Cathepsin-mediated fibrin(ogen)olysis in engineered microvascular networks and chronic coagulation in sickle cell disease

Abstract

Cysteine cathepsins are powerful proteases involved in tissue destructive disease progression, including angiogenesis and pathogenic vascular remodeling. However, some of their functions and mechanisms in biological processes remains unclear. For example, their potential role in polymerizing and degrading fibrin, an essential blood clotting protein and biomaterial scaffold for tissue repair, is not well characterized. The central hypothesis of this dissertation is that cysteine cathepsins have fibrin(ogen)olytic properties which can facilitate fibrin matrix remodeling. To identify the role of cathepsin-mediated fibrin(ogen)olysis we investigated, firstly, fibrin-based constructs as a biological mimicking test bed and secondly, sickle cell disease for a pathological condition. Our results show that fibrin is a novel substrate for human cysteine cathepsins, with unique properties to sustain activity over extended periods of time. This work contributes to our understanding of the role of cathepsin-mediated fibrin degradation in vitro and how cathepsins remodel matrix of microvascular networks, as well as identifying cathepsin involvement in chronic coagulation activation in sickle cell anemia.