The Roles of Matrix Stiffness and ß-Catenin Signaling in Endothelial-to-Mesenchymal Transition of Aortic Valve Endothelial Cells

Zhong, Aileen; Mirzaei, Zahra; Simmons, Craig A.

doi:10.1007/s13239-018-0363-0

Cited by 70 publications

(51 citation statements)

References 30 publications

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“…In summary, these results validate the proposed cell identities and confirm their differentiation trajectories, demonstrating that endothelial cells are able to undergo EHT and endothelial-to-mesenchymal transition (EndoMT) (27, 28, 29, 30, 31) to generate haematopoietic and mesenchymal populations, respectively. Additionally, we identified a sorting strategy to enrich for HPCs generated in vitro and confirmed their multilineage haematopoietic potential using differentiation assays.…”

Section: Resultssupporting

confidence: 78%

Analysis of Endothelial-to-Haematopoietic Transition at the Single Cell Level identifies Cell Cycle Regulation as a Driver of Differentiation

Canu

Athanasiadis

Grandy

et al. 2020

Preprint

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Haematopoietic stem cells (HSC) first arise during development in the aorta-gonad-mesonephros (AGM) region of the embryo from a population of haemogenic endothelial cells which undergo endothelial-to-haematopoietic transition (EHT). Despite the progress achieved in recent years, the molecular mechanisms driving EHT are still poorly understood, especially in human where the AGM region is not easily accessible. In this study, we took advantage of a human pluripotent stem cell (hPSC) differentiation system and single-cell transcriptomics to recapitulate EHT in vitro and uncover mechanisms by which the haemogenic endothelium generates early haematopoietic cells. We show that most of the endothelial cells reside in a quiescent state and progress to the haematopoietic fate within a defined time window, within which they need to re-enter into the cell cycle. If cell cycle is blocked, haemogenic endothelial cells lose their EHT potential and adopt a non-haemogenic identity. Furthermore, we demonstrated that CDK4/6 and CDK1 play a key role not only in the transition but also in allowing haematopoietic progenitors to establish their full differentiation potential. Therefore, we propose a direct link between the molecular machineries that control cell cycle progression and EHT.

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Section: Resultssupporting

confidence: 78%

Analysis of Endothelial-to-Haematopoietic Transition at the Single Cell Level identifies Cell Cycle Regulation as a Driver of Differentiation

Canu

Athanasiadis

Grandy

et al. 2020

Preprint

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“…β-catenin signaling has been involved in epithelial-to-mesenchymal transition in pulmonary disease and cancer [8,12,26]. Also, β-catenin has been reported to promote EndMT through nuclear accumulation and subsequent activation of TCF/Lef transcription factors [13, 14]. In the current study, we revealed that overexpression of FAM13A decelerates the EndMT process in association with reduced active β-catenin levels and its nuclear accumulation in endothelial cells.…”

Section: Discussionsupporting

confidence: 55%

“…β-catenin is crucially involved in the epithelial-mesenchymal transition that play an important role in the pathogenesis of cancer [12] and pulmonary fibrosis. Also, there are many reports describing the role of β-catenin in EndMT that is implicated in the vascular remodeling for pulmonary hypertension [13–15]. These findings urged us to investigate a potential role of FAM13A in the pathogenesis of pulmonary hypertension, and we here identified a protective role of FAM13A in the development of pulmonary hypertension.…”

Section: Introductionmentioning

confidence: 53%

Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition

Rinastiti

Ikeda

Rahardini

et al. 2019

Preprint

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1819 Pulmonary hypertension is a progressive lung disease with poor prognosis due to the 20 consequent right heart ventricular failure. Pulmonary artery remodeling and dysfunction 21 are culprits for pathologically increased pulmonary arterial pressure, but their 22 underlying molecular mechanisms remain to be elucidated. Previous genome-wide 23 association studies revealed a significant correlation between the genetic locus of family 24 with sequence similarity 13, member A (FAM13A) and various lung diseases such as 25 chronic obstructive pulmonary disease and pulmonary fibrosis; however whether 26 FAM13A is also involved in the pathogenesis of pulmonary hypertension remained 27 unknown. Here, we identified a significant role of FAM13A in the development of 28 pulmonary hypertension. FAM13A expression was reduced in mouse lungs of 29 hypoxia-induced pulmonary hypertension model. We identified that FAM13A was 30 expressed in lung vasculatures, especially in endothelial cells. Genetic loss of FAM13A 31 exacerbated pulmonary hypertension in mice exposed to chronic hypoxia in association 32 with deteriorated pulmonary artery remodeling. Mechanistically, FAM13A decelerated 3 33 endothelial-to-mesenchymal transition potentially by inhibiting -catenin signaling in 34 pulmonary artery endothelial cells. Our data revealed a protective role of FAM13A in 35 the development of pulmonary hypertension, and therefore increasing and/or preserving 36 FAM13A expression in pulmonary artery endothelial cells is an attractive therapeutic 37 strategy for the treatment of pulmonary hypertension. 38 39 Introduction 40 41 Pulmonary hypertension is a progressive and fatal lung disease diagnosed by a 42 sustained elevation of pulmonary arterial pressure more than 20 mmHg [1]. Pulmonary 43 arterial hypertension including idiopathic pulmonary arterial hypertension and 44 pulmonary hypertension related with collagen disease is characterized by pathological 45 pulmonary artery remodeling such as intimal and medial thickening of muscular arteries, 46 vaso-occlusive lesions, and fully muscularized small diameter vessels that are normally 47 non-muscular peripheral vessels. These vascular remodeling is a result from endothelial 48 cell dysfunction, smooth muscle cell and endothelial cell proliferation, and also cellular 4 49 transdifferentiation [2]. Although detailed molecular mechanisms remain to be 50 elucidated, many pathogenic pathways in pulmonary arterial hypertension have been 51 revealed. These include TGF- signaling, inflammation, pericyte-mediated vascular 52 remodeling, iron homeostasis, and endothelial-to-mesenchymal transition (EndMT) [3]. 53 Recent genome-wide association studies identified family with sequence similarity 54 13, member A (FAM13A) gene as a genetic locus associated with pulmonary function 55 [4], and it is known to be associated with lung diseases including chronic obstructive 56 pulmonary disease (COPD) [5], asthma [6] and pulmonary fibrosis [7-9]. Moreover, 57 causative role of FAM13A in the development of COPD...

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“…β-catenin signaling has been involved in epithelial-to-mesenchymal transition in pulmonary disease and cancer [8,12,26]. Also, β-catenin has been reported to promote EndMT through nuclear accumulation and subsequent activation of TCF/Lef transcription factors [13,14]. In the current study, we revealed that overexpression of FAM13A decelerates the (n = 3 each).…”

Section: Discussionsupporting

confidence: 53%

“…β-catenin is crucially involved in the epithelial-mesenchymal transition that plays an important role in the pathogenesis of cancer [12] and pulmonary fibrosis. Also, there are many reports describing the role of β-catenin in EndMT that is implicated in the vascular remodeling for pulmonary hypertension [13][14][15]. These findings urged us to investigate a potential role of FAM13A in the pathogenesis of pulmonary hypertension, and we here identify a protective role of FAM13A in the development of pulmonary hypertension.…”

Section: Introductionmentioning

confidence: 70%

Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition

et al. 2020

View full text Add to dashboard Cite

Pulmonary hypertension is a progressive lung disease with poor prognosis due to the consequent right heart ventricular failure. Pulmonary artery remodeling and dysfunction are culprits for pathologically increased pulmonary arterial pressure, but their underlying molecular mechanisms remain to be elucidated. Previous genome-wide association studies revealed a significant correlation between the genetic locus of family with sequence similarity 13, member A (FAM13A) and various lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis; however whether FAM13A is also involved in the pathogenesis of pulmonary hypertension remained unknown. Here, we identified a significant role of FAM13A in the development of pulmonary hypertension. FAM13A expression was reduced in the lungs of mice with hypoxia-induced pulmonary hypertension. We identified that FAM13A was expressed in lung vasculatures, especially in endothelial cells. Genetic loss of FAM13A exacerbated pulmonary hypertension in mice exposed to chronic hypoxia in association with deteriorated pulmonary artery remodeling. Mechanistically, FAM13A decelerated endothelial-to-mesenchymal transition potentially by inhibiting β-catenin signaling in pulmonary artery endothelial cells. Our data revealed a protective role of FAM13A in the development of pulmonary hypertension, and therefore increasing and/or preserving FAM13A expression in pulmonary artery endothelial cells is an attractive therapeutic strategy for the treatment of pulmonary hypertension.

show abstract

The Roles of Matrix Stiffness and ß-Catenin Signaling in Endothelial-to-Mesenchymal Transition of Aortic Valve Endothelial Cells

Cited by 70 publications

References 30 publications

Analysis of Endothelial-to-Haematopoietic Transition at the Single Cell Level identifies Cell Cycle Regulation as a Driver of Differentiation

Analysis of Endothelial-to-Haematopoietic Transition at the Single Cell Level identifies Cell Cycle Regulation as a Driver of Differentiation

Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition

Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition

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