Critical Role of Fibrinolysis in Hematopoietic Recovery After Myelosuppression

Authors

• TP Nguyen
• YG Jiang
• F Ferraresso
• CJ Kastrup
• MJ Flick
• TH Bugge
• LM Silva

Abstract

Persistent fibrin deposition is implicated in a wide range of inflammatory pathologies and aberrant tissue repair. 5-fluorouracil (5-FU) is a widely used anti-metabolite chemotherapy that targets rapidly dividing cells, including the hematopoietic stem cells in the bone marrow. Hematopoietic regeneration has been shown to require plasmin, a serine protease that degrades fibrin. Fibrin deposition occurs in the bone marrow niche within three days after 5-FU treatment. Here, we evaluated the role of plasmin-mediated fibrinolysis in hematopoietic recovery by using plasminogen-deficient (Plg-/-) mice. Genetic (Plg-/-Fib-/-) and pharmacological depletion of fibrinogen with a siRNA (siFib) prolonged the survival of myelosuppressed Plg-/- mice, suggesting that fibrin plays a critical role in hematopoietic regeneration. To determine how fibrin abrogates hematopoietic regeneration, we investigated the role of fibrin–myeloid integrin αMβ2 binding using a mouse model expressing a mutated version of fibrin that cannot bind to the αMβ2 integrin (Plg-/-Fibγ390-396A/390-396A). Our results revealed that fibrin attenuates hematopoietic recovery via the engagement of αMβ2 integrin present on myeloid cells. Collectively, our data indicate that fibrin plays a critical role in mediating hematopoietic recovery, and pharmacological depletion of fibrinogen enhances hematopoietic recovery after myelosuppressive chemotherapy treatment.

Scientific Focus Area: Molecular Biology and Biochemistry

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