Modulation of Stem Cell Plasticity in Old Age by Sirtuins, Oxidative Stress and Calcium Signals - Experimental Strategies for the Restoration of Stem Cell Properties in ASC of advanced Age Patients

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Background: Mesenchymal stem cells (MSC) are life-long contributing to the maintenance and repair of tissues. However, the capacity of MSC for self-renewal and differentiation is declining with increasing age. This considerably compromises natural healing and repair processes as well as the applicability of MSC in tissue engineering and cell therapy.Accountable for the decreasing plasticity of stem cells with increasing age of life are presumably augmenting levels of reactive oxygen species (ROS) which correlate with a decreasing concentration of nitric oxide (NO). Potentially, self-renewal and stem cell plasticity are also regulated by Ca2+ oscillations. These are occurring in undifferentiated stem cells, are lost during the differentiation process, and are regulated by ROS/NO. The manner by which ROS/NO and Ca2+ oscillations are regulating the expression of stem cell genes is so far not known and will be investigated in the present study. We assume that sirtuins (Sirt1/7) play a key role and are integrated as histone acetylases in the cellular redox regulation, stem cell gene expression and the control of differentiation. Hypothesis: Ca2+ oscillations, ROS and NO are regulating the plasticity of stem cells as intracellular messengers. The plasticity is lost with advanced age through increased oxidative stress and changes in sirtuin gene expression. Sirtuins influence the levels of ROS/NO and - related with this - Ca2+ oscillations which specifically determine the plasticity of stem cells. Hence, sirtuins, ROS and Ca2+ oscillations are key determinants in age- and gender-dependent control of stem cell plasticity. The reduced plasticity of stem cells in elderly people can be reversed by modulation of this pathway.Aims: In the current research proposal the plasticity of adipose tissue-derived stem cells (ASC) from donors (male/female) of different life age will be analyzed and interrelated with the expression pattern of sirtuins, the intracellular redox state (ROS/NO) and the characteristics of Ca2+ oscillations. Particularly, determinants in gender and age will be elaborated. The signaling cascade of specific sirtuins, ROS/NO and Ca2+ oscillations down to gene expression of stem cell genes will be investigated. By modulation of the signaling cascade on the level of sirtuin gene expression, ROS and Ca2+ oscillations the plasticity of ASC from elderly male and female patients will be normalized.