The central hypothesis of this proposal is that a pool of neural crest derived adult stem cells in the adrenal medulla is a requirement to provide the necessary plasticity for adaptation to increased physiological needs. It is furthermore hypothesized that this pool of progenitor cells bears the potential for tumourigenic development. The general aim is to uncover the mechanism of stem cell activation in the context of adaptation to stress and tumourigenesis. Specifically the aims are:
(I) Defining the role of SA progenitors in the adrenal’s response to stress.
a) What are the consequences of prolonged stress on proliferation and differentiation of SA progenitors within the adrenal medulla?
b) Which possible mechanisms link stress induced hyperplasia to the genetic programs of proliferation and differentiation?
(II) Establishing serum-free monolayer cultures of chromaffin progenitors from the adult adrenal medulla.
The establishment of serum-free monolayer cultures will allow the derivation of homogenous cultures to study the self-renewal properties of these cells and to study the differentiation of these cells at the level of signal transduction. We will study at the cellular level the effect of stress hormones on SA progenitor cells. Mechanisms behind stress adaptation and regeneration will be identified.
(III) Identifying molecular pathways that control progenitor cell numbers by comparing quiescent, activated, and neoplastic cells.
It is suggested that pheochromocytomas arise from chromaffin progenitor cells within the adrenal medulla. Therefore, characterization of the developmental potential of these cells will form the basis for identifying genetic changes leading to tumourigenic development. In a close collaboration with G. Eisenhofer, genes expressed and pathways activated identified in I and II will be compared to the expression profiles (microarray data) of pheochromocytomas.
Significance: The adaptation of the adrenal gland as the central stress organ is of vital importance in the regulation of homeostasis; dysregulation of adrenal function results in severe health problems in humans. The proposed project will provide important insights into the adaptation of the adrenal medulla to stress and the involvement of chromaffin progenitor cells in this adaptation. In addition, the proposed project is likely to provide mechanistic insights into the control of adrenomedullary SA progenitor proliferation and differentiation. Due to the close relation to neurons, these insights will be important for the understanding of neural progenitor proliferation and differentiation. The implemented culture conditions will provide the basis for culturing and proliferating these cells under controlled conditions. This is important for the potential use of these cells in regenerative therapies.
Furthermore, it is suggested that pheochromocytomas arise from chromaffin progenitor cells within the adrenal medulla. Therefore, characterization of the developmental potential of these cells will form the basis for identifying genetic changes leading to tumourigenic development.
Figure: Experimental approach. In vivo, in vitro, and in silico systems to study the mechanism of activation of progenitors from the adrenal medulla. At each stage of the project, interaction and data exchange will ensure that the genes involved in the regulation of progenitor cell function, their adaptation to stress and their involvement in tumourigenesis will be characterized.