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Activation of the TGF? pathway impairs endothelial to haematopoietic transition.

ABSTRACT: The endothelial to haematopoietic transition (EHT) is a key developmental process where a drastic change of endothelial cell morphology leads to the formation of blood stem and progenitor cells during embryogenesis. As TGF? signalling triggers a similar event during embryonic development called epithelial to mesenchymal transition (EMT), we hypothesised that TGF? activity could play a similar role in EHT as well. We used the mouse embryonic stem cell differentiation system for in vitro recapitulation of EHT and performed gain and loss of function analyses of the TGF? pathway. Quantitative proteomics analysis showed that TGF? treatment during EHT increased the secretion of several proteins linked to the vascular lineage. Live cell imaging showed that TGF? blocked the formation of round blood cells. Using gene expression profiling we demonstrated that the TGF? signalling activation decreased haematopoietic genes expression and increased the transcription of endothelial and extracellular matrix genes as well as EMT markers. Finally we found that the expression of the transcription factor Sox17 was up-regulated upon TGF? signalling activation and showed that its overexpression was enough to block blood cell formation. In conclusion we showed that triggering the TGF? pathway does not enhance EHT as we hypothesised but instead impairs it.

SUBMITTER: Vargel O

PROVIDER: S-EPMC4759586 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Activation of the TGFβ pathway impairs endothelial to haematopoietic transition.

Vargel Özge Ö Zhang Yang Y Kosim Kinga K Ganter Kerstin K Foehr Sophia S Mardenborough Yannicka Y Shvartsman Maya M Enright Anton J AJ Krijgsveld Jeroen J Lancrin Christophe C

Scientific reports 20160219

The endothelial to haematopoietic transition (EHT) is a key developmental process where a drastic change of endothelial cell morphology leads to the formation of blood stem and progenitor cells during embryogenesis. As TGFβ signalling triggers a similar event during embryonic development called epithelial to mesenchymal transition (EMT), we hypothesised that TGFβ activity could play a similar role in EHT as well. We used the mouse embryonic stem cell differentiation system for in vitro recapitul ...[more]

PMID: 26891705

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Project description:Aims:The pathogenic mechanisms of pulmonary arterial hypertension (PAH) remain unclear, but involve dysfunctional endothelial cells (ECs), dysregulated immunity and inflammation in the lung. We hypothesize that a developmental process called endothelial to haematopoietic transition (EHT) contributes to the pathogenesis of pulmonary hypertension (PH). We sought to determine the role of EHT in mouse models of PH, to characterize specific cell types involved in this process, and to identify potential therapeutic targets to prevent disease progression. Methods and results:When transgenic mice with fluorescence protein ZsGreen-labelled ECs were treated with Sugen/hypoxia (Su/Hx) combination to induce PH, the percentage of ZsGreen+ haematopoietic cells in the peripheral blood, primarily of myeloid lineage, significantly increased. This occurrence coincided with the depletion of bone marrow (BM) ZsGreen+ c-kit+ CD45- endothelial progenitor cells (EPCs), which could be detected accumulating in the lung upon PH-induction. Quantitative RT-PCR based gene array analysis showed that key transcription factors driving haematopoiesis were expressed in these EPCs. When transplanted into lethally irradiated recipient mice, the BM-derived EPCs exhibited long-term engraftment and haematopoietic differentiation capability, indicating these EPCs are haemogenic in nature. Specific inhibition of the critical haematopoietic transcription factor Runx1 blocked the EHT process in vivo, prevented egress of the BM EPCs and ultimately attenuated PH progression in Su/Hx- as well as in monocrotaline-induced PH in mice. Thus, myeloid-skewed EHT promotes the development of PH and inhibition of this process prevents disease progression in mouse models of PH. Furthermore, high levels of Runx1 expression were found in circulating CD34+ CD133+ EPCs isolated from peripheral blood of patients with PH, supporting the clinical relevance of our proposed mechanism of EHT. Conclusion:EHT contributes to the pathogenesis of PAH. The transcription factor Runx1 may be a novel therapeutic target for the treatment of PAH.

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Activation of the TGF? pathway impairs endothelial to haematopoietic transition.

Publications

Activation of the TGFβ pathway impairs endothelial to haematopoietic transition.

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