Cellular mechanisms of regenerative effects of granulocyte colony-stimulating factor (G-CSF) in hindlimb ischemia

点击翻译按钮获取中文摘要

Recombinant granulocyte colony-stimulating factor (rG-CSF) relieves the functional consequencesof ischemia in heart, brain and limbs. rG-CSF-mediated mobilization of bone marrow-derived cells,leading to their increased homing in the ischemic tissue where they could act by paracrinemechanisms, may underly this effect. In addition or alternatively, rG-CSF may exert direct effects inthe ischemic tissue as its receptor (G-CSFR) is expressed on various resident cell types including vascular cells. However, while therapeutic effects of rG-CSF are indisputable the role of endogeneous G-CSF in autonomous regeneration in ischemic diseases is enigmatic. Therefore, the present project shall reveal the impact of endogeneous G-CSF for compensatory vessel growth in a murine hindlimb ischemia model using G-CSF- and G-CSFR knockout mice. To examine the functional consequences of deficient G-SCF signalling in these mice Laser Doppier Perfusion Imaging (LDPI) and Nuclear Magnetic Resonance Imaging (NMRI) will be applied. The mechanisms of potential effects of endogeneous G-CSF may be those currently discussed, but not definitively explored for rG-CSF effects (see above). Therefore, several types of transgenic, bone marrow-chimeric mice will be used to reveal possible mechanisms of action of endogeneous G-CSF and exogeneous rGCSF in parallel. These investigations will comprise the analysis of the relative contributions of bone marrow cell-dependent and -independent G-CSF effects in compensatory vessel growth. Cellular activities, such as proliferation, differentiation and apoptosis potentially contributing to these effects shall be investigated.