Characterization of Stem-like Cells of the HPA axis

Dr. Charlotte Steenblock, PhD

Principal Investigator

• Adrenal stem cells

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The endocrine system involves communication among different tissues in distinct organs, including the pancreas and components of the hypothalamic-pituitary-adrenal (HPA) axis.

To regulate body weight, the hypothalamus must interpret and integrate incoming signals such as levels of glucose, free fatty acids and amino acids but also hormones like leptin, ghrelin and insulin from the periphery (stomach, pancreas and adipose tissue). It then synthesizes and secretes hormones that affect other endocrine glands such as the pituitary and, subsequently the adrenal. Recently, we have provided evidence that also adrenomedullary dysfunction is a characteristic feature of obesity that involves both reduced adrenal secretion of epinephrine and size of adrenal medullary epinephrine stores [1]. Therefore, further insights into the regulation of the HPA axis are critical to the understanding of obesity and diabetes pathogenesis (Funding: IRTG 2251).

Response of the endocrine system to stress is also characterized by activation of the HPA axis and the sympathetic adrenomedullary system, associated with hypersecretion of adrenal hormones, particularly adrenocortical glucocorticoids and adrenomedullary epinephrine. Long-term adaptation to chronic stress in addition to hormone release also includes hyperplasia of the gland, involving both the adrenal cortex and the adrenal medulla. However, very little is known about the adaptation of the adrenal medulla to long-term stress at the cellular level and the involvement of progenitors and stem cells.

Adrenomedullary progenitors and their role in stress
Under basal conditions glia-like Nestin-GFP cells express the progenitor markers Nestin and Sox10 as well as the glia marker S100-B and GFAP. These cells are almost quiescent under normal conditions. However, under stress situations a fraction of the Nestin-GFP cells proliferate and differentiate predominantly towards the chromaffin lineage.

Research from the Bornstein group showed that multipotent neural crest derived progenitors with glia-like properties persist in the adrenal medulla, where they contribute to the adaptation of the adrenal medulla to physiological needs by differentiation [2]. To study these cells in vitro specific cell culture conditions were developed [3] and recent data from Nestin-GFP mice, where eGFP is expressed under the regulation of the Nestin promotor and from inducible Nes-Cre-ERT/Rosa26-eYFP mice indicate that progenitor cells with similar properties also exist in the adrenal cortex [4]. Similar to the adrenal medulla, stress seems to influence their number, suggesting their involvement in the stress adaptation also of the adrenal cortex (Funding: CRC/TRR 205).

Recent evidence from our groups suggests that a common pathway, STAT3-Ser/Hes3, regulates adult stem cells in several different tissues like pancreas and all components of the HPA axis [5]. We demonstrated that progenitors express the transcription factor Hes3 and that treatments activating Hes3 expression also promote cell growth, similar to our findings on neural stem cells [6]. Our preliminary data with high fat diet models strongly suggest that Hes3 expression is also regulated in the brain of diabetic mice and thus provides a link between diabetes and central stem/progenitor cell regulation.