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Inhibition of plasminogen activator inhibitor type-1 activity enhances rapid and sustainable hematopoietic regeneration

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Ibrahim, Abd Aziz Yahata, Takashi Onizuka, Makoto Dan, Takashi Van Ypersele De Strihou, Charles [UCL] Ando, Kiyoshi

The prognosis of patients undergoing hematopoietic stem cell transplantation (HSCT) depends on the rapid recovery and sustained life-long hematopoiesis. The activation of the fibrinolytic pathway promotes hematopoietic regeneration; however, the role of plasminogen activator inhibitor-1 (PAI-1), a negative regulator of the fibrinolytic pathway, has not yet been elucidated. We herein demonstrate that bone marrow (BM) stromal cells, especially osteoblasts, produce PAI-1 in response to myeloablation, which negatively regulates the hematopoietic regeneration in the BM microenvironment. Total body irradiation in mice dramatically increased the local expression levels of fibrinolytic factors, including tissue-type plasminogen activator (tPA), plasmin, and PAI-1. Genetic disruption of the PAI-1 gene, or pharmacological inhibition of PAI-1 activity, significantly improved the myeloablation-related mortality and promoted rapid hematopoietic recovery after HSCT through the induction of hematopoiesis-promoting factors. The ability of a PAI-1 inhibitor to enhance hematopoietic regeneration was abolished when tPA-deficient mice were used as recipients, thus indicating that PAI-1 represses tPA-dependent hematopoietic regeneration. The PAI-1 inhibitor not only accelerated the expansion of the donor HSCs during the early-stage of regeneration, but also supported long-term hematopoiesis. Our results indicate that the inhibition of PAI-1 activity could be a therapeutic approach to facilitate the rapid recovery and sustained hematopoiesis after HSCT.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2014
Language Anglais
Journal information "Stem Cells" - Vol. 32, no. 4, p. 946-958 (2014)
Peer reviewed yes
Publisher AlphaMed Press ((United States) Dayton, OH)
issn 1066-5099
e-issn 1549-4918
Publication status Publié
Affiliations UCL - SSS/IREC/NEFR - Pôle de Néphrologie
UCL - (SLuc) Service de néphrologie
Links
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Bibliographic reference Ibrahim, Abd Aziz ; Yahata, Takashi ; Onizuka, Makoto ; Dan, Takashi ; Van Ypersele De Strihou, Charles ; et. al. Inhibition of plasminogen activator inhibitor type-1 activity enhances rapid and sustainable hematopoietic regeneration. In: Stem Cells, Vol. 32, no. 4, p. 946-958 (2014)
Permanent URL http://hdl.handle.net/2078.1/142006