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The Plasminogen Fibrinolytic Pathway Is Required for Hematopoietic Regeneration

Cell Stem Cell. Vol.1: 658-670. 2007
Beate Heissig,1,2 Leif R. Lund,3 Haruyo Akiyama,1 Makiko Ohki,1 Yohei Morita,1 John Romer,3 Hiromitsu Nakauchi,1 Ko Okumura,2 Hideoki Ogawa,2 Zena Werb,4 Keld Dano,3 and Koichi Hattori1,2
1: Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
2: Atopy (Allergy) Research Center, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
3: Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, 2100 Copenhagen, Denmark
4: Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0452, USA

Hematopoietic stem cells within the bone marrow exist in a quiescent state. They can differentiate and proliferate in response to hematopoietic stress (e.g., myelosuppression),thereby ensuring a well-regulated supply of mature and immature hematopoietic cells within the circulation. However, little is known about how this stress response is coordinated. Here, we show that plasminogen (Plg), a classical fibrinolytic factor, is a key player in controlling this stress response. Deletion of Plg in mice prevented hematopoietic stem cells from entering the cell cycle and undergoing multilineage differentiation after myelosuppression, leading to the death of the mice. Activation of Plg by administration of tissue-type plasminogen activator promoted matrix metalloproteinase-mediated release of Kit ligand from stromal cells, thereby promoting hematopoietic progenitor cell proliferation and differentiation. Thus, activation of the fibrinolytic cascade is a critical step in regulating the hematopoietic stress response.