Membrane-anchored uPAR regulates the proliferation, marrow pool size, engraftment, and mobilization of mouse hematopoietic stem/progenitor cells.
The mechanisms of BM hematopoietic stem/progenitor cell (HSPC) adhesion, engraftment, and mobilization remain incompletely identified. Here, using WT and transgenic mice, we have shown that membrane-anchored plasminogen activator, urokinase receptor (MuPAR) marks a subset of HSPCs and promotes the preservation of the size of this pool of cells in the BM. Loss or inhibition of MuPAR increased HSPC proliferation and impaired their homing, engraftment, and adhesion to the BM microenvironment. During mobilization, MuPAR was inactivated by plasmin via proteolytic cleavage. Cell-autonomous loss of the gene encoding MuPAR also impaired long-term engraftment and multilineage repopulation in primary and secondary recipient mice. These findings identify MuPAR and plasmin as regulators of the proliferation, marrow pool size, homing, engraftment, and mobilization of HSPCs and possibly also of HSCs.
Tjwa
Marc
M
VIB--Vesalius Research Center, Katholieke Universiteit Leuven, Leuven, Belgium.
Sidenius
Nicolai
N
Moura
Rute
R
Jansen
Sandra
S
Theunissen
Koen
K
Andolfo
Annapaola
A
De Mol
Maria
M
Dewerchin
Mieke
M
Moons
Lieve
L
Blasi
Francesco
F
Verfaillie
Catherine
C
Carmeliet
Peter
P
D000818:Animals; D002462:Cell Membrane / Q000502:physiology; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D006085:Graft Survival; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010958:Plasminogen / Q000172:deficiency / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
C524899:Plaur protein, mouse; D055293:Receptors, Urokinase Plasminogen Activator; D010958:Plasminogen