LUHMES demonstrate an attractive model for diverse fields of disease-related research in neuroscience, due to the following characteristics:
The extremely high conversion rate to post-mitotic neurons (> 99%), the fast and highly homogeneous differentiation procedure,
two clearly different states (proliferation vs. differentiated), the fact that exogenous growth factors are not necessarily needed, the adaptable DA phenotype,
as well as the origin from healthy human tissue.
The studies included in this thesis demonstrated that LUHMES are well suited for studies of PD-related questions. But also other fields for applications might profit from this cell line.
The new differentiaton protocol that does not require cAMP and GDNF to develop a mature neuronal phenotype allows studies that need to be performed in absence of those factors. One neurodevelopmental study doing so used the LUHMES system in a quantitative test method for the detection of toxic effects on neurite outgrowth in high density cultures. The LUHMES neurite outgrowth assay represents a system for screenings in the field of developmental neurotoxicity (Stiegler et al. 2011). LUHMES might furthermore be suited for studies on the regeneration of neurites. The length of neurites of up to 1 mm makes the cells interesting for studies using chambers that separate cell bodies from neurites, and thereby allow a partial treatment of e.g. neurites only. Another hot field, in which the LUHMES model might contribute, is epigenetics. Developmental changes in LUHMES occur within a short time period and allow the study of epigenetic changes in neuronal development. First studies in our group already used LUHMES in this field and will soon be ready for publication (Tanja Waldmann, personal communication). Epigenetic changes are at present also discussed as key mechanisms in neurodegenerative disease. Recent studies demonstrated that Paraquat, a toxin associated with PD, induced epigenetic changes in a cell model of DA neurons (Song et al.
2011). The LUHMES/MPP+ model would also be interesting for such studies. The unlimited availability of LUHMES and the improved differentiation protocol, which allows a very homogeneous seeding in 96-well and 384-well plates (not shown), renders LUHMES also suited for larger screenings. Those could include screenings on developmental neurotoxic effects and effects of chemicals, potential neurotoxins or natural compounds on mature DA neurons. Concrete applications of LUHMES are realized in our group at the moment. For the study of genetic components in PD, the general resistance of LUHMES to lipid-based
transfections of plasmid DNA had to be overcome. Effective lentivirus-based genetic manipulation strategies have been established in order to up- and down-regulate genes of interest. LUHMES lines overexpressing BACE (Diana Scholz, unpublished results), ASYN (unpublished results), fluorescent proteins (see chapter 4), autophagic (unpublished results) and mitochondrial markers (see chapter 5), as well as shRNA-based knockdown lines (Matthias Weng, unpublished results) have already been created. These are at present used in diverse studies on AD, PD and epigenetics in our group. The modulation of ASYN levels and the expression of mutant forms in the LUHMES/MPP+ model will help to further understand its role in parkinsonian DA neuron degeneration. An ASYN aggregation model, and a model of seeded aggregation of ASYN, is currently established in LUHMES cells. These might be used to screen for substances reducing, preventing or even removing ASYN aggregates, and to further understand the possible prion-like spreading of ASYN in PD (Danzer et al. 2009).
Furthermore, first important steps in co-culturing LUHMES cells with astrocytes (Schildknecht et al. 2012), as well as long-term cultures of LUHMES (Pöltl and Kuegler, unpublished results) have been taken. These allow studies on inflammation and chronic exposure to substances that require long-living cultures. The high homogeneity of LUHMES cultures allows the use of “omics” technologies, a progressive field for studying mechanisms and pathways of toxicity underlying toxin-induced neurodegeneration. First studies in this field, using and combining transcriptomics and metabolomics technologies in LUHMES cells are ongoing in collaboration with the European Union supported ESNATS project and Thomas Hartung, CAAT (Center for Alternatives to Animal Testing), John Hopkins Bloomberg School of Public Health. Also continuative studies on mitochondrial dynamics, transport and morphology are performed in our group (Cornelius Kullmann, unpublished data).
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