Essential roles of EphrinB2 in mammalian heart: from development to diseases

Su, Sheng-an; Xie, Yao; Zhang, Yuhao; Xi, Yutao; Cheng, Jie; Xiang, Meixiang

doi:10.1186/s12964-019-0337-3

Cited by 16 publications

(14 citation statements)

References 90 publications

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“…We also found expression of cxcl18b, sele, atf3, and fosl1a to be much higher at 2 and 7 dpi compared to uninjured and 14 dpi eEC2 cells (Appendix Fig S5E), suggesting transient activation of this cell type (Munch et al , 2017; Sanchez‐Iranzo et al , 2018). eEC3 did not show significant frequency change after injury (Fig 3I), and it highly expressed genes implicated in cardiac valve development and function such as frzb, bmp6, wnt11r, and tgfbi (Kim et al , 2001; Norris et al , 2005; Person et al , 2005; Sinha et al , 2015; Touma et al , 2017; Su et al , 2019) (Appendix Fig S5C and F), suggesting its identity as valvular endothelial cells. eEC4 was a small cluster of proliferating cells (Fig 2I; Appendix Fig S5C, G and H).…”

Section: Resultsmentioning

confidence: 99%

Functional coordination of non‐myocytes plays a key role in adult zebrafish heart regeneration

Ma¹,

Liu²,

Yang

et al. 2021

EMBO Reports

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Cardiac regeneration occurs primarily through proliferation of existing cardiomyocytes, but also involves complex interactions between distinct cardiac cell types including non-cardiomyocytes (non-CMs). However, the subpopulations, distinguishing molecular features, cellular functions, and intercellular interactions of non-CMs in heart regeneration remain largely unexplored. Using the LIGER algorithm, we assemble an atlas of cell states from 61,977 individual non-CM scRNA-seq profiles isolated at multiple time points during regeneration. This analysis reveals extensive non-CM cell diversity, including multiple macrophage (MC), fibroblast (FB), and endothelial cell (EC) subpopulations with unique spatiotemporal distributions, and suggests an important role for MC in inducing the activated FB and EC subpopulations. Indeed, pharmacological perturbation of MC function compromises the induction of the unique FB and EC subpopulations. Furthermore, we developed computational algorithm Topologizer to map the topological relationships and dynamic transitions between functional states. We uncover dynamic transitions between MC functional states and identify factors involved in mRNA processing and transcriptional regulation associated with the transition. Together, our single-cell transcriptomic analysis of non-CMs during cardiac regeneration provides a blueprint for interrogating the molecular and cellular basis of this process.

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Section: Resultsmentioning

confidence: 99%

Functional coordination of non‐myocytes plays a key role in adult zebrafish heart regeneration

Ma¹,

Liu²,

Yang

et al. 2021

EMBO Reports

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“… 18 , 19 EPHB4 is mainly expressed in the developmental phase of three-dimensionally organized human tissue structures such as vascular formations and tissue border formations. 20 , 21 Stimulation of EPHB4 by its ligand, EPHRIN B2, generates a bidirectional signaling cascade in both the cell expressing the receptor and the cell presenting the ligand. 22 The EPHB4-EPHRIN B2 axis regulates various cellular functions such as cell migration, repulsion, and adhesion.…”

Section: Introductionmentioning

confidence: 99%

“… 22 The EPHB4-EPHRIN B2 axis regulates various cellular functions such as cell migration, repulsion, and adhesion. 21 , 22 Interestingly, ligand-independent activation of EPHB4 in cancer cells results in cell proliferation and malignant transformation. By contrast, ligand-dependent activation of EPHB4 induces apoptosis in some tumors.…”

Section: Introductionmentioning

confidence: 99%

Development of non-viral, ligand-dependent, EPHB4-specific chimeric antigen receptor T cells for treatment of rhabdomyosarcoma

Kubo

Yagyu

Nakamura

et al. 2021

Molecular Therapy - Oncolytics

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Ephrin type-B receptor 4 (EPHB4), expressed in tumors including rhabdomyosarcoma, is a suitable target for chimeric antigen receptor (CAR)-T cells. Ligand-independent activation of EPHB4 causes cell proliferation and malignant transformation in rhabdomyosarcoma, whereas ligand-dependent stimulation of EPHB4 induces apoptosis in rhabdomyosarcoma. Therefore, we hypothesized that ligand-based, EPHB4-specific CAR-T cells may kill rhabdomyosarcoma cells without stimulating downstream cell proliferation mechanisms. We developed novel CAR-T cells by targeting EPHB4 via EPHRIN B2, a natural ligand of EPHB4. The generation of EPHB4-CAR-T cells via piggyBac (PB) transposon-based gene transfer resulted in sufficient T cell expansion and CAR positivity (78.5% ± 5.9%). PB-EPHB4-CAR-T cells displayed a dominant stem cell memory fraction (59.4% ± 7.2%) as well as low PD-1 expression (0.60% ± 0.21%) after 14 days of expansion. The PB-EPHB4-CAR-T cells inhibited EPHB4-positive tumor cells without activating cell proliferation downstream of EPHB4, even after multiple tumor re-challenges and suppressed tumor growth in xenograft-bearing mice. Therefore, PB-EPHB4-CAR-T cells possess a memory-rich fraction without early T cell exhaustion and show potential as promising therapeutic agents for treating rhabdomyosarcoma and other EPHB4-positive tumors.

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“…Erythropoietin-producing hepatocellular (Eph) receptoreinteracting proteins (Ephrin) are ubiquitously expressed membrane-tethered proteins that function as extracellular ligands for Eph tyrosine kinase receptors. 7,8 EphrinB2 is a preferred ligand for EphB4, functioning as an important regulator of blood vessel formation and remodeling in both embryos and adults. [8][9][10] EphrinB2 is predominantly expressed in arteries, whereas EphB4 is principally expressed in veins.…”

Section: Introductionmentioning

confidence: 99%

Activation of EphrinB2 Signaling Promotes Adaptive Venous Remodeling in Murine Arteriovenous Fistulae

Wang

Liu

et al. 2021

Journal of Surgical Research

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Background: Arteriovenous fistulae (AVF) are the preferred mode of vascular access for hemodialysis. Before use, AVF remodel by thickening and dilating to achieve a functional conduit via an adaptive process characterized by expression of molecular markers characteristic of both venous and arterial identity. Although signaling via EphB4, a determinant of venous identity, mediates AVF maturation, the role of its counterpart EphrinB2, a determinant of arterial identity, remains unclear. We hypothesize that EphrinB2 signaling is active during AVF maturation and may be a mechanism of venous remodeling. Methods: Aortocaval fistulae were created or sham laparotomy was performed in C57Bl/6 mice, and specimens were examined on Days 7 or 21. EphrinB2 reverse signaling was activated with EphB4-Fc applied periadventitially in vivo and in endothelial cell culture medium in vitro. Downstream signaling was assessed using immunoblotting and immunofluorescence. Results: Venous remodeling during AVF maturation was characterized by increased expression of EphrinB2 as well as Akt1, extracellular signal-regulated kinases 1/2 (ERK1/ 2), and p38. Activation of EphrinB2 with EphB4-Fc increased phosphorylation of Eph-rinB2, endothelial nitric oxide synthase, Akt1, ERK1/2, and p38 and was associated with increased diameter and wall thickness in the AVF. Both mouse and human endothelial cells treated with EphB4-Fc increased phosphorylation of EphrinB2, endothelial nitric oxide synthase, Akt1, ERK1/2, and p38 and increased endothelial cell tube formation and migration. Conclusions: Activation of EphrinB2 signaling by EphB4-Fc was associated with adaptive venous remodeling in vivo while activating endothelial cell function in vitro.

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Essential roles of EphrinB2 in mammalian heart: from development to diseases

Cited by 16 publications

References 90 publications

Functional coordination of non‐myocytes plays a key role in adult zebrafish heart regeneration

Functional coordination of non‐myocytes plays a key role in adult zebrafish heart regeneration

Development of non-viral, ligand-dependent, EPHB4-specific chimeric antigen receptor T cells for treatment of rhabdomyosarcoma

Activation of EphrinB2 Signaling Promotes Adaptive Venous Remodeling in Murine Arteriovenous Fistulae

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