Characterizing Adrenal Stem Cells in Metabolic Disease

The HPA axis plays an essential role in the coordination of endocrine responses to physiological stressors. Chronic stress leads to hyperactivity of this system with consequences that play a role in various pathological states, such as obesity and insulin resistance. Metabolic disease represents an increasing problem in our societies and has itself been categorised as a source of chronic stress, thus constituting a vicious cycle of metabolic and HPA-axis dysregulation.

The adaptability of endocrine function of the HPA axis in response to physiological challenges relies on flexibility of the adrenal cortex and the anterior pituitary gland. In both organs, stem/progenitor cell populations have been identified including Nestin expressing cells. These cells have been shown to be involved in the plasticity of the two endocrine glands, and in the adrenal cortex have been shown to be activated from their basal quiescent state by stress.  

Therefore, the major goal of this thesis was to identify whether Nestin expressing cells of the anterior pituitary and adrenal cortex can be activated by metabolic stress, and directed to preferentially differentiate into functional endocrine cells involved in stress response. Progenitors were isolated from the anterior pituitary and the adrenal cortex and cultured with high concentrations of insulin or leptin. Gene and protein expression of relevant stem cell markers, metabolic receptors, and differentiation markers were assessed using RT-qPCR and western blotting. Additionally, the fate of Nestin⁺ cells and their progeny was analysed using the NesCreER:Rosa26YFP lineage tracing model in order to assess their differentiation behaviour in response to metabolic stress.

Overall, expression of most stem cell markers was not affected by insulin or leptin. Adrenocortical progenitors were more susceptible to insulin than leptin signalling, and insulin treated cultures produced more total cells. This was observed to a lesser extent in pituitary cultures, although both adrenocortical and adenohypophyseal progenitors appeared to express receptors for both hormones to a certain extent. Leptin reduced the number of Nestin⁺ cells differentiating into aldosterone producing cells, while insulin preferentially directed the Nestin derived cells towards this adrenocortical lineage. Insulin also increased the number of cells differentiating towards corticotroph cell lineages of the anterior pituitary. These data, taken into the context of available literature, allow us to propose a model for the interaction of metabolic disease and HPA dysregulation. Adrenocortical and adenohypophyseal Nestin expressing progenitors may be involved in the hyperactivation of the HPA axis and thus play a role in the vicious cycle associated with the crosstalk between metabolic disease and HPA axis dysregulation.

The induction of stem cells in response to stress has been proposed to be a mechanism for adjusting to the challenges of daily life and disease. In turn, the modifications derived hereby may however predispose to disease later in life. In this study, we have shown the activation of HPA stem cells in response to metabolic stress in the form of insulin. Continual adaptation and modulation of the HPA axis through induction of its progenitor populations may therefore contribute to the development and worsening of metabolic disease.

Publications:

Adrenal cortex–medulla interactions in adaptation to stress and disease.  S.R. Bornstein, I. Berger, L. Scriba, A. Santambrogio, C. Steenblock. Curr Opin Endocr Metab Res. 2019;8:9-14.

Cancer Stem Cells in Pheochromocytoma and Paraganglioma.  L.D. Scriba, S.R. Bornstein, A. Santambrogio, G. Mueller, A. Huebner, J. Hauer, A. Schedl, B. Wielockx, G. Eisenhofer, C.L. Andoniadou, C. Steenblock. Front Endocrinol (Lausanne). 2020;11:79.

Insulin and obesity transform hypothalamic-pituitary-adrenal axis stemness and function in a hyperactive state.  M. Werdermann, I. Berger, L.D. Scriba, A. Santambrogio, P. Schlinkert, H. Brendel, H. Morawietz, A. Schedl, M. Peitzsch, A.J.F. King, C.L. Andoniadou, S.R. Bornstein, C. Steenblock. Mol Metab. 2021;43:101112.