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Recent advances in the in vitro characterization of human adult enteric neural progenitor cells have opened new possibilities for cell-based therapies in gastrointestinal motility disorders. However, whether these cells are able to integrate within an in vivo gut environment is still unclear. In this study, we transplanted neural progenitor-containing neurosphere-like bodies (NLBs) in a mouse model of hypoganglionosis and analyzed cellular integration of NLB-derived cell types and functional improvement. NLBs were propagated from postnatal and adult human gut tissues. Cells were characterized by immunohistochemistry, quantitative PCR and subtelomere fluorescence in situ hybridization (FISH). For in vivo evaluation, the plexus of murine colon was damaged by the application of cationic surfactant benzalkonium chloride which was followed by the transplantation of NLBs in a fibrin matrix. After 4 weeks, grafted human cells were visualized by combined in situ hybridization (Alu) and immunohistochemistry (PGP9.5, GFAP, SMA). In addition, we determined nitric oxide synthase (NOS)-positive neurons and measured hypertrophic effects in the ENS and musculature. Contractility of treated guts was assessed in organ bath after electrical field stimulation. NLBs could be reproducibly generated without any signs of chromosomal alterations using subtelomere FISH. NLB-derived cells integrated within the host tissue and showed expected differentiated phenotypes i.e. enteric neurons, glia and smooth muscle-like cells following in vivo transplantation. Our data suggest biological effects of the transplanted NLB cells on tissue contractility, although robust statistical results could not be obtained due to the small sample size. Further, it is unclear, which of the NLB cell types including neural progenitors have direct restoring effects or, alternatively may act via 'bystander' mechanisms in vivo. Our findings provide further evidence that NLB transplantation can be considered as feasible tool to improve ENS function in a variety of gastrointestinal disorders.
The observation of neutrino masses and lepton mixing has highlighted the incompleteness of the Standard Model of particle physics. In conjunction with this discovery, new questions arise: why are the neutrino masses so small, which form has their mass hierarchy, why is the mixing in the quark and lepton sectors so different or what is the structure of the Higgs sector. In order to address these issues and to predict future experimental results, different approaches are considered. One particularly interesting possibility, are Grand Unified Theories such as SU(5) or SO(10). GUTs are vertical symmetries since they unify the SM particles into multiplets and usually predict new particles which can naturally explain the smallness of the neutrino masses via the seesaw mechanism. On the other hand, also horizontal symmetries, i.e., flavor symmetries, acting on the generation space of the SM particles, are promising. They can serve as an explanation for the quark and lepton mass hierarchies as well as for the different mixings in the quark and lepton sectors. In addition, flavor symmetries are significantly involved in the Higgs sector and predict certain forms of mass matrices. This high predictivity makes GUTs and flavor symmetries interesting for both, theorists and experimentalists. These extensions of the SM can be also combined with theories such as supersymmetry or extra dimensions. In addition, they usually have implications on the observed matter-antimatter asymmetry of the universe or can provide a dark matter candidate. In general, they also predict the lepton flavor violating rare decays mu -> e gamma, tau -> mu gamma and tau -> e gamma which are strongly bounded by experiments but might be observed in the future. In this thesis, we combine all of these approaches, i.e., GUTs, the seesaw mechanism and flavor symmetries. Moreover, our request is to develop and perform a systematic model building approach with flavor symmetries and to search for phenomenological implications. This provides a new perspective in model building since it allows us to screen models by its predictions on the theoretical and phenomenological side, i.e., we can apply further model constraints to single out a desired model. The results of our approach are, e.g., diverse lepton flavor and GUT models, a systematic scan of lepton flavor violation, new mass matrices, a new understanding of lepton mixing angles, a general extension of the idea of quark-lepton complementarity theta_12=pi/4-epsilon/sqrt{2} and for the first time the QLC relation in an SU(5) GUT.