Critical Role of Fibrinolysis in Hematopoietic Recovery After Myelosuppression

Authors

• TP Nguy·ªÖn
• YG Jiang
• LJ Juang
• CJ Kastrup
• LM Silva
• TH Bugge

Abstract

Bone marrow responds to myelosuppression by expanding the hematopoietic stem cell population. Fibrinolysis is the breakdown of fibrin. Plasmin, a fibrinolytic protease, has been shown to be required for hematopoietic recovery. Fibrin deficiency alleviates many pathologies seen in plasmin-deficient (Plg-/-) mice such as impaired wound healing and periodontitis. 5-Fluorouracil (5-FU), a highly used chemotherapy drug, induces bone marrow injury, and elevated fibrin deposition in bone marrow has been observed within three days after treatment. Our study aims to evaluate the importance of fibrinolysis in hematopoietic recovery by investigating whether fibrin mediates myelosuppression. Using an in vivo model, we determined mouse survival and fibrin deposition after 5-FU treatment to see if hematopoietic recovery is critical for survival. An siRNA targeting fibrinogen (siFibrin) or a scrambled control (siLuciferase) was used to determine whether 5-FU toxicity in Plg-/- mice is fibrin-dependent. We found that plasmin is required for hematopoietic recovery in a 5-FU-induced myelosuppression model, and that reduced fibrin deposition improved survival. Our work suggests that the pharmacological depletion of fibrin via siFibrin partially rescues myelosuppressed Plg-/- mice and improves sustained hematopoietic recovery. Collectively, these data suggest that pharmacological reduction of fibrin may reduce toxicity of myelosuppressive chemotherapy drugs.

Scientific Focus Area: Molecular Biology and Biochemistry

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