Stress and Hematopoiesis
A study published in Nature Medicine suggests that stress mediators may also directly activate hematopoietic stem cells (HSCs), which increase proliferation and differentiate into downstream progenitor cells, with the end result of an accelerated neutrophil and monocyte production.
Acute stress is known to induce a transient leukocytosis. This is explained by the prompt effect of stress mediators, such as catecholamines (CAs) on the mobilization of these cells from depots, such as the spleen or the lung, or the marginating pool in blood vessels. Characteristically, two phases are recognized after catecholamine administration: a quick (<30 min) mobilization of lymphocytes, followed by an increase in granulocyte numbers with decreasing lymphocyte numbers. Many studies have shown that catecholamines predominantly affect natural killer (NK) cell and granulocyte circulation, whereas T- and B-cell numbers remain relatively unaffected. (Benschop RJ, Rodriguez-Feuerhahn M & Schedlowski M, Brain Behav Immun, 1996, 10:77).
It is known that the bone marrow, similar to all lymphoid organs, receives extensive sympathetic/noradrenergic innervation. In 1972, JW Byron suggested that early hematopoietic progenitors may be very sensitive to small amounts of CAs and that β-adrenoceptor stimulation might serve to trigger hemopoietic stem cells into their cell cycle (Exp Cell Res 1972, 71:228-32).
It is also known that CXCL12, originating from mesenchymal stem cells, osteoblasts and endothelial, is the key factor that inhibits hematopoietic stem and progenitor cell (HSPC) proliferation and migration. Recent research indicates that the HSCs’ release is regulated through circadian norepinephrine secretion by the sympathetic nervous system (SNS), and that noradrenergic signals, locally delivered by sympathetic nerves in the bone marrow are transmitted to stromal cells by the β3-adrenergic receptor (Méndez-Ferrer S et al., Nature, 2008; 452:442).
It remains unknown, however, whether chronic stress changes hematopoietic stem cell activity.
In the Nature Medicine study, Timo Heidt and colleagues from the Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA, and the University Heart Center, Freiburg, Germany demonstrated that stress increases proliferation of these most primitive hematopoietic progenitors, giving rise to higher levels of disease-promoting inflammatory leukocytes.
While investigating the source of leukocytosis in mice, the authors discovered that stress activates upstream hematopoietic stem cells. Thus, mice subjected to chronic variable stress had increased numbers of leukocytes, mostly neutrophils and monocytes in the blood, and the bone marrow itself.
The investigators found that in mice exposed to stress, the catecholamine norepinephrine (noradrenaline), the primary neurotransmitter released during an increased SNS activity caused a decreased CXCL12 expression in the hematopoietic stem cell niche, and, thus, accelerated HSC proliferation. This, in turn, increased the output of neutrophils and inflammatory monocytes from the bone marrow. Of note, the investigators also found that noradrenaline levels increased in the bone marrow of stressed mice. Thus, immunoreactive staining for tyrosine hydroxylase (TH), a rate–limiting enzyme for noradrenaline synthesis, rose along blood vessels in the bone marrow.
Heidt et al., also describe the clinical implications of their results, testing the hypothesis that chronic stress may act on the bone marrow via an increased SNS activity, and, thus, increase the inflammatory leukocyte supply to atherosclerotic lesions.
In atherosclerosis-prone Apoe−/− mice they found that the release of inflammatory leukocytes into the circulation promoted atherosclerotic plaque inflammation, whereas the administration of a β3-adrenoreceptor antagonist decreased the number of inflammatory immune cells in the atherosclerotic lesions and limited the inflammatory process.
In conclusion, the study describes a new axis of interaction between the central nervous system, immunity and atherosclerosis. In experimental settings and mice exposed to stress, the increased SNS activity decreased CXCL12 expression in the hematopoietic stem cell niche, accelerated HSC proliferation, and enhanced neutrophil and monocyte production. These mechanisms yielded extensive release of inflammatory leukocytes into circulation and promoted plaque inflammation.
The study provides further insights into the link between stress and inflammation, and as discussed by the authors, better understanding of the SNS signaling via the β3-adrenergic receptor, and targeting of the CXCL12-CXCR4 interaction in the bone marrow may suggest new potential therapeutic avenues.
Source: Nat Med. 2014, 20:754. doi: 10.1038/nm.3589. Epub 2014 Jun 22.
Read more: Nature Medicine
Updates
2016
A 2016 study by Sanja Vignjević Petrinović et al. found that in mice chronic restraint stress enhanced the number of both erythroid progenitors and precursors in the spleen. Of note, the stress-induced increase in the number of splenic late erythroid progenitors as well as in the percentage of CD71+Ter119+-double-positive precursors was significantly more pronounced in macrophage migration inhibitory factor (MIF)-KO (knock-out) mice compared to wild-type (WT) animals.
According to the authors their observations suggested that MIF regulates extramedullary erythropoiesis by inhibiting an overexpansion of splenic immature erythroid cells during chronic stress and indicate a novel role for this cytokine under chronic stress conditions.
2020
A 2020 review summarized the recent advances in our understanding of hematopoietic regulation under stress conditions such as inflammation, aging, mitochondrial defects, and damage to DNA or endoplasmic reticulum.
2023
In their previous research, Sanja Momčilović et al. demonstrated that chronic exposure to restraint stress induces anemia and stimulates erythropoiesis in the bone marrow and spleen.
In their 2023 study Sanja Momčilović et al. extended their previous research and showed that depletion of macrophages further worsened anemia and abolished the effects of repeated stress on immature erythroid cells in the bone marrow and spleen.
These authors found that repeated exposure to psychological stress increased ATP levels, purinergic P2X7R expression, and CD39 specific activity and expression in the bone marrow and spleen. Overall, this study demonstrated the stimulative effects of repeated stress on erythroid cells, extracellular ATP levels, P2X7R expression, CD39 activity and expression within the bone marrow and spleen, as well as the essential role of macrophages in stress-induced changes.
2024a
A 2024 study by Bastien Dolfi et al. revealed that psychosocial experimental stress induced neutrophilia in male, but not female mice. Of note, the authors found that B-cell numbers were reduced in female, but not male mice upon exposure to stress.
The authors reported that lymphocytes (T cells and B cells) were the main cell types increased in stress-exposed animals. While myelopoiesis was increased in males, B-cell BM generation was higher in females culminating in increased antibody titers in plasma.
According to the authors, the sex-related changes could be due to a different level of expression of the glucocorticoid receptor (GR) and androgen receptor (AR) on progenitors and mature immune cells between female and male mice.
The authors also reported that adrenal glands in females produce more corticosterone in comparison to males upon experimental stress. The authors demonstrated for the first time the contribution of androgens on stress response and hematopoiesis, particularly on B-cell and T-cell generation.
2024b
Another 2024 study by Emiko Kasahara et al. is perhaps the first to show that psychological stress disrupts systemic iron homeostasis by activating the hepcidin-ferroportin axis.
In this study the social defeat stress (SDS) model did not induce erythrocyte destruction, hemolysis, or bleeding in the gastrointestinal tract of the mice. However, the reported decrease in iron concentration and increase in iron stores in the liver and spleen suggested that SDS impaired iron utilization in vivo.
Background: The liver peptide hepcidin, an important regulator of systemic iron homeostasis, determines circulating iron levels mainly by controlling intestinal iron absorption and macrophage iron recycling. Hepcidin inhibits the release of iron into the circulating blood by reducing ferroportin expression in intestinal and splenic macrophages, thus reducing the amount of iron available to the hematopoietic system in the bone marrow.
In this 2024 study, the SDS mice had high blood hepcidin levels, and the administration of hepcidin inhibitors prevented the reduction of circulating iron levels. Thus, according to the authors, this suggests that reduced protein expression of ferroportin in the duodenum of SDS mice may impair the transfer of iron from the gastrointestinal tract to the circulating blood.
2024c
According to Ioanna Mosialou and Stavroula Kousteni in their recent article Mou et al. identified a brain-bone marrow axis reinforcing myelopoiesis and neuroinflammation during psychological stress, culminating in depression.
In their 2024 study Rong Mou et al. found that arginine vasopressin (AVP) is able to promote myeloid-biased hematopoietic stem cells (HSCs) differentiation by activating neutrophils. AVP administration increased neutrophil and Ly6Chi monocyte production by triggering HSCs that rely on intrinsic S100A9 in mice.
Furthermore, the authors reported that when stimulated with AVP, neutrophils returned to the bone marrow and released interleukin 36G (IL-36G), which interacted with interleukin 1 receptor-like 2 (IL-1RL2) on HSCs to produce neutrophils with high Elane expression that infiltrated the brain and induced neuroinflammation.
2025
A 2025 review article entitled: Chronic stress, gut microbiota, and immunity: interconnections and implications for health Hexiao Jia et al. provides a summary of the research about the relationships between stress, the gut microbiota and hematopoiesis.
Related stories you may like:
Alpha-Adrenergic Receptors And Hematopoiesis
Tachykinins, Bone Marrow and Hematopoiesis
Circadian oscillations in leukocyte migration and their control by sympathetic nerves
Autonomic Nervous System Control of Leukocyte Distribution: Physiology and Implications