Tissue factor variants induce monocyte transformation and transdifferentiation into endothelial cell-like cells

Area of Science:

• Cell Biology
• Angiogenesis Research
• Immunology

Background:

• Monocytes (Mo) contribute to neovascularization through mediator release or transdifferentiation into endothelial cell-like (ECL) cells.
• Previous research indicated Mo-microvascular endothelial cell (mEC) crosstalk induces mEC tissue factor (TF) expression, promoting angiogenesis.
• The specific impact of TF on Mo behavior and differentiation remained largely unexplored.

Purpose of the Study:

• To investigate whether tissue factor (TF) can induce the transdifferentiation of monocytes (Mo) into endothelial cell-like (ECL) cells.
• To elucidate the role of TF in the crosstalk between Mo and mECs in the context of angiogenesis.

Main Methods:

• Overexpression of full-length TF (flTF) and alternatively spliced TF (asTF) in mECs.
• Analysis of Mo transdifferentiation markers (CD16, VEC markers) using fluorescence-activated cell sorting.
• Assessment of ECL cell-like function (tube formation) in 3D cultures and TF signaling pathway analysis.

Main Results:

• TF expression and release from mECs were upregulated by Mo-conditioned media.
• TF variants promoted Mo expansion of a CD16+ subset and transdifferentiation into ECL-like cells expressing VEC markers.
• TF-induced Mo exhibited increased expression of VE-cadherin, VWF, and eNOS, and could form new microvessels. Blocking β1-integrin inhibited these effects.

Conclusions:

• Monocytes stimulate mECs to produce and release TF.
• TF acts in a paracrine manner to drive CD16- Mo differentiation into CD16+ ECL-like cells.
• This TF-mediated positive feedback loop between Mo and mECs is a novel mechanism stimulating Mo differentiation and promoting angiogenesis.