. Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse. Neuron. 2016 Jan 6;89(1):37-53. Epub 2015 Dec 10 PubMed.


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  1. This study by Zhang et al. developed a novel technique to isolate and culture human astrocytes in serum-free conditions, thus recapitulating the resting, non-reactive state normally observed in healthy astrocytes in vivo. The study then went on to show how the technique can be applied to model and study fetal and mature astrocytes in health and disease.

    Fortunately for mouse users everywhere, the findings in this study demonstrate that human astrocytes are effectively very similar in their functional capacity when compared to mouse astrocytes. However, the authors also illustrated that human astrocytes still possess unique qualities at the genomic and functional levels. Exploring the differences between rodent and human astrocytes can yield interesting insights into the differences between our species such as in cognitive function, aging, and disease.

    Another important application of this model is that it can be a useful way to shed light on the fundamental processes behind astrocyte maturation in humans. The initial excitement of using induced pluripotent stem cells (iPSCs) to model diseases has since been quelled by the fact that we still lack the ability to drive cells to a mature and/or aged state in vitro. A better understanding of human astrocyte development is crucial to be able to eventually mature and age iPSC-derived astrocytes.

    While the widespread usage of this in vitro model of primary human astrocytes may be hindered due to the limited availability of fresh human tissue, the methodologies and data presented in this study will be useful in validating findings from mouse models and creating better models of mature human astrocytes. With so many therapeutics failing in clinical trial after performing brilliantly in mouse models, this study makes a strong case for understanding the complexities and intricacies of human astrocytes. 

    View all comments by Melanie Das
  2. Glial cells constitute more than 50 percent of the cells in the human brain. Astrocytes, which make up the largest glial population, are crucial to the regulation of synaptic connectivity and plasticity, brain tissue repair, formation of the blood-brain barrier (BBB), and regulation of cerebral blood flow (CBF). Although transcriptional profiling to detect astrocyte functions has been done on numerous occasions in multiple animal models, how relevant these data are to human astrocytes remains largely unknown.

    Zhang and colleagues developed a new immunopanning and culture approach to generate populations of fetal and adult human astrocytes that contain faithful characteristics of astrocytes in vivo. They provided a functional and molecular comparison of human and murine astrocytes in vitro using standard assays in order to detect potential differences and/or similarities between species. They first reported that primary human astrocytes are larger and contain more processes than primary rat astrocytes, and also implied different signaling mechanisms. Interestingly, human astrocytes respond differently to neurotransmitters such as glutamate, suggesting that calcium responses might be fundamentally different in human than in rodent astrocytes. That should also differentially affect brain functions including modification of cerebral blood flow (CBF) and blood-brain barrier (BBB) permeability modification.

    Even though about 90 percent of the genes are similar between species, human astrocytes have hundreds of unique genes when compared to mice. Here, the authors used an RNA-seq protocol to understand the genes expressed uniquely in human astrocytes, and in other brain cell types as well, e.g., neurons, endothelial cells, oligodendrocytres, and microglia. They applied this method in a variety of conditions including development (i.e., fetal brains) and diseases (i.e., brain cancer or epilepsy surgeries). Zhang and coworkers showed that astrocytes derived from the tumor core were more transcriptionally similar to fetal immature astrocytes, whereas astrocytes obtained from the tumor periphery were more similar to adult mature astrocytes. It is known from animal studies that astrocytes become highly reactive in neurodegenerative diseases and change their morphology and phenotype accordingly. Further studies screening drugs that can promote or knock down the expression of specific genes are needed to increase knowledge about astrocyte functions. Thus, Zhang et al. concluded their thought-provoking study saying that the observed functional and morphological differences between human and murine astrocytes might be explained by differences in gene expression.

    Finally, another interesting discovery is that astrocytes exist in at least two distinct developmental stages, i.e., progenitor and mature cells. These results enable new perspectives and future directions to better understand astrocyte developmental origins, genetic regulation, and terminal differentiation. These recent findings will be useful to continue seeking new treatment approaches, especially in neurodevelopmental disorders, as well as autoimmune and neurodegenerative diseases.

    The identification of novel astrocyte-encoded genes will certainly allow for discovering new roles for astrocytes during brain development, normal brain aging, and under pathological conditions. These new insights herald the concept that astrocytes represent a diverse population of genetically tractable cells that mediate various roles in health and disease, and that might provide new opportunities to treat central nervous system disorders.

    View all comments by Axel Montagne

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