The plasminogen fibrinolytic pathway is required for hematopoietic regeneration.
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.
Heissig
Beate
B
Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
Lund
Leif R
LR
Akiyama
Haruyo
H
Ohki
Makiko
M
Morita
Yohei
Y
Rømer
John
J
Nakauchi
Hiromitsu
H
Okumura
Ko
K
Ogawa
Hideoki
H
Werb
Zena
Z
Danø
Keld
K
Hattori
Koichi
K
D000818:Animals; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005342:Fibrinolysis; D017353:Gene Deletion; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D020782:Matrix Metalloproteinases / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D010958:Plasminogen / Q000235:genetics* / Q000494:pharmacology; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000187:drug effects / Q000378:metabolism
D019089:Stem Cell Factor; D010958:Plasminogen; D020782:Matrix Metalloproteinases