20 Feb 2019
Regenerative medicine hopes to use stem cells to repair organs. Scientists at LMU and the Helmholtz Zentrum München have now identified the protein AKNA as a key regulator of neural stem cell behavior, and elucidated its mode of action.
The research team led by Professor Magdalena Götz, Chair of Physiological Genomics of the LMU Biomedical Center and Director of the Institute for Stem Cell Research (ISF) at the Helmholtz Zentrum München, set out to identify the factors that regulate the maintenance or differentiation of neural stem cells. To this end, the scientists isolated neural stem cells, which either self-renew and generate additional neural stem cells or differentiate. “We found that the AKNA protein is present in higher concentrations in stem cells that generate neurons,” explains ISF researcher German Camargo Ortega, first author of the study together with Dr. Sven Falk. “Our experiments showed that low levels of the AKNA protein cause stem cells to remain in the stem cell niche, whereas higher levels stimulate them to detach from the niche, thus promoting differentiation.”
The scientists were surprised to discover the position of the protein − namely at the centrosome, an organelle in the cell’s interior that acts as the chief architect of the organization of the cytoskeleton, and regulates cell division. “We discovered that an incorrect amino-acid sequence was originally published for this protein,” Sven Falk reports. “However, our work clearly showed that AKNA is located directly at the centrosome.” The researchers were able to show that AKNA recruits and anchors microtubules at the centrosome. This in turn weakens the connections to neighboring cells, and promotes detachment and migration from the stem cell niche. According to the authors, the core facilities for monoclonal antibodies and proteomics at the Helmholtz Zentrum München were essential for this discovery, which could not have been made without the expertise of Drs. Regina Feederle, Arie Geerlof and Stefanie Hauck.
“Our experiments show that this function also plays an important role in a process known as the epithelial-to-mesenchymal transition, or EMT for short”, explains the study leader Magdalena Götz. “In this process, cells detach from a cluster, proliferate and begin to migrate. This occurs, for example, when stem cells migrate to form new neurons, but it can also be harmful in disease states, as when cancer cells leave a tumor to form metastases elsewhere in the body. The novel mechanism that we identified by studying the function of AKNA therefore appears to play a key role in a broad range of medically relevant processes.” In the next step, the research team plans to investigate the role of AKNA in other stem cells and in the immune system. (Helmholtz Zentrum München/LMU)Nature 2019