Researchers have discovered crucial physiological differences between human and mouse astrocytes, with implications for studies on neurological disorders.
Mice are the most used mammalian model for disease research. This is due to their easily manipulated genome and shared common genetic features with humans. Also, a high-quality draft of the mouse genome was published in 2002, meaning that a cohort of data from previous trials is accessible. However, humans and mice differ greatly in terms of body size, life span, ecological niche, behaviour and pathogenic challenges.
Astrocytes are specialised types of glial cells in the central nervous system that are crucial for the development and function of the brain. Damaged astrocytes play many roles in neurological disorders, such as strokes and neurodegeneration.
Despite human astrocytes being larger and more morphologically complex, most knowledge about astrocyte biology is based on studies of mouse models. However, little is known about the species-dependent differences of astrocytes and the impact that they have on response to diseases. Unfortunately, over 90% of promising neurological drug candidates in mice fail when tested on humans. This demonstrates the urgent need for a thorough understanding of the cellular and molecular differences between the human and mouse brain.
Studying the differences between human and mouse astrocytes
Recently, scientists at the University of California (UCLA) systematically examined human and mouse astrocytes under several conditions. Extensive conservation in gene expression levels between astrocytes from both species were found in some cellular processes, whereas divergence was discovered in others.
The two most significant species-specific differences between human and mouse astrocytes were:
- Mitochondrial resting state respiration differed between mouse and human astrocytes. Mitochondrial and energy metabolism changes are important in the pathogenesis of many neurological disorders. For example, many genes linked to Parkinson’s disease are involved in mitochondrial function.
- Human astrocytes were more susceptible to oxidative stress than mouse astrocytes. Oxidative stress is caused by an imbalance of oxygen reactive species in cells or tissues and is a critical pathological process in neurodegeneration.
Some research using mouse models may be readily translatable to humans due to similar gene expression levels in astrocytes. This includes studies of mRNA metabolic processes, intracellular transport and glial cell differentiation. However, more caution should be taken before extrapolating mitochondrial and cytokine findings from mouse models to humans because gene expression levels in those astrocytes were found to be species-specific.
Furthermore, the greater resilience of mouse astrocytes to oxidative stress suggests that reducing detoxification activities in mouse models may improve their resemblance to human models in neurodegeneration studies. The discovery of mitochondrial and energy metabolism differences between human and mouse cells should also be considered in translational research.
Should we genomically ‘humanise’ mouse models to study neurodegenerative disease?
These findings have revealed important information about the mechanistic differences between human and mouse astrocytes, which have large implications for improving translational research into human neurological disorders, such as Alzheimer’s and Parkinson’s disease. Revealing species-specific properties of astrocytes will enable neuroscientists to account for these differences and take a more informed approach to preclinical studies.
Notably, recent advances in genome engineering are enabling researchers to create a variety of mouse models that carry human DNA. These technical innovations allow the study of diseases by the targeted replacement of mouse genomic regions with orthologous human sequences. The result is the creation of refined genomically humanised mice, which could increasingly offer opportunities to test drugs and gene therapies for the treatment of neurodegenerative diseases.
Image credit: FreePik olga_kuzmina
