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

Abd Aziz Ibrahim, Takashi Yahata, Makoto Onizuka, Takashi Dan, Charles Van Ypersele De Strihou, Toshio Miyata, Kiyoshi Ando

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)946-958
Number of pages13
JournalStem Cells
Volume32
Issue number4
DOIs
Publication statusPublished - 2014 Apr

Keywords

  • Bone marrow stromal cells
  • Hematopoiesis
  • Hematopoietic stem cells
  • Osteoblast
  • Stem cell transplantation
  • Tissue regeneration

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Inhibition of plasminogen activator inhibitor type-1 activity enhances rapid and sustainable hematopoietic regeneration'. Together they form a unique fingerprint.

Cite this