title: Cdc42 inhibitor ML141 enhances G-CSF-induced hematopoietic stem and progenitor cell mobilization.
abstract: G-CSF is the most often used agent in clinical hematopoietic stem and progenitor cell (HSPC) mobilization. However, in about 10 % of patients, G-CSF does not efficiently mobilize HSPC in clinically sufficient amounts. Cdc42 activity is involved in HSPC mobilization. In the present study, we explore the impact of Cdc42 inhibitor ML141 on G-CSF-mediated HSPC mobilization in mice. We found that the use of ML141 alone only triggered modest HSPC mobilization effect in mice. However, combination of G-CSF and ML141 significantly promoted HPSC counts and colony forming units in peripheral blood, as compared to mice treated with G-CSF alone. ML141 did not significantly alter the levels of SDF-1 and MMP-9 in the bone marrow, when used alone or in combination with G-CSF. We also found that G-CSF administration significantly increases the level of GTP-bound Cdc42, but does not alter the expression of Cdc42 in the bone marrow. Our data indicate that the Cdc42 signal is a negative regulator in G-CSF-mediated HSPC mobilization, and that inhibition of the Cdc42 signal efficiently improves mobilization efficiency. These findings may provide a new strategy for efficient HSPC mobilization, especially in patients with poor G-CSF response.
authors.affiliation: Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, No. 99, West Huaihai Road, Xuzhou, 221002, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Chen
authors.forename: Xuguang
authors.initials: X
authors.lastname: Song
authors.forename: Sha
authors.initials: S
authors.lastname: Ma
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Huanxin
authors.initials: H
authors.lastname: Zhang
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Wu
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.forename: Jiang
authors.initials: J
authors.lastname: Cao
authors.forename: Jianlin
authors.initials: J
authors.lastname: Qiao
authors.forename: Xiaoshen
authors.initials: X
authors.lastname: Sun
authors.forename: Depeng
authors.initials: D
authors.lastname: Li
authors.forename: Lingyu
authors.initials: L
authors.lastname: Zeng
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Li
authors.forename: Kailin
authors.initials: K
authors.lastname: Xu
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors; D000096926:Benzenesulfonamides
chemical_list: D054377:Chemokine CXCL12; D016179:Granulocyte Colony-Stimulating Factor; D020780:Matrix Metalloproteinase 9; D011720:Pyrazoles; D013449:Sulfonamides; D020764:cdc42 GTP-Binding Protein; C581055:CID2950007; D000096926:Benzenesulfonamides