Dataset Information

GFI1 regulates chromatin state essential in human endothelial-to-haematopoietic transition.

ABSTRACT:

Objectives

During embryonic haematopoiesis, haematopoietic stem/progenitor cells (HSPCs) develop from hemogenic endothelial cells (HECs) though endothelial to haematopoietic transition (EHT). However, little is known about how EHT is regulated in human. Here, we report that GFI1 plays an essential role in enabling normal EHT during haematopoietic differentiation of human embryonic stem cells (hESCs).

Results

GFI1 deletion in hESCs leads to a complete EHT defect due to a closed chromatin state of hematopoietic genes in HECs. Mechanically, directly regulates important signaling pathways essential for the EHT such as PI3K signaling.etc.

Conclutions

Together, our findings reveal an essential role of GFI1 mediated epigenetic mechanism underlying human EHT during hematopoiesis.

SUBMITTER: Kang B

PROVIDER: S-EPMC9136496 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

GFI1 regulates chromatin state essential in human endothelial-to-haematopoietic transition.

Kang Baoqiang B Zhang Tian T Huang Ke K Wang Tianyu T Li Yuhang Y Mai Yuchan Y Li Jinbing J Dang Shiying S Zhang Zhishuai Z Huang Wenhao W Wang Junwei J Gao Minghui M Wang Yi Y Pan Guangjin G

Cell proliferation 20220503 5

<h4>Objectives</h4>During embryonic haematopoiesis, haematopoietic stem/progenitor cells (HSPCs) develop from hemogenic endothelial cells (HECs) though endothelial to haematopoietic transition (EHT). However, little is known about how EHT is regulated in human. Here, we report that GFI1 plays an essential role in enabling normal EHT during haematopoietic differentiation of human embryonic stem cells (hESCs).<h4>Results</h4>GFI1 deletion in hESCs leads to a complete EHT defect due to a closed chr ...[more]

PMID: 35504619

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Project description:AimsThe 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 resultsWhen 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.ConclusionEHT contributes to the pathogenesis of PAH. The transcription factor Runx1 may be a novel therapeutic target for the treatment of PAH.

Dataset Information

GFI1 regulates chromatin state essential in human endothelial-to-haematopoietic transition.

Objectives

Results

Conclutions

Publications

GFI1 regulates chromatin state essential in human endothelial-to-haematopoietic transition.

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