Chronic psychological stress activates BMP4‐dependent extramedullary erythropoiesis

Abstract

Psychological stress affects different physiological processes including haematopoiesis. However, erythropoietic effects of chronic psychological stress remain largely unknown. The adult spleen contains a distinct microenvironment favourable for rapid expansion of erythroid progenitors in response to stressful stimuli, and emerging evidence suggests that inappropriate activation of stress erythropoiesis may predispose to leukaemic transformation. We used a mouse model to study the influence of chronic psychological stress on erythropoiesis in the spleen and to investigate potential mediators of observed effects. Adult mice were subjected to 2 hrs daily restraint stress for 7 or 14 consecutive days. Our results showed that chronic exposure to restraint stress decreased the concentration of haemoglobin in the blood, elevated circulating levels of erythropoietin and corticosterone, and resulted in markedly increased number of erythroid progenitors and precursors in the spleen. Western blot analysis revealed significantly decreased expression of both erythropoietin receptor and glucocorticoid receptor in the spleen of restrained mice. Furthermore, chronic stress enhanced the expression of stem cell factor receptor in the red pulp. Moreover, chronically stressed animals exhibited significantly increased expression of bone morphogenetic protein 4 (BMP4) in the red pulp as well as substantially enhanced mRNA expression levels of its receptors in the spleen. These findings demonstrate for the first time that chronic psychological stress activates BMP4-dependent extramedullary erythropoiesis and leads to the prolonged activation of stress erythropoiesis pathways. Prolonged activation of these pathways along with an excessive production of immature erythroid cells may predispose chronically stressed subjects to a higher risk of leukaemic transformation.

Severe trauma and chronic stress activates extramedullary erythropoiesis

“…The initial sympathetic response following trauma is a necessary physiologic response but when this stressful state is prolonged it impacts many organs. This finding is supported by the work of Vignjevic et al 30 who demonstrated that psychological stress alone activates extramedullary erythropoiesis in adult mice.…”

“…Yet, chronic stress alone in mice did not increase the total number of Ter119 positive cells after seven days. 30 It took 14 days of restraint stress to increase the number of Ter119 positive cells suggesting that chronic stress led to a delay in terminal erythroid differentiation. 30 This confirms that extramedullary erythropoiesis in the spleen works rapidly to produce mature erythroid cells.…”

“…30 It took 14 days of restraint stress to increase the number of Ter119 positive cells suggesting that chronic stress led to a delay in terminal erythroid differentiation. 30 This confirms that extramedullary erythropoiesis in the spleen works rapidly to produce mature erythroid cells. Similarly, in our model of LCHS/CS, 70% of the HPCs in the spleen were viable and proliferating cells, suggesting that the majority of HPCs in the spleen are maturing.…”

“…This is supported by findings of decreased EPOr and glucocorticoid receptor expression in the spleen following chronic psychological stress. 30 The glucocorticoid receptor cooperates with EPOr to enhance the proliferation of splenic erythroid progenitors demonstrating the importance of sympathetic activation in this process.…”

Activin A more prominently regulates muscle mass in primates than does GDF8

“…The erythropoietic growth factors BMP2 or 7 are unlikely to account for the induction of extramedullary hematopoiesis, since they are ligands for ActRIIB.hFc. A similar situation exists for BMP4, another ActRIIB.hFc ligand that has previously been shown to induce extramedullary hematopoiesis in mice57. Interestingly, the type III TGF-β receptor has been shown to be a marker that distinguishes ‘early' and ‘late' burst-forming unit erythroid progenitors58.…”