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.

Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34 + progenitors

“…Key regulators of the actin cytoskeleton CDC42 and RHOA have already been shown to be associated with thrombocytopenia, due to defects in cytoskeleton organization. [37][38][39][40][41] In affected individuals, we found abnormal tubulin organization in proplatelet-forming megakaryocytes and altered actin polymerization in platelets. Rescue experiments with CDC42 lentiviral particles were not able to fully reverse the phenotype, although the cells produced thinner extensions and swellings, which were barely observed in control cells.…”

Vascular Endothelial Cell-Specific Connective Tissue Growth Factor (CTGF) Is Necessary for Development of Chronic Hypoxia-Induced Pulmonary Hypertension

“…One week after the last injection, mice were then harvested for histology and hemodynamic measurements, similar to hypoxia-treated groups. ML141 (5 mg per kg body weight), a Cdc42 inhibitor, was dissolved in dimethyl sulfoxide (DMSO), and was intraperitoneally injected daily throughout bleomycin administration protocol (Chen et al, 2015 ), in described experiments.…”

Direct Modulation of Small GTPase Activity and Function

“…Furthermore, 2 proved useful for combination with colony-stimulation factor (G-CSF) in the mobilization of hematopoietic stem and progenitor cells. [53] Another study identified EHT1864 (3)asaRac1 inhibitor,which effectively reduces Ab peptide levels in models of Alzheimers diesease in vitro (Figure 3a). [54] Further investigation of the mode of action led to the postulate that the compound tightly binds Rac1 with low nanomolar affinity (dissociation constant K d = 40 nm).…”