Endothelial Smad4 restrains the transition to hematopoietic progenitors via suppression of ERK activation

Lan, Yu; He, Wenyan; Li, Zhuan; Wang, Yu; Wang, Jun; Gao, Junying; Wang, Weili; Cheng, Tao; Liu, Bing; Yang, Xiao

doi:10.1182/blood-2013-09-526053

Cited by 24 publications

(24 citation statements)

References 48 publications

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“…; Lan et al . ). Cre‐mediated recombination within the reporter locus activates YFP expression, which indelibly marks liver sinusoidal endothelial cells and their progeny for their entire lifespan (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…; Lan et al . ), mice expressing Cre recombinase under the control of the VE‐Cadherin promoter (Zovein et al . ) were used to trace the fate of endothelial cells during liver regeneration.…”

Section: Resultsmentioning

confidence: 99%

“…To track the in vivo fate of pre-existing LSECs in liver regeneration, we used double transgenic mice harboring Tie2-cre and floxed ROSA26-loxP-stop-loxP-EYFP (herein ROSA EYFP ; Quoix et al 2007) reporter alleles. Tie2-Cre is expressed in the vascular endothelium, including that of neurological tissues (Li et al 2012;Lan et al 2014). Cre-mediated recombination within the reporter locus activates YFP expression, which indelibly marks liver sinusoidal endothelial cells and their progeny for their entire lifespan (Fig.…”

Section: Lsecs Can Convert Into Hepatocytes During Liver Regenerationmentioning

confidence: 99%

“…Unlike LSECs, progenitor cells such as oval cells and/or hepatic stellate cells have been previously reported to convert into hepatocytes during liver regeneration Ji et al 2015). Since Tie2-Cre-mediated excision could also occur in non-endothelial populations such as mesenchymal cells surrounding the vitelline artery (Li et al 2006;Lan et al 2014), mice expressing Cre recombinase under the control of the VE-Cadherin promoter (Zovein et al 2008) were used to trace the fate of endothelial cells during liver regeneration. Unlike Tie2-Cre transgenic mice, Cre recombinase is only expressed in the endothelium of developing and quiescent vessels in VE-Cadherin-Cre (VE-CAD-Cre) transgenic mice (Huang et al 2014; Fig.…”

Section: Gene Primermentioning

confidence: 99%

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Lineage tracing reveals conversion of liver sinusoidal endothelial cells into hepatocytes

Tan

Chen²,

Shao³

et al. 2016

Dev Growth Differ

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Although liver sinusoidal endothelial cells (LSECs) have long been known to contribute to liver regeneration following injury, the exact role of these cells in liver regeneration remains poorly understood. In this work, we performed lineage tracing of LSECs in mice carrying Tie2-Cre or VE-cadherin-Cre constructs to facilitate fate-mapping of LSECs in liver regeneration. Some YFP-positive LSECs were observed to convert into hepatocytes following a two-thirds partial hepatectomy (PH). Furthermore, human umbilical vein endothelial cells (HUVECs) could be triggered to convert into cells that closely resembled hepatocytes when cultured with serum from mice that underwent an extended PH. These findings suggest that mature non-hepatocyte LSECs play an essential role in mammalian liver regeneration by converting to hepatocytes. The conversion of LSECs to hepatocyte-like (iHep) cells may provide a new approach to tissue engineering.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Lsecs Can Convert Into Hepatocytes During Liver Regenerationmentioning

confidence: 99%

Section: Gene Primermentioning

confidence: 99%

See 2 more Smart Citations

Lineage tracing reveals conversion of liver sinusoidal endothelial cells into hepatocytes

Tan

Chen²,

Shao³

et al. 2016

Dev Growth Differ

View full text Add to dashboard Cite

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“…To our knowledge, this is the first study linking ETS and GATA factors to the regulation of BMP pathway activity in endothelial cells and provides an important framework to study the relationship in other contexts where both are crucial, including blood development (38,39).…”

Section: Discussionmentioning

confidence: 99%

SMAD1 and SMAD5 Expression Is Coordinately Regulated by FLI1 and GATA2 during Endothelial Development

Marks-Bluth

Khanna

Chandrakanthan

et al. 2015

Molecular and Cellular Biology

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hThe bone morphogenetic protein (BMP)/SMAD signaling pathway is a critical regulator of angiogenic sprouting and is involved in vascular development in the embryo. SMAD1 and SMAD5, the core mediators of BMP signaling, are vital for this activity, yet little is known about their transcriptional regulation in endothelial cells. Here, we have integrated multispecies sequence conservation, tissue-specific chromatin, in vitro reporter assay, and in vivo transgenic data to identify and validate Smad1؉63 and the Smad5 promoter as tissue-specific cis-regulatory elements that are active in the developing endothelium. The activity of these elements in the endothelium was dependent on highly conserved ETS, GATA, and E-box motifs, and chromatin immunoprecipitation showed high levels of enrichment of FLI1, GATA2, and SCL at these sites in endothelial cell lines and E11 dorsal aortas in vivo. Knockdown of FLI1 and GATA2 but not SCL reduced the expression of SMAD1 and SMAD5 in endothelial cells in vitro. In contrast, CD31؉ cKit ؊ endothelial cells harvested from embryonic day 9 (E9) aorta-gonad-mesonephros (AGM) regions of GATA2 null embryos showed reduced Smad1 but not Smad5 transcript levels. This is suggestive of a degree of in vivo selection where, in the case of reduced SMAD1 levels, endothelial cells with more robust SMAD5 expression have a selective advantage.

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Nupr1 Negatively Regulates Endothelial to Hematopoietic Transition in the Aorta‐Gonad‐Mesonephros Region

et al. 2023

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In the aorta of mid-gestational mouse embryos, a specialized endothelial subpopulation termed hemogenic endothelial cells (HECs) develops into hematopoietic stem and progenitor cells (HSPCs), through a conserved process of endothelial-to-hematopoietic transition (EHT). EHT is tightly controlled by multiple intrinsic and extrinsic mechanisms. Nevertheless, the molecular regulators restraining this process remain poorly understood. Here, it is uncovered that, one of the previously identified HEC signature genes, Nupr1, negatively regulates the EHT process. Nupr1 deletion in endothelial cells results in increased HSPC generation in the aorta-gonad-mesonephros region. Furthermore, single-cell transcriptomics combined with serial functional assays reveals that loss of Nupr1 promotes the EHT process by promoting the specification of hematopoiesis-primed functional HECs and strengthening their subsequent hematopoietic differentiation potential toward HSPCs. This study further finds that the proinflammatory cytokine, tumor necrosis factor 𝜶 (TNF-𝜶), is significantly upregulated in Nupr1-deficient HECs, and the use of a specific TNF-𝜶 neutralizing antibody partially reduces excessive HSPC generation in the explant cultures from Nupr1-deficient embryos. This study identifies a novel negative regulator of EHT and the findings indicate that Nupr1 is a new potential target for future hematopoietic stem cell regeneration research.

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Endothelial Smad4 restrains the transition to hematopoietic progenitors via suppression of ERK activation

Abstract: Key Points Endothelial Smad4 is a physiological suppressor that functions specifically during the transition to hematopoietic progenitors. Endothelial Smad4 lies upstream of the subaortic microenvironment to control the hematopoietic fate of aortic endothelium.

Cited by 24 publications

References 48 publications

Lineage tracing reveals conversion of liver sinusoidal endothelial cells into hepatocytes

Lineage tracing reveals conversion of liver sinusoidal endothelial cells into hepatocytes

SMAD1 and SMAD5 Expression Is Coordinately Regulated by FLI1 and GATA2 during Endothelial Development

Nupr1 Negatively Regulates Endothelial to Hematopoietic Transition in the Aorta‐Gonad‐Mesonephros Region

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