Tissue Factor Pathway Inhibitor Increases Hematopoietic Stem Cell Homing and Engraftment by Glypican-3 Mediated Inhibition of CD26 Activity

Abstract 725

Directional migration is an important factor that determines homing of transplanted hematopoietic stem cells (HSC). The SDF-1α-CXCR4 axis is one of the most important determinants of this process. CD26, expressed on various cell types, leads to proteolytic cleavage of SDF-1α, which leads to the inactivation of its chemokine activity. We identified tissue factor pathway inhibitor (TFPI) as an inhibitor of CD26. Culture of murine bone marrow derived c-kit⁺Lin⁻Sca-1⁺ (KLS) cells or human umbilical cord blood derived Lin⁻CD34⁺ cells with TFPI significantly inhibited CD26 activity, which resulted in significantly increased migration towards SDF-1α. Moreover, TFPI treatment of murine KLS cells led to significant improvement in homing following intravenous injection and long-term reconstitution upon transplantation in competitive repopulation assays. We found that the effects of TFPI were mediated by the heparan sulphate proteoglycan, Glypican-3 (Gpc3). TFPI directly bound Gpc3; TFPI did not affect CD26 activity, migration or homing of Gpc3^−/− KLS cells, but affected Gpc1^−/− KLS cells similar to the wild type. Finally, KLS cells from Gpc3^−/− but not Gpc1^−/− mice homed significantly less following IV injection. Hence, we present a novel molecule that can be used in an HSC specific manner to enhance HSC migration, homing and engraftment.