Research carried out by the RCSI University of Medicine and Health Sciences has revealed new information about how blood clots are formed during wound healing. The study “Platelets drive fibronectin fibrillogenesis using integrin αIIbβ3,” published in Science Advances, examines the behavior of platelets at a wound site, specifically their ability to sense where within a blood clot they are and remodel their surroundings accordingly.

Platelets are key to initiating wound healing and the formation of thrombus. Fibroblasts are connective tissue cells that are essential for the later stages of wound healing. Fibroblasts invade the clot that has been formed and produce vital proteins, including fibronectin, that then form a structural framework to build the new tissue needed to heal.

This new study indicates that platelets can also form a provisional fibronectin matrix in their surroundings, similar to what fibroblasts do in the later stages of wound healing. This has potential implications for how the integrity of blood clots might be maintained during vascular repair.

Platelets interact with multiple adhesion proteins during thrombogenesis, yet little is known about their ability to assemble fibronectin matrix. In vitro three-dimensional super resolution microscopy complemented by biophysical and biochemical methods revealed fundamental insights into how platelet contractility drives fibronectin fibrillogenesis,” write the investigators.

“Platelets adhering to thrombus proteins (fibronectin and fibrin) versus basement membrane components (laminin and collagen IV) pull fibronectin fibrils along their apical membrane versus underneath their basal membrane, respectively. In contrast to other cell types, platelets assemble fibronectin nanofibrils using αIIbβ3 rather than α5β1 integrins. Apical fibrillogenesis correlated with a stronger activation of integrin-linked kinase, higher platelet traction forces, and a larger tension in fibrillar-like adhesions compared to basal fibrillogenesis.

“Our findings have potential implications for how mechanical thrombus integrity might be maintained during remodeling and vascular repair.”

“We have identified an additional unexpected role for the most prominent platelet adhesion receptor,” said Ingmar Schoen, PhD, from the school of pharmacy and biomolecular sciences at RCSI. Our results show that platelets not only form the clot but also can initiate its remodeling by erecting a fibrous scaffold. This finding challenges some existing paradigms in the field of wound healing, which is dominated by research on fibroblasts.”

Super resolution microscopy, which enables sharper images of structures inside or around cells to be captured and observed in vitro in a laboratory, played a major role in this research. Observation of this platelet behavior in vivo will be required to further develop this finding. “Without super-resolution microscopy, this discovery would not have been possible,” added  Schoen.

The research was carried out in collaboration with researchers at ETH Zurich, Julius-Maximilians-University Würzburg, University of Freiburg, and University Hospital Zurich.

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