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 1

MuPAR marks a subset of HSPCs and preserves their pool size in the BM.

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MuPAR marks a subset of HSPCs and preserves their pool size in the BM. ...
(A) Decreased steady-state counts of various HSPC populations in the BM of Plaur–/– compared with WT mice. *P < 0.05 versus WT (n = 4–9). (B) WT and Plaur–/– mice were transplanted with syngeneic WT or Plaur–/– BMCs after lethal irradiation. At 6 weeks after transplantation, peripheral blood counts in the recipient mice were fully normalized (not shown). Counting of the number of CFU-Cs in the BM revealed that the number of HSPCs was reduced in the BM of mice grafted with Plaur–/– BM. Consistent herewith, fewer CFU-Cs were detected in nontransplanted Plaur–/– mice (not shown). *P < 0.05 (n = 4). (C) Fewer lethally irradiated splenectomized WT mice survived when transplanted with 1 × 105Plaur–/– BMCs compared with WT BMC transplantation. P < 0.05 versus WT, Cox regression analysis (n = 17).