Oxidative Stress Caused by Immune Cells Contributes to the Age-Related Decline in Liver Regenerative Capacity

Researchers here provide evidence for the age-related decline in regenerative capacity of the liver to be caused in part by oxidative stress produced by innate immune cells. This makes the adult stem cells responsible for tissue maintenance less likely to activate, but when removed from the tissue environment the cells appear more or less as capable as those of younger individuals. In some other tissues, such as muscle, where stem cell biology is better studied, it is also thought that changes in the surrounding environment rather than internal damage drives the majority of the decline in stem cell activity with aging. This means that therapies capable of activating stem cells in older individuals may prove to be less risky and more useful than would otherwise be the case.

Like all the other organs, there are structural and functional changes in the liver during aging, including diminished functions. Notably, a decrease in regenerative capacity in aging liver has been observed in old patients who had severe viral and toxic injury. In addition, studies on liver transplantation in human patients showed lower graft and recipient survival if the donor was in advanced age. Similar results were also observed after liver transplantation in rats. Therefore, investigating the mechanisms of declined regeneration in liver is critical to understand age-associated hepatic pathologies and diseases.
Decreased tissue regeneration and homeostasis are frequently associated with impaired stem cell function, implicating alterations of stem cells within tissues and organs during aging. As recently reported, aging-associated phenotypical and functional variations have been observed for adult stem cells or progenitor cells in various tissues, including epidermis, muscle, blood and brain. Age-related decrements in stem-cell functionality may occur at different levels, including cell-autonomous dysfunction, altered niche where stem cells reside, systemic milieu and the external environment. Liver is an organ with low turnover in homeostasis, but high regenerative capacity under acute injury. However, little is known about the changes of stem cells within liver responsible for liver regeneration upon liver injury during aging.
Liver progenitor cells (LPCs), also known as ‘oval cells’, are a stem cell population within the liver. Upon massive liver injury, LPCs may be activated. LPC expansion occurs in many human liver diseases and experimental animal models, and treatment with LPCs could prevent liver injury in rodents. Therefore, LPCs play an important role in maintaining the homeostasis and regeneration of the liver. Characterizing biological properties LPCs during aging will be important to gain insight into age-associated liver pathologies and disease.
According to the ‘free-radical theory’ of aging, endogenous oxidants could be generated in cells and resulted in cumulative damage. Those oxidants, free reactive oxygen species (ROS), are specific signaling molecules regulating biological processes under both physiological and pathophysiological conditions. Within a certain extent, the generation of ROS is essential to the maintenance of cellular homeostasis. However, excessive generation of ROS might lead to the damage of various cell components and the activation of specific signaling pathways, which will influence aging and the development of age-related diseases. Neutrophils can be recruited by a variety of cytokines or signals. Neutrophil-derived ROS are generated during the process of respiratory burst and are important for neutrophil bactericidal activity. Previous studies have found that spontaneous ROS production from neutrophils may increase with age and represent the different aspect of age-associated immune dysregulation.
Our findings demonstrate that liver regeneration and LPC activation are negatively regulated during aging. Impairment of liver regeneration in old mice might not be resulted from intrinsic changes of LPCs, but from changes of the stem cell niche including neutrophils and hepatic stellate cells. Based on our findings, we propose the following model. In old mice, upon induced liver injury, hepatic stellate cells produce CXCL7 to recruit neutrophils into liver. After neutrophils infiltrate into liver, they are activated and a neutrophil oxidative burst is induced. Then, neutrophil-derived excessive oxidative stress induces DNA double strand damage in LPCs and restricts LPC proliferation, leading to the impairment of liver regeneration. Our findings establish a mechanistic link between LPCs and the stem cell niche including neutrophils and hepatic stellate cells, during liver regeneration in old mice.

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