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| Author(s): |
Maria Fernanda Pereira de Araújo Demonte Forni
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) |
| Defense date: | 2013-03-14 |
| Examining board members: |
Mari Cleide Sogayar;
Lygia da Veiga Pereira Carramaschi;
Deborah Schechtman;
Luis Eduardo Soares Netto;
Alexander Henning Ulrich
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| Advisor: | Mari Cleide Sogayar |
| Abstract | |
The skin is continuously self-renewing thanks to several stem cell niches. Epidermal progenitor cells arise during embryonic development and contribute to the replenishment of the epidermis during the lifetime of mammals. We set out to analyze the glutathione (GSH) antioxidant system during embryonic epidermis stratification and follicle development and the effect of glutathione withdrawal in this process. We found that glutathione plays an important role during epidermis proliferation and hairshaft formation. The changes observed in the absence of GSH were related to a differential phosphorylation pattern of the forkhead-homeobox-type-O (FOXO) transcription factors. In brief, a correlation between GSH status, FOXO phosphorylation and skin development was established. To further study the importance of GSH in adult skin maintenance and understand the effects of ROS in the Akt/FOXO pathway, we treated cells and mice with an inhibitor of GSH synthesis, and with N-acetyl-cysteine. Increased Akt phosphorylation, altered FOXO phosphorylation patterns and increased gene expression of differentiation-related genes were observed. Our results show that the Akt/FOXO pathway plays an important role in maintenance/differentiation of epidermal stem cells. Chronological ageing leads to morphological/functional changes causing a decline in self-renewal, as well as decreased levels of GSH. We also observed that a cell cycle hyperproliferative response was the link between stem cell exaustion in GSH-depletion and ageing. Dermal mesenchymal stem cells (MSCs), are capable of adipo-chondro- and osteogenesis. Little is known about the impact of ROS in MSC differentiation. We induced murine skin MSCs to differentiate into bone (Alizarin-Red/Von-Kossastain+, increased levels of mRNA for alkalinephosphatase/ osteopontin/osterix). In brief, the balance of GSH/GSSG and related antioxidant system is differentially regulated during this process, found to be regulated in a redox-dependent fashion through the MAPK pathway. When depleted, GSH leads to an adipogenic switch in MSC differentiation. In conclusion, our data leads us to propose a central role for glutathione in the maintenance/commitment of stem cells in skin. (AU) | |