Alterations in the spatiotemporal expression of the chemokine receptor CXCR4 in endothelial cells cause failure of hierarchical vascular branching

Li, Wenling; Liu, Chengyu; Burns, Nathan; Hayashi, Jeffery; Yoshida, Akihisa; Sajja, Aparna; González-Hernández, Sara; Gao, Ji; Murphy, Philip M.; Kubota, Yoshiaki; Zou, Yong; Nagasawa, Takashi; Mukouyama, Yoh‐suke

doi:10.1016/j.ydbio.2021.05.008

Cited by 6 publications

(5 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies in the mouse showed that loss of function of Cxcr4 caused defective vascular development, while gain of function of Cxcr4 in ECs resulted in defective vascular remodeling, which suggest a dosage sensitive requirement of Cxcr4 in ECs for normal vascular development. [62][63][64] Other cell adhesion/migration genes such as Adm, Col15a1, Lama4, Mcam, Itga2 and Itga2b, were also up-regulated in ECs in the mutants. Malfunctions of preprohormone gene Adm [72][73][74][75] and collagen gene Col15a1 65,66 also caused angiogenesis and/or vascular defects.…”

Section: Discussionmentioning

confidence: 94%

“…We also performed a GO analysis of Biological Processes in the STRING database and the results are similar (Supplementary Data 4). Multiple angiogenesis and cell migration genes were up-regulated in the ECs in the cKO versus control embryos, such as NOTCH signaling genes Dll4 [32][33][34]36,38,59 , Hey1 37 and Notch4 60,61 , chemokine receptor gene Cxcr4 [62][63][64] , collagen gene Col15a1 65,66 , hypoxia signaling genes Epas1 67,68 , Hif3a 69 and Ddit4 70 , growth factor gene Pdgfb 71 , and preprohormone gene Adm [72][73][74][75] (Fig. 5D-F).…”

Section: Upregulation Of Genes Crucial For Angiogenesis and Vasculatu...mentioning

confidence: 99%

See 1 more Smart Citation

Crk/Crklregulates early angiogenesis in mouse embryos by accelerating endothelial cell maturation

Morrow

Shi

Song

et al. 2023

Preprint

View full text Add to dashboard Cite

Rationale: Ubiquitously expressed cytoplasmic adaptors CRK and CRKL mediate multiple signaling pathways in mammalian embryogenesis. They are also associated with cardiovascular defects occurring in Miller-Dieker syndrome and 22q11.2 deletion syndrome, respectively. The embryonic mesoderm contributes to the formation of the cardiovascular system, yet the roles that Crk and Crkl play there are not understood on a single cell level. Objectives: To determine functions of Crk and Crkl in the embryonic mesoderm during early mouse vascular development. Secondly, we will examine the molecular mechanisms responsible for early embryonic endothelial cell (EC) defects by performing single cell RNA-sequencing (scRNA-seq) and in vivo validation experiments. Methods and Results: Inactivation of both Crk and Crkl together using Mesp1Cre resulted embryonic lethality with severe vascular defects. Although vasculogenesis appeared normal, angiogenesis was disrupted both in the yolk sac and embryo proper, leading to disorganized vascular networks. We performed scRNA-seq of the Mesp1Cre mesodermal lineage and found that there was upregulation of a great number of angiogenesis and cell migration related genes in ECs in the mutants, including NOTCH signaling genes such as Dll4 and Hey1. Further bioinformatic analysis of EC subpopulations identified a relative increase in the number of more differentiated angiogenic ECs and decrease in EC progenitors. Consistent with this, we identified an expansion of Dll4 expressing cells within abnormal arteries, in vivo. Also, our bioinformatic data indicates that there is dysregulated expression of lineage genes that promote EC differentiation causing accelerated cell fate progression during EC differentiation. Conclusions: Our results show that Crk and Crkl are crucial for regulating early embryonic angiogenesis. Combined inactivation of Crk/Crkl caused precocious EC maturation with an increase of atypical differentiated angiogenic ECs and failed vascular remodeling. This is in part due to increased NOTCH signaling and altered expression of cell migration genes.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Upregulation Of Genes Crucial For Angiogenesis and Vasculatu...mentioning

confidence: 99%

Crk/Crklregulates early angiogenesis in mouse embryos by accelerating endothelial cell maturation

Morrow

Shi

Song

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The activation of TNF signaling and the downregulation of EP3 gene in AL, may conduct to the upregulation of CCL27 in keratinocytes as CCL27 production is known to be specific of these cells 47 , 48 . The upregulation of CXCR4 and CXCR7 , coding for two cognate receptors of CXCL12/SDF1, may be also associated with chemotaxis and activation of macrophages and T-cells as well as vascular branching-morphogenesis 49 – 51 . TNFRSF21 , IL7R , SOCS1 , DOCK8 , SAMD9 are other important genes known to sustain the migration, homeostasis and integrity of T-lymphocytes 52 – 56 .…”

Section: Discussionmentioning

confidence: 99%

A chronic pro-inflammatory environment contributes to the physiopathology of actinic lentigines

Duval,

Bourreau,

Warrick

et al. 2024

Sci Rep

View full text Add to dashboard Cite

Actinic lentigines (AL) or age spots, are skin hyperpigmented lesions associated with age and chronic sun exposure. To better understand the physiopathology of AL, we have characterized the inflammation response in AL of European and Japanese volunteers. Gene expression profile showed that in both populations, 10% of the modulated genes in AL versus adjacent non lesional skin (NL), i.e. 31 genes, are associated with inflammation/immune process. A pro-inflammatory environment in AL is strongly suggested by the activation of the arachidonic acid cascade and the plasmin pathway leading to prostaglandin production, along with the decrease of anti-inflammatory cytokines and the identification of inflammatory upstream regulators. Furthermore, in line with the over-expression of genes associated with the recruitment and activation of immune cells, immunostaining on skin sections revealed a significant infiltration of CD68+ macrophages and CD4+ T-cells in the dermis of AL. Strikingly, investigation of infiltrated macrophage subsets evidenced a significant increase of pro-inflammatory CD80+/CD68+ M1 macrophages in AL compared to NL. In conclusion, a chronic inflammation, sustained by pro-inflammatory mediators and infiltration of immune cells, particularly pro-inflammatory M1 macrophages, takes place in AL. This pro-inflammatory loop should be thus broken to normalize skin and improve the efficacy of age spot treatment.

show abstract

“…Li et al. have found that the expression of CXCR4 is strictly regulated in arterial endothelial cells, and the enhanced or down-regulated function of CXCR4 can lead to abnormal development of coronary artery vessels ( 32 ). Meanwhile, vascular endothelial cell injury and dysfunction is a pathogenetic mechanism of KD.…”

Section: Discussionmentioning

confidence: 99%

Case Report: A Novel CXCR4 Mutation in a Chinese Child With Kawasaki Disease Causing WHIM Syndrome

Wang

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

WHIM syndrome, an extremely rare congenital disease with combined immunodeficiency, is mainly caused by heterozygous gain-of-function mutation in the CXCR4 gene. There have been no previous case reports of WHIM syndrome with Kawasaki disease. We herein report a case of a boy who developed Kawasaki disease at the age of 1 year. After treatment, the number of neutrophils in his peripheral blood decreased continuously. His medical history revealed that he had been suffering from leukopenia, neutropenia and low immunoglobulin since birth, and his neutrophils could return to the normal level in the presence of infection or inflammation. Clinical targeted gene sequencing of 91 genes associated with granulocyte-related disease revealed that the patient had a novel heterozygous NM_003467; c.1032_1033delTG;p.(E345Vfs*12) variant in exon 2 of CXCR4 gene. Family verification analysis by Sanger sequencing showed that his father also had heterozygous variation at this site, while other family members did not. The computer prediction software indicated that the variation had a high pathogenicity. The computational structure analysis of the mutant revealed significant structural and functional changes in the CXCR4 protein. It should be noted that when unexplained persistent neutropenia with low immunoglobulin occurs after birth, especially when there is a family history of neutropenia, immunodeficiency should be investigated with genetic testing.

show abstract

Alterations in the spatiotemporal expression of the chemokine receptor CXCR4 in endothelial cells cause failure of hierarchical vascular branching

Cited by 6 publications

References 54 publications

Crk/Crklregulates early angiogenesis in mouse embryos by accelerating endothelial cell maturation

Crk/Crklregulates early angiogenesis in mouse embryos by accelerating endothelial cell maturation

A chronic pro-inflammatory environment contributes to the physiopathology of actinic lentigines

Case Report: A Novel CXCR4 Mutation in a Chinese Child With Kawasaki Disease Causing WHIM Syndrome

Contact Info

Product

Resources

About