Elucidation of multinumerous centrosomes and their impact on migration in dendritic cells

Centrosomes act as major microtubule organizing center (MTOC) in most animal cells and are well known for their role in building up the mitotic spindle during cell division. Core structure of the centrosome are two tubulus shaped centrioles, which are connected by linker fibers and surrounded by a protein-rich matrix (pericentriolar material, PCM). The centrosome duplicates precisely once during the cell cycle leading to the presence of one centrosome in G1 phase and two centrosomes after centriole duplication in S phase. However, studies in our lab showed that about 20-30 % of mature murine bone marrow-derived dendritic cells (BMDCs) and dermal dendritic cells (dermal DCs) harbor more than one centrosome in G1 phase. The phenomenon of additional centrosomes has so far only been described for very few non-malignant cells, but is commonly observed in solid and haematological malignancies. In some cancer types, the degree of centrosome amplification is positively associated with tumor aggressiveness partly explainable by the fact that extra centrosomes can contribute to the development of metastasis. Prerequisite for the dissemination of primary tumor cells is the acquisition of a migratory phenotype. Against this backdrop, our findings of multinumerous centrosomes shed new light on DCs – cells specialized in trafficking through complex and versatile environments –, raising the question of whether the presence of excess centrosomes in DCs has any impact on the cells’ migratory behavior. In order to elucidate the origin of additional centrosomes in murine DCs we took a closer look at the cell cycle and studied centrosomes in vitro, ex vivo and in situ. We found that supernumerary centrosomes are neither the consequence of ongoing cell proliferation nor the result of culturing conditions. Instead, we revealed that mature DCs arrest in G1 phase of the cell cycle. Moreover, we unraveled that extra centrosomes occur by accumulation due to a modified cell division cycle or cytokinesis failures, leading to tetraploid ...