Membrane-anchored uPAR regulates the proliferation, marrow pool size, engraftment, and mobilization of mouse hematopoietic stem/progenitor cells
Marc Tjwa, … , Catherine Verfaillie, Peter Carmeliet
Marc Tjwa, … , Catherine Verfaillie, Peter Carmeliet
Published March 9, 2009
Citation Information: J Clin Invest. 2009;119(4):1008-1018. https://doi.org/10.1172/JCI36010.
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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 3

MuPAR regulates HSPC homing, adhesion, and engraftment.

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MuPAR regulates HSPC homing, adhesion, and engraftment. (A) Homing ...
(A) Homing of BMCs in lethally irradiated nonsplenectomized recipient mice. Compared with control IgG, pretreatment with 2 μg anti-MuPAR per 106 cells reduced the number of GFP+ BMCs homing to the BM, but not to the spleen, 5 days after transplantation of 5 × 106 donor cells. *P < 0.05 versus control IgG (n = 4). (B) Homing and early engraftment of Ly5.1+Lin–cKit+ HSPCs to the BM of lethally irradiated splenectomized Ly5.2+ recipient mice. Compared with control IgG, pretreatment with anti-MuPAR inhibited the homing and early engraftment of HSPCs to the BM 5 days after transplantation. *P < 0.05 versus control IgG (n = 5–6). (C–E) Adhesion of 5 × 104 WT Lin–cKit+ HSPCs to a monolayer of OP9 mouse BM stromal cells (C), sVCAM-1 (D), or fibronectin (E). Compared with control IgG, pretreatment with anti-MuPAR inhibited HSPC adhesion. *P < 0.05 versus control IgG (n = 8). (F) Compared with control IgG, fewer lethally irradiated splenectomized WT mice survived when transplanted with 1 × 105 WT BMCs pretreated with anti-MuPAR, indicating that the expression of MuPAR on HSPCs promotes engraftment. P < 0.05 versus control (Cox regression; n = 10).