floxed (β3-floxed) mice to 2 endothelial-specific Cre models and examined angiogenic responses in vivo, ex vivo, and in vitro. We show that acute depletion of endothelial β3-integrin inhibits tumor growth and angiogenesis preventatively, but not in already established tumors. However, the effects are transient, and long-term depletion of the molecule is ineffective. Furthermore, long-term depletion of the molecule correlates with many molecular changes, such as reduced levels of focal adhesion kinase expression and a misbalance in focal adhesion kinase phosphorylation, which may lead to a release from the inhibitory effects of decreased endothelial β3-integrin expression. Conclusions:

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The contribution of the Tie2⁺ lineage to primitive and definitive hematopoietic cells

Cited by 147 publications

References 17 publications

Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

Acute Depletion of Endothelial β3-Integrin Transiently Inhibits Tumor Growth and Angiogenesis in Mice

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The contribution of the Tie2+ lineage to primitive and definitive hematopoietic cells

Cited by 147 publications

References 17 publications

Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

Acute Depletion of Endothelial β3-Integrin Transiently Inhibits Tumor Growth and Angiogenesis in Mice

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The contribution of the Tie2⁺ lineage to primitive and definitive hematopoietic cells