title: Inhibition of plasminogen activator inhibitor type-1 activity enhances rapid and sustainable hematopoietic regeneration.
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.
authors.affiliation: Division of Hematopoiesis, Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Abd Aziz
authors.initials: AA
authors.lastname: Ibrahim
authors.forename: Takashi
authors.initials: T
authors.lastname: Yahata
authors.forename: Makoto
authors.initials: M
authors.lastname: Onizuka
authors.forename: Takashi
authors.initials: T
authors.lastname: Dan
authors.forename: Charles
authors.initials: C
authors.lastname: Van Ypersele De Strihou
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
mesh_terms: D064591:Allografts; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D051379:Mice; D012038:Regeneration; D058258:Serpin E2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055153:Stem Cell Niche; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D058258:Serpin E2; C511869:Serpine2 protein, mouse
keywords: Bone marrow stromal cells; Hematopoiesis; Hematopoietic stem cells; Osteoblast; Stem cell transplantation; Tissue regeneration