Molecular Psychiatry (2018) 24:2–9 https://doi.org/10.1038/s41380-018-0244-9 GUEST EDITORIAL Stress-inducible-stem cells: a new view on endocrine, metabolic and mental disease? 1,2,3,4,5 1 6 7,8 9,10 11 12,13 S R Bornstein ● C Steenblock ● G P Chrousos ● A V Schally ● F Beuschlein ● G Kline ● N P Krone ● 14,15 14,15 1,16 1,17 5 18 1,2 J Licinio ● M L Wong ● E Ullmann ● G Ruiz-Babot ● B O Boehm ● A Behrens ● A Brennand ● 1,19 1 1 20 1 1,21 1 A Santambrogio ● I Berger ● M Werdermann ● R Sancho ● A Linkermann ● J W Lenders ● G Eisenhofer ● C L Andoniadou 1,19 Received: 19 July 2018 / Accepted: 25 July 2018 / Published online: 21 September 2018 © The Author(s) 2018. This article is published with open access Introduction will trigger and contribute to metabolic and cardiovascular diseases [4, 5]. In general terms we all use the word “stress” to describe our Endocrine and neural responses to stress have been well- discomfort in coping with challenges of daily life. This is defined and involve an activation of both the hypothalamic- mostly related to our subjective perceptions of workload pituitary-adrenal axis (HPA) and the sympathoadrenal sys- 1234567890();,: 1234567890();,: and/or other unexpected physical or mental efforts we are tem. A wide variety of external and internal stimuli, exposed to. The term is derived from the concept of stress as including inflammation, infection, as well as physical and a reaction to internal and external stimuli requiring acute or mental stressors induces the release of corticotropin- chronic adaptations, as introduced by Hans Selye in the releasing hormone (CRH) from the paraventricular second half of the last century [1–3]. nucleus (PVN) of the hypothalamus. CRH in turn is both a In 1998 on a WHO conference on stress a more compre- central activator of the HPA axis, as well as the sym- hensive definition of the term was provided: pathoadrenal system, since CRH mediates the release of adrenocorticotropic hormone (ACTH) from the pituitary “Stress may be defined as a mechanism of acute and and hence adrenocortical glucocorticoids as well as the chronic adaptation necessary for evolution and release of epinephrine from the adrenal medulla [4]. In survival. The integrated stress response is part of the addition to CRH as a main regulator of the HPA axis there homoeostatic balance, and dysfunction of such are numerous CRH and ACTH-independent factors, response may contribute to disease. Alternations of including neuropeptides, cytokines, the microbiota-gut- the endocrine, neural and immune responses to stress brain axis [6], and even bacterial and viral pathogens that are involved both in etiology and the pathophysiology are capable of activating the release of adrenal stress ster- of the most common health problems in modern oids [7]. society.” (World Health Organization_WHO/RPS/ Finally, central activation of the autonomic nervous 98.3). system will lead to an acute activation of the adrenal medulla by the splanchnic nerves triggering the release of In a biological sense stress is a two-edged sword repre- epinephrine and other neuropeptides. Interestingly, senting a positive side (eustress) and a negative side (dis- splanchnic nerve stimulation will also provoke the release tress). On one hand, eustress helps to deal with challenges of adrenal glucocorticoids and mineralocorticoids, which is of daily life and disease, and it is also a driver of evolution mediated in a paracrine way by the released catecholamines and development. On the other hand, a chronic response to [8]. stress with chronic activation of the endocrine stress axis Thus, there is a complex network of neuronal and cel- lular interactions within the end organ of the endocrine and neuroendocrine stress system. It is no coincidence that the adrenal gland combines the steroid-producing adrenal cor- * S R Bornstein tex and the catecholamine-producing adrenal medulla under [email protected] a common organ capsule. In fact, there is an active cellular Extended author information available on the last page of the article. and functional interaction of cortical and chromaffin cells Stress-inducible-stem cells: a new view on endocrine, metabolic and mental disease? 3 within the gland. Whereas adrenocortical glucocorticoids to steroid-induced cell death (apoptosis) through glucocorti- are required for the biosynthesis of adrenomedullary epi- coid receptor (GR) signaling [16], providing a model for the nephrine, catecholamines regulate the release of steroids sensitivity of neuronal stem cells to metabolic cellular turn- and the cellular function of the adrenal cortex [9]. Fur- over and/or cellular loss induced by stress. thermore, patients with disorders of the adrenal cortex such Interestingly, we have identified CRH1 and CRH2 receptors as Addison’s disease or congenital adrenal hyperplasia not only in NSCs but also in hematopoietic stem cells display a dysfunction of the adrenal medulla resulting in an (HSCs) [17]. CRH receptors are involved in the systemic impaired stress response [10–12]. stress response and intriguingly CRH receptor expression is In addition to the cellular crosstalk between the two increased among immature hematopoietic progenitors but endocrine cell systems in the adrenal there is an important not in fully differentiated blood cells. Stimulation with CRH role for the vasculature and the immune system. Nearly decreases intracellular cAMP demonstrating active signal- each adrenal cell is in close proximity to endothelial cells ing of this central stress hormone in HSCs [17]. Recently, and the gland receives ten times more blood than expected the CNS has been shown to regulate embryonic HSCs via from its size [9]. Therefore, the intact physical and bio- the HPA axis, as GR activation leads to HSC expansion chemical communication between vascular and endocrine while GR loss reduces HSC formation [18]. Likewise cells is critical for the functional integrity and adaptation to chronic stress exposures also activate HSC formation [19]. stress of the entire gland, as vascular vulnerability may lead While, we are only beginning to understand the role of to ruptures, hemorrhage and adrenal failure with life- stress hormones on HSCs, their roles on NSCs and neuro- threatening consequences for the patient [13, 14]. Similarly, genesis have been explored more comprehensively. Most intact interactions with the systemic and resident immune importantly stress hormones exert a differential effect on cells are critical for proper functioning of the adrenal and its neurogenesis depending on age, time, location, and nature of ability to cope with the increased stress of inflammation and the exposure. Conditions that strongly elevate CRH, ACTH sepsis [13, 14]. and glucocorticoids, such as physical activity, enriched In addition to this complex interplay of cellular and environmental housing, or mental stress induce proliferation neuronal networks in mounting and maintaining an ade- and survival of newborn neurons and promote neurogenesis quate adrenal stress response, regulation of the secretion of [20]. Conversely, chronic endogenous or pharmacological peripheral and central stress hormones is under strict cir- exposure of NSCs to glucocorticoids has been clearly asso- cadian and ultradian control [15]. Thus, the entire endocrine ciated with reduced neurogenesis [20]. This has been linked to stress system is embedded in an even more complex and not the activation of GRs or to changes in the expression of genes fully explored cybernetic model of positive and negative associated with cellular senescence [21–23]. Why the acti- feedback regulations, which mature postnatally to become vation of the HPA axis leads to enhanced neurogenesis in fully functional only after puberty. some instances yet the loss of neural stem cells in others has This leads to the obvious question of how stress in early not been fully understood [20]. life may shape the development and maturation of the major Proliferating neuronal progenitors express higher levels cellular response elements including the HPA axis. Before of CRH receptors and are enhanced in the human fetal brain we try to explore this intriguing question we should reflect [24]. Moreover, CRH-deficient mice show reduced pro- on what is known-up to now on the role of the classical liferation and increased apoptosis among neural progenitors. stress hormones on the regulation of stem cells in general. Thus, it has been suggested that CRH, as the major mediator of the adaptive response to stressors, could reverse damaging Role of stress steroids on progenitor/stem cell effects of glucocorticoids on stem/progenitor cells [24]. populations If CRH could reverse the damaging effects of gluco- corticoids it may be assumed that the negative feedback on Progenitor and stem cell populations are both required for the CRH with elevated glucocorticoid levels contributes to the successful homeostasis and adaptation of most tissues. reduction of neurogenesis observed during chronic stress. In Human hematopoietic stem and progenitor cells provide addition, we and others have shown that during the acute lifelong production of mature blood cells dependent on the and chronic stress of inflammation and sepsis but also in changing requirements of each individual. Therefore, hema- mental and metabolic disorders, several extra-hypothalamic topoiesis is a cellular process defined by a clear balance of and extra-pituitary factors including cytokines, pathogens, self-renewal and commitment to differentiation. Hemato- adipokines, growth factors, inflammatory lipids, morpho- poietic progenitors are also able to transdifferentiate into non- gens, catecholamines, and neuropeptides can stimulate hematopoietic cells and exhibit overlapping genetic programs adrenal glucocorticoid release [7, 9]. Consequently, the with mesenchymal and neural stem cells (NSCs). Importantly, neuroprotective effect of CRH may get lost during both neuronal stem cells in mice have been reported to be sensitive acute and chronic stress. Another explanation may relate to 4 S. R. Bornstein et al. the pattern of glucocorticoid secretion during stress as it has form the mature HPA axis [29, 30].