Conservation and divergence of vulnerability and responses to stressors between human and mouse astrocytes

Introduction: 

Progress in biological research has advanced rapidly over the preceding decades, largely thanks to the use of model organisms to understand basic biological principals. Of these model organisms, rodents are the most widely used¹, though it should be noted that all model organisms carry scientific value. Mouse models have gained ground largely due to the availability of genetic manipulation techniques. Despite a variety of conserved mechanisms in development², differences between mouse and human brains must be addressed. Astrocytes are the most abundant glial cell type in the human brain³ and carry out many vital functions which include providing a constant energy supply⁴, forming and maintaining the blood-brain barrier⁵, and synapse formation and pruning⁶ to name a few. Li and colleagues take on the task of parsing out key differences in mouse and human astrocytes, with a clear focus on addressing disparities in disease progression between mouse models and human patients.

Summary of results:

Purification and maintenance of human adult astrocytes is notoriously tricky. Astrocyte cultures are generally maintained in serum-containing media, which inadvertently induces a reactive-like state. Li et al. used a recently developed technique⁷ to provide serum-free conditions to yield cultured astrocytes which more closely resemble those in a resting-state. Transcriptomic analysis revealed an overall downregulation of reactive astrocyte associated genes in serum-free cultures when compared to serum-selected counterparts. Additionally, the authors preserved in-vivo gene expression profiles of acutely purified (AP) human astrocytes immediately following purification and after a few days of serum-free culture. They found a vast majority of genes are similarly expressed in serum-free cultured and AP human astrocytes.

Mouse and human appear to be quite different organisms on the outside, but how do our astrocytes compare? The authors describe a rather conserved transcriptome, with over half of observed genes sharing expression profiles in both species. That being said, thousands of genes were differentially expressed and GO term analysis revealed certain genes with higher expression in mouse were related to metabolism, while differentially expressed genes in human astrocytes were associated with the extracellular space and secreted cytokines.

Mouse and human astrocytes are clearly different, but is this due to cell-autonomous genetic programs or are differentially expressed genes influenced by community effects? The authors addressed this question by transplanting human fetal astrocytes into immunocompromised mice. After about 8 months, they sequenced the transplanted human and mouse astrocytes and compared these to the transcriptome of serum-free cultured and AP human astrocytes. Surprisingly, the transcriptomic signature of transplanted human astrocytes resembled that of acutely purified human astrocytes, more so even than astrocytes maintained in serum-free culture. These data suggest the differentially expressed genes are largely intrinsically programmed and not significantly influenced by community effects.

How do transcriptomic differences affect overall function of these cells in their respective species? The authors tested these questions by running disease-relevant stress tests on mouse and human astrocytes. Astrocytes were subjected to reactive oxygen species (ROS), ROS have been increasingly associated with a variety of neurological and neuropsychiatric conditions. Interestingly, nearly twice as many mouse astrocytes survived H₂O₂ exposure compared to their human counterparts. Why this disparity in survival following exposure to ROS? In short, mouse astrocytes ramp up ATP production and make that extra energy source available to protective pathways, while human mitochondria are damaged quickly and simply don’t respond in time. They show mouse astrocyte resilience was, at least in part, due to upregulation of a few genes within detoxification pathways.

Mouse models aren’t only resilient to oxidative stress, but also recover rather well after ischemic strokes. Following hypoxic conditions, mouse astrocytes upregulated a network of genes associated with neurogenesis and neural repair. Transcriptomic changes in human astrocytes were comparatively minute and lacked neural repair-associated genes. The intrinsic repair program coupled with the upregulation of detoxification pathway genes may explain the overall resilience of mouse models, whereas human patients often experience irreparable damage.

The authors exposed human and mouse astrocytes to a variety of pro-inflammatory agents, such as TNFα and Poly I:C to perform a comparative study of their responses. In contrast to their distinct responses to hypoxia and ROS, a variety of cytokine-response associated genes were similarly upregulated in both mouse and human astrocytes. Despite the shared subset of differentially expressed genes, pro-inflammatory agents induced a significant increase in 3 MHC Class I genes in human, not mouse, astrocytes. Similarly, TNFα and Poly I:C induced significant upregulation in pathways responsible for activating interferon signalling in human astrocytes. Although pro-inflammatory agents elicited some shared responses, astrocytes upregulated distinct genetic programs following exposure to either compound.

 

Why I liked this preprint:

Model organisms are one of our most powerful allies in the life sciences. Mouse models have aided us in gaining a deeper understanding of the mechanisms which underlie neurological and neuropsychiatric disorders. This deeper understanding has resulted in technological and pharmacological advances to help treat such disorders. However, millions of years of evolution have resulted in humans and mice adapting to best respond to their unique environmental challenges. This study helps explain the incongruence in resilience to certain neurological insults and disorders between mouse models and human patients. Mouse models are not perfect, and no model system will be, but by understanding our differences we can use such models to their full potential and interpret results in a more accurate manner.

Questions for the authors:

1. Some of the data shown here points to a possible solution for the scarcity of mature human tissue. Would you consider it feasible to scale up the process of “incubating” fetal human astrocytes in mice? Is it preferable to waiting for fresh adult human samples?
2. The transcriptomic signatures of transplanted human fetal astrocytes were remarkably similar to acutely purified samples. Would this hold true in the case of more mature cells? When transplanting immature human astrocytes into mouse, do you expect these to mature in a cell-autonomous fashion? Or will the mouse environment influence their developmental clock?
3. Were higher TNFα and Poly I:C concentrations ever tested on mouse astrocytes? Could they have an attenuated response at the concentration in which human astrocytes were highly responsive?

Referenced works:

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3. Colombo E, Farina C. Astrocytes: Key Regulators of Neuroinflammation. Trends Immunol. 2016;37(9):608–620. doi:10.1016/j.it.2016.06.006
4. Magistretti PJ, Pellerin L. Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Philos Trans R Soc Lond B Biol Sci. 1999;354(1387):1155–1163. doi:10.1098/rstb.1999.0471
5. Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7(1):41–53. doi:10.1038/nrn1824
6. Ullian EM, Sapperstein SK, Christopherson KS, Barres BA. Control of synapse number by glia. Science. 2001;291(5504):657–661. doi:10.1126/science.291.5504.657
7. Zhang Y, Sloan SA, Clarke LE, et al. Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse. Neuron. 2016;89(1):37–53. doi:10.1016/j.neuron.2015.11.013

Tags: chimera mice, cns, comparative biology, cortex, disease models, human biology, neuroscience

doi: https://doi.org/10.1242/prelights.19369

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