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Can emotional stress impact drug and treatment efficiency?

Chronic psychological stress has been associated with a greater risk of developing diseases such as cardiovascular disorders, diabetes and autoimmune diseases. Studies undertaken in humans and animal models have provided convincing evidence that the central nervous system interacts with the endocrine and immune systems and that stress responses have complex effects upon immunity usually leading to a down-regulation of the immune system. The body responds to a psychological stress (e.g. depression, work-related burnout, divorce, survival to a natural disaster etc.) principally through the activation of the hypothalamus-pituitary-adrenal (HPA) axis. This causes the secretion of releasing factors, mainly corticotrophin releasing hormone (CRH), from the hypothalamus. CRH stimulates the pituitary gland to secrete adrenocorticotropin hormone, causing the adrenal glands to release glucocorticoids into the blood (predominantly cortisol in humans and corticosterone in rodents). Glucocorticoid receptors (GR) are expressed on many cells, including immune cells such as T and B cells, neutrophils, monocytes, macrophages. Ligand binding to these receptors has a number of inhibitory effects. In particular, expression of proinflammatory cytokines and cell adhesion molecules is reduced. Several studies in the field of psychoneuroimmunology have shown that psychological stress increases the susceptibility towards infectious diseases like influenza virus or herpes simplex virus, and can prolong illness episodes. Studies with vaccines have indicated that people suffering of chronic stress have a weaker antibody reaction and virus-specific T-cell response to the vaccines compared to controls which would place them at greater risk for infection and more severe illness. Finally, stress was shown to influence wound healing by down-regulating the production of pro-inflammatory cytokines, which are known to be important in the early stages of wound repair such as transforming growth factor-β (TGF-β), IL-1α and IL-1β (R. Glaser and J.K. Kiecolt-Glaser, 2005).


While chronic stress has been recognized to play a role in the occurrence and development of various diseases, it remains unclear whether it can also influence disease therapy. In their recent work published in Cell Death & Disease, Yang and colleagues from the Chinese Academy of Sciences in Shanghai investigated the effect of chronic stress on the therapeutic potential of mesenchymal stem cells (MSCs) in the treatment of liver injury in mice. With the growing enthusiasm of stem cell therapy, the application of MSCs in the clinic attracts more and more attention. Free of ethical concerns, without the risk of teratoma formation and with low immunogenicity, MSCs have better clinical potential than embryonic stem (ES) cells or induced pluripotent stem (iPS) cells. The former are being strongly debated for their ethical issues related to their isolation while the latter can form teratoma. MSCs possess self-renewal ability and multidifferentiation potential into various cell types. They can be easily isolated from a wide number of tissues and can be successfully expanded in vitro. From animal models to clinical trials, MSCs have been shown to be applicable in the treatment of numerous diseases, mainly tissue injury and immune disorders, but therapy efficiency varies among patients. Several parameters have been investigated, including cell viability, number of passages, tissue origin, but the emotional state which always accompanies patients through a disease has been, more often than not, neglected.

In the work of Yang et al., mice were fed with carbon tetrachloride (CCl4) to induce liver injury and treated by injection of green fluorescent protein (GFP)-MSCs, isolated from GFP-expressing transgenic mice. It is known that when liver injury occurs, endogenous MSCs are recruited from the bone marrow and participate to the repair process besides in situ cells i.e. hepatic stellate cells and fibroblasts. Injected GFP-MSCs were able to migrate towards the injury site and repair the liver by promoting fibrosis and by differentiating into myofibroblasts (MF) as demonstrated by the de novo expression of the MF marker α-smooth muscle actin (α-SMA) in GFP-positive cells. In order to investigate the role of chronic stress during MSC therapy, space restraint was applied to one group of mice after GFP-MSCs injection. Stress did not affect the migration of MSCs into the injury site but the efficiency of MSCs differentiation into MFs was significantly reduced in stressed animals. The level of the stress hormone corticosterone was measured using Enzo’s Corticosterone ELISA kit and was found to be two-to-three fold higher in serum of stressed mice compared to control groups, independently on whether the mice were treated with CCl4 or not. MSCs are known to express GR and the injection of a GR antagonist, RU486, could reverse the effect of chronic stress in vivo. To investigate the role of corticosterone, MFs differentiation from cultured MSCs was assessed in vitro using medium supplemented with either serum from stressed mice, corticosterone or RU486. Serum from stressed mice and corticosterone inhibited MF differentiation, whereas RU486 could reverse the effect. Further in vivo and in vitro experiments showed that stressed-associated corticosterone attenuates MFs differentiation by reducing the expression of TGF-β1 in MSCs, which is known to be the key-inducing factor at the initial stage of MFs differentiation. All these data suggest that corticosterone triggered by chronic stress impairs liver injury repair by MSCs by down regulating TGF-β1 expression which results in reduced differentiation of MSCs into MFs. RU486 reversed the effect of corticosterone in vitro and in vivo and thus further studies should be envisaged to clarify if the use of GR antagonists may help increasing the efficiency of MSCs therapy for liver injury in stressed patients.

Enzo Life Sciences offers a comprehensive product portfolio for advancing your research in immunology, endocrinology, and stem cells including ELISA kits, live cell analysis kits, IHC kits and RT-PCR products some of which are listed below:

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References:

  1. R. Glaser and J.K. Kiecolt-Glaser. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol. (2005) 5: 243-51.
  2. X. Yang, et al. Chronic restraint stress decreases the repair potential from mesenchymal stem cells on liver injury by inhibiting TGF-β1 generation. Cell Death Dis. (2014) 5: e1308.

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