Work

Plasmin-mediated fibrinolysis is required for hematopoietic recovery after 5-FU–induced myeloablation

Year: 2026

Type: article

Abstract: ABSTRACT: Hematopoietic recovery after myeloablation plays a critical role in the survival of patients who receive chemotherapy or hematopoietic stem cell transplantation. Understanding the mechanisms underlying hematopoiesis helps identify the molecular and/or cellular determinants that could be targeted to enhance hematopoietic recovery. Although several mechanisms by which the plasminogen (Plg) activation system promotes hematopoietic recovery after myelosuppression have been reported, the specific role fibrinolysis plays in hematopoietic recovery is unclear. The current study employs 5-fluorouracil-mediated myeloablation in murine models and provides a clear demonstration of uniform extravascular fibrin deposits in the bone marrow (BM) niche upon myeloablation. Persistent fibrin deposits in Plg-deficient mice lead to failure of hematopoietic recovery. Genetic and pharmacological depletion of fibrinogen after myeloablation restored hematopoietic recovery, revealing the critical role fibrin plays in this process. Moreover, defective fibrinolysis led to delayed hematopoietic recovery via a mechanism that involves fibrin engagement with the major myeloid integrin αMβ2. Importantly, similar fibrin-rich marrow niches were also observed in human BM injury and failure states. The study identifies a novel molecular pathway that could be therapeutically targeted to enhance hematopoietic recovery after myeloablation.

Source: Blood Advances

DOI: 10.1182/bloodadvances.2025019416