Functional consequences of complement activation on vascular endothelial cells – Results of a pilot RNA seq study

AbstractKeloid is a benign dermal fibrotic disorder with some features similar to malignant tumors such as hyper-proliferation, apoptosis resistance and invasion. keloid remains a therapeutic challenge in terms of high recurrence rate and lack of satisfactory medical therapies, which is partially due to the incomplete understanding of keloid pathogenesis. A thorough understanding of the cellular and molecular mechanism of keloid pathogenesis would facilitate the development of novel medical therapies for this disease. Here, we performed single-cell RNA-seq of 28,064 cells from keloid skin tissue and adjacent relatively normal tissue. Unbiased clustering revealed substantial cellular heterogeneity of the keloid tissue, which included 21 cell clusters assigned to 11 cell lineages. Differential proportion analysis revealed significant expansion for fibroblasts and vascular endothelial cells in keloid compared with control, reflecting their strong association with keloid pathogenesis. We then identified five previously unrecognized subpopulations of keloid fibroblasts and four subpopulations of vascular endothelial cells. Comparative analyses were performed to identify the dysregulated pathways, regulators and ligand-receptor interactions for keloid fibroblasts and vascular endothelial cells, the two important cell lineages in keloid pathogenesis and for medical interventions. Our results highlight the roles of transforming growth factor beta and Eph-ephrin signaling pathways in both the aberrant fibrogenesis and angiogenesis of keloid. Critical regulators and signaling receptors implicated in the fibrogenesis of other fibrotic disorders, such as TWIST1, FOXO3, SMAD3 and EPHB2, ranked at the top in the regulatory network of keloid fibroblasts. In addition, tumor-related pathways such as negative regulation of PTEN transcription were found to be activated in keloid fibroblasts and vascular endothelial cells, which may be responsible for the malignant features of keloid. Our study put novel insights into the pathogenesis of keloid, and provided potential targets for medical therapies. Our dataset also constitutes a valuable resource for further investigations of the mechanism of keloid pathogenesis.

Download Full-text

Human Peripheral Blood-Derived Endothelial Colony-Forming Cells Are Highly Similar to Mature Vascular Endothelial Cells yet Demonstrate a Transitional Transcriptomic Signature

Cells ◽

10.3390/cells9040876 ◽

2020 ◽

Vol 9 (4) ◽

pp. 876 ◽

Cited By ~ 3

Author(s):

Anton G. Kutikhin ◽

Alexey E. Tupikin ◽

Vera G. Matveeva ◽

Daria K. Shishkova ◽

Larisa V. Antonova ◽

...

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Gene Expression Profile ◽

Vascular Endothelial Cells ◽

Vascular Grafts ◽

Global Gene Expression ◽

Tube Formation ◽

Vascular Endothelial ◽

Rna Seq ◽

Endothelial Colony Forming Cells

Endothelial colony-forming cells (ECFC) are currently considered as a promising cell population for the pre-endothelialization or pre-vascularization of tissue-engineered constructs, including small-diameter biodegradable vascular grafts. However, the extent of heterogeneity between ECFC and mature vascular endothelial cells (EC) is unclear. Here, we performed a transcriptome-wide study to compare gene expression profiles of ECFC, human coronary artery endothelial cells (HCAEC), and human umbilical vein endothelial cells (HUVEC). Characterization of the abovementioned cell populations was carried out by immunophenotyping, tube formation assay, and evaluation of proliferation capability while global gene expression profiling was conducted by means of RNA-seq. ECFC were similar to HUVEC in terms of immunophenotype (CD31+vWF+KDR+CD146+CD34-CD133-CD45-CD90-) and tube formation activity yet had expectedly higher proliferative potential. HCAEC and HUVEC were generally similar to ECFC with regards to their global gene expression profile; nevertheless, ECFC overexpressed specific markers of all endothelial lineages (NRP2, NOTCH4, LYVE1), in particular lymphatic EC (LYVE1), and had upregulated extracellular matrix and basement membrane genes (COL1A1, COL1A2, COL4A1, COL4A2). Proteomic profiling for endothelial lineage markers and angiogenic molecules generally confirmed RNA-seq results, indicating ECFC as an intermediate population between HCAEC and HUVEC. Therefore, gene expression profile and behavior of ECFC suggest their potential to be applied for a pre-endothelialization of bioartificial vascular grafts, whereas in terms of endothelial hierarchy they differ from HCAEC and HUVEC, having a transitional phenotype.

Download Full-text

M.629 Homocysteine inhibits lysyl oxidase (LOX) and downregulates LOX expression in vascular endothelial cells

Atherosclerosis ◽

10.1016/s0021-9150(04)90627-2 ◽

2004 ◽

Vol 5 (1) ◽

pp. 146

Author(s):

B RAPOSO

Keyword(s):

Endothelial Cells ◽

Vascular Endothelial Cells ◽

Lysyl Oxidase ◽

Vascular Endothelial

Download Full-text

Anti-metalloproteinase-9 Activities of Selected Indonesian Zingiberaceae Rhizome Extracts in Lipopolysaccharide-induced Human Vascular Endothelial Cells In Vitro

Planta Medica ◽

10.1055/s-0031-1282610 ◽

2011 ◽

Vol 77 (12) ◽

Author(s):

Y Yanti ◽

N Steven ◽

A Wiharja ◽

S Fajarianto

Keyword(s):

Endothelial Cells ◽

Vascular Endothelial Cells ◽

Vascular Endothelial ◽

Metalloproteinase 9

Download Full-text

The Endothelial Cell and the Factor VIII Bypassing Activity of Prothrombin Complex Concentrate

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647034 ◽

1988 ◽

Vol 60 (02) ◽

pp. 226-229 ◽

Cited By ~ 2

Author(s):

Jerome M Teitel ◽

Hong-Yu Ni ◽

John J Freedman ◽

M Bernadette Garvey

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Factor Viii ◽

Prothrombin Complex Concentrate ◽

Vascular Endothelial Cells ◽

Vascular Endothelial ◽

Monolayer Cultures ◽

Coagulant Activity ◽

Time Courses ◽

Privileged Site

SummarySome classical hemophiliacs have a paradoxical hemostatic response to prothrombin complex concentrate (PCC). We hypothesized that vascular endothelial cells (EC) may contribute to this “factor VIII bypassing activity”. When PCC were incubated with suspensions or monolayer cultures of EC, they acquired the ability to partially bypass the defect of factor VIII deficient plasma. This factor VIII bypassing activity distributed with EC and not with the supernatant PCC, and was not a general property of intravascular cells. The effect of PCC was even more dramatic on fixed EC monolayers, which became procoagulant after incubation with PCC. The time courses of association and dissociation of the PCC-derived factor VIII bypassing activity of fixed and viable EC monolayers were both rapid. We conclude that EC may provide a privileged site for sequestration of constituents of PCC which express coagulant activity and which bypass the abnormality of factor VIII deficient plasma.

Download Full-text

Alterations in Vascular Endothelial Cell-related Plasma Proteins In Thalassaemic Patients and their Correlation with Clinical Symptoms

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649879 ◽

1995 ◽

Vol 74 (04) ◽

pp. 1045-1049 ◽

Cited By ~ 38

Author(s):

P Butthep ◽

A Bunyaratvej ◽

Y Funahara ◽

H Kitaguchi ◽

S Fucharoen ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Immunosorbent Assay ◽

Plasma Proteins ◽

Clinical Symptoms ◽

Vascular Endothelial Cells ◽

Vascular Endothelial Cell ◽

Enzyme Linked Immunosorbent Assay ◽

Vascular Endothelial ◽

Leg Ulcers

SummaryAn increased level of plasma thrombomodulin (TM) in α- and β- thalassaemia was demonstrated using an enzyme-linked immunosorbent assay (ELISA). Nonsplenectomized patients with β-thalassaemia/ haemoglobin E (BE) had higher levels of TM than splenectomized cases (BE-S). Patients with leg ulcers (BE-LU) were found to have the highest increase in TM level. Appearance of larger platelets in all types of thalassaemic blood was observed indicating an increase in the number of younger platelets. These data indicate that injury of vascular endothelial cells is present in thalassaemic patients.

Download Full-text