Huber Bruno C, Beetz Nick L, Laskowski Alexandra, Ziegler Tilman, Grabmaier Ulrich, Kupatt Christian, Herbach Nadja, Wanke Ruediger, Franz Wolfgang-Michael, Massberg Steffen, Brunner Stefan
Medical Department I, Campus Grosshadern and Campus Innenstadt, Ludwig-Maximilians-University, Munich, Germany.
J Cell Mol Med. 2015 May;19(5):1033-41. doi: 10.1111/jcmm.12494. Epub 2015 Mar 8.
Granulocyte-colony stimulating factor (G-CSF) has been shown to promote mobilization of bone marrow-derived stem cells (BMCs) into the bloodstream associated with improved survival and cardiac function after myocardial infarction. Therefore, the aim of the present study was to investigate whether G-CSF is able to attenuate cardiac remodelling in a mouse model of pressure-induced LV hypertrophy focusing on mobilization and migration of BMCs. LV hypertrophy was induced by transverse aortic constriction (TAC) in C57BL/6J mice. Four weeks after TAC procedure. Mice were treated with G-CSF (100 μg/kg/day; Amgen Biologicals) for 2 weeks. The number of migrated BMCs in the heart was analysed by flow cytometry. mRNA expression and protein level of different growth factors in the myocardium were investigated by RT-PCR and ELISA. Functional analyses assessed by echocardiography and immunohistochemical analysis were performed 8 weeks after TAC procedure. G-CSF-treated animals revealed enhanced homing of VLA-4(+) and c-kit(+) BMCs associated with increased mRNA expression and protein level of the corresponding homing factors Vascular cell adhesion protein 1 and Stem cell factor in the hypertrophic myocardium. Functionally, G-CSF significantly preserved LV function after TAC procedure, which was associated with a significantly reduced area of fibrosis compared to control animals. Furthermore, G-CSF-treated animals revealed a significant improvement of survival after TAC procedure. In summary, G-CSF treatment preserves cardiac function and is able to diminish cardiac fibrosis after induction of LV hypertrophy associated with increased homing of VLA-4(+) and c-kit(+) BMCs and enhanced expression of their respective homing factors VCAM-1 and SCF.
粒细胞集落刺激因子（G-CSF）已被证明可促进骨髓来源干细胞（BMCs）动员至血液中，这与心肌梗死后生存率提高及心脏功能改善相关。因此，本研究的目的是在压力诱导的左心室肥厚小鼠模型中，研究G-CSF是否能够通过关注BMCs的动员和迁移来减轻心脏重塑。通过对C57BL/6J小鼠进行主动脉缩窄（TAC）诱导左心室肥厚。TAC手术后四周，小鼠接受G-CSF（100μg/kg/天；安进生物）治疗两周。通过流式细胞术分析心脏中迁移的BMCs数量。通过RT-PCR和ELISA研究心肌中不同生长因子的mRNA表达和蛋白水平。在TAC手术后八周通过超声心动图和免疫组织化学分析进行功能分析。接受G-CSF治疗的动物显示VLA-4(+)和c-kit(+) BMCs的归巢增强，这与肥厚心肌中相应归巢因子血管细胞黏附蛋白1和干细胞因子的mRNA表达增加及蛋白水平升高相关。在功能上，G-CSF在TAC手术后显著保留了左心室功能，这与对照组动物相比，纤维化面积显著减少相关。此外，接受G-CSF治疗的动物在TAC手术后生存率有显著提高。总之，G-CSF治疗可保留心脏功能，并能够在诱导左心室肥厚后减少心脏纤维化，这与VLA-4(+)和c-kit(+) BMCs归巢增加及其各自归巢因子VCAM-1和SCF表达增强相关。
