Membrane-anchored uPAR regulates the proliferation, marrow pool size, engraftment, and mobilization of mouse hematopoietic stem/progenitor cells
Marc Tjwa, Nicolai Sidenius, Rute Moura, Sandra Jansen, Koen Theunissen, Annapaola Andolfo, Maria De Mol, Mieke Dewerchin, Lieve Moons, Francesco Blasi, Catherine Verfaillie, Peter Carmeliet
Marc Tjwa, Nicolai Sidenius, Rute Moura, Sandra Jansen, Koen Theunissen, Annapaola Andolfo, Maria De Mol, Mieke Dewerchin, Lieve Moons, Francesco Blasi, Catherine Verfaillie, Peter Carmeliet
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Research Article

Membrane-anchored uPAR regulates the proliferation, marrow pool size, engraftment, and mobilization of mouse hematopoietic stem/progenitor cells

Abstract

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.

Authors

Marc Tjwa, Nicolai Sidenius, Rute Moura, Sandra Jansen, Koen Theunissen, Annapaola Andolfo, Maria De Mol, Mieke Dewerchin, Lieve Moons, Francesco Blasi, Catherine Verfaillie, Peter Carmeliet

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Figure 4

Impaired HSPC mobilization in Plg–/– mice.

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Impaired HSPC mobilization in Plg–/– mice. (A and B) Fewer circulati...
(A and B) Fewer circulating CFU-Cs (A) and CFU-Ss (B) were observed in Plg–/– mice 5 days after G-CSF treatment, but not in steady-state conditions. *P < 0.05 versus WT (n = 8–15). (C) Fewer lethally irradiated syngeneic WT recipients survived after transplanting 1 × 105 PBMCs from G-CSF–treated Plg–/– mice than from WT mice. P < 0.05, Cox regression analysis (n = 20–39). (D) The median fluorescence intensity (MFI) BR4 signal, which specifically recognizes only intact MuPAR (see Methods), on Sca-1+ BMCs was reduced 2 days after 5-FU treatment in WT but not Plg–/– mice. #P < 0.05 versus baseline (n = 4). (E and F) Fewer circulating CFU-Cs (E) and CFU-Ss (F) were observed in Plaur–/– mice 5 days after G-CSF treatment, but not in steady-state conditions. *P < 0.05 versus WT (n = 11–15). (G and H) Compared with controls, fewer CFU-Cs (G; n = 12–18) and CFU-Ss (H; n = 10) were mobilized after G-CSF treatment in Plaur–/– or WT recipients of Plaur–/– BM transplant. Transplantation of WT BM into Plaur–/– recipients completely restored CFU-C and CFU-S mobilization after G-CSF treatment. *P < 0.05.