Mice models play a crucial role in enabling human research. Right from testing the efficacy of drugs to understanding mechanisms associated with diseases (including COVID-19), these rodent models have helped further medical research whose goal is to benefit mankind. However, a new study has found that the human and mouse brain cells possess crucial differences that have important implications in the use of the mice models to study human neurological diseases.
According to a new study led by scientists from UCLA (University of California-Los Angeles), the comparison of brain cells known as astrocytes in mice and humans revealed that the response of the cells in the two species to a damaging mechanism called oxidative stress is very different from each other. Mice astrocytes were found to be more resilient to the effect than human ones. The research draws attention to the need of reassessing the use of mice for studying neurological disorders such as Alzheimer's disease that are driven by oxidative stress.
"We show species-dependent properties of astrocytes, which can be informative for improving translation from mouse models to humans," wrote the authors. The study was published in the journal Nature Communications.
A Star-Shaped Repairman
Modern medical research to find answers to human diseases and disorders is incomplete with the use of animal models. Mice models, in particular, are a mainstay in such experiments. However, findings from these studies may not always translate to complete human application. This holds true especially for research involving neurological diseases. For example, over 90 percent of potential drug candidates that exhibit promising results in preclinical studies eventually fail to replicate the same efficiency in human trials. This is largely driven by the lack of knowledge about the variations in neural cells of the two species.
One such cell is the astrocyte. These star-shaped cells play a vital role in the development and the functioning of the brain. Astrocytes are a subtype of glial cells—non-nerve cells that protect and support the function of neurons. They enable the supply of oxygen and nutrients to neurons in their vicinity; and also to microglia that serve as the immune defense of the central nervous system (CNS). In the event of an infection or an injury, astrocytes—that are in a resting state—enter a reactive state where they assist in the brain's repair. However, they can also give rise to harmful inflammation. Their role in the neurological disorders is considered to be a significant one. Although, it is poorly understood.
Oxidative stress is the imbalance between the production of reactive oxygen species (also known as free radicals) and the ability of the body to counter or detoxify their damaging effects using antioxidants. A full antioxidant response of astrocytes initiates the decomposition and clearance of free radicals produced by nerve cells (or neurons). Several neurodegenerative diseases such as Alzheimer's and Parkinson's disease are greatly affected by oxidative stress. Therefore, the response of astrocytes to oxidative stress is a crucial area of study.
Closer Look At Astrocytes
For the study, the authors examined developing cells purified from human and mouse brain tissues. They also investigated cells that were grown in serum-free cultures from astrocytes. An antibody-based method that was designed by Dr. Ye Zhang (corresponding author of the study) was employed to select the star-shaped cells.
The standard method of selecting astrocytes through their growth in a serum—a mixture fats, hormones, minerals and proteins—mobilizes them into a reactive state akin to the ones triggered by an injury or infection. Therefore, the need for the novel technique developed by Dr. Zhang arose. Utilizing the new method, the team was able to observe astrocytes in a healthy state under controlled conditions such as lack of oxygen, oxidative stress, and excessive inflammation.
Differences Between Mice and Human Astrocytes
The researchers learnt that, unlike human astrocytes, mouse astrocytes were more irrepressible or resilient to oxidative stress. They also found that while inflammation triggers immune-response genes in human astrocytes, they did not do so in mice astrocytes. Also, while the lack of oxygen leads to the triggering of molecular repair in mice astrocytes, it was not the same in their human counterparts.
According to the authors, as mouse astrocytes fair better against oxidative stress, laboratory models for the study of neurodegenerative diseases could be engineered to reduce resistance, which can help emulate human astrocytes. Additionally, the capacity of mouse astrocytes for repair in response to depravation of oxygen may open new doors for research on stroke.
The findings of the study also call for an informed approach towards preclinical studies where the variations in response to inflammation between the astrocytes in the two species can be accounted for, along with the metabolic differences recognized in the study. Most importantly, the learnings open new avenues for basic and translational research associated with neurological disorders whose primary mechanisms involve excessive inflammation, lack of oxygen and oxidative stress.
