Human Astrocytes Exhibit Tumor Microenvironment-, Age-, and Sex-Related Transcriptomic Signatures.

Autor:	Krawczyk MC; Department of Psychiatry and Biobehavioral Sciences, Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, 90024., Haney JR; Department of Psychiatry and Biobehavioral Sciences, Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, 90024., Pan L; Department of Psychiatry and Biobehavioral Sciences, Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, 90024., Caneda C; Department of Psychiatry and Biobehavioral Sciences, Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, 90024., Khankan RR; Department of Psychiatry and Biobehavioral Sciences, Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, 90024., Reyes SD; Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California, 90024., Chang JW; Department of Psychiatry and Biobehavioral Sciences, Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, 90024.; Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California, 90024., Morselli M; Department of Molecular, Cell and Developmental Biology, UCLA-DOE Institute for Genomics and Proteomics, Institute for Quantitative and Computational Biosciences - The Collaboratory at University of California, Los Angeles, California, 90024., Vinters HV; Department of Pathology and Lab Medicine (Neuropathology) and Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, 90024.; Ronald Reagan UCLA Medical Center, Los Angeles, California, 90024., Wang AC; Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California, 90024., Cobos I; Department of Pathology, Stanford University, Stanford, California, 94305., Gandal MJ; Department of Psychiatry and Biobehavioral Sciences, Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, 90024.; Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine; Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, 90024., Bergsneider M; Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California, 90024., Kim W; Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California, 90024., Liau LM; Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California, 90024.; Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California, 90024., Yong W; Department of Pathology, University of California, Irvine, California, 90095., Jalali A; Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, 77030., Deneen B; Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, 77030.; Center for Cell and Gene Therapy, Department of Neuroscience, Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, 77030., Grant GA; Department of Neurosurgery, Stanford University, Stanford, California, 94305., Mathern GW; Department of Psychiatry and Biobehavioral Sciences, Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, 90024.; Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California, 90024., Fallah A; Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California, 90024., Zhang Y; Department of Psychiatry and Biobehavioral Sciences, Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, 90024 yezhang@ucla.edu.; Brain Research Institute at UCLA, Los Angeles, California, 90095.; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, Los Angeles, California, 90095.; Molecular Biology Institute at UCLA, Los Angeles, California, 90095.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2022 Feb 23; Vol. 42 (8), pp. 1587-1603. Date of Electronic Publication: 2022 Jan 05.
DOI:	10.1523/JNEUROSCI.0407-21.2021
Abstrakt:	Astrocytes are critical for the development and function of synapses. There are notable species differences between human astrocytes and commonly used animal models. Yet, it is unclear whether astrocytic genes involved in synaptic function are stable or exhibit dynamic changes associated with disease states and age in humans, which is a barrier in understanding human astrocyte biology and its potential involvement in neurologic diseases. To better understand the properties of human astrocytes, we acutely purified astrocytes from the cerebral cortices of over 40 humans across various ages, sexes, and disease states. We performed RNA sequencing to generate transcriptomic profiles of these astrocytes and identified genes associated with these biological variables. We found that human astrocytes in tumor-surrounding regions downregulate genes involved in synaptic function and sensing of signals in the microenvironment, suggesting involvement of peritumor astrocytes in tumor-associated neural circuit dysfunction. In aging, we also found downregulation of synaptic regulators and upregulation of markers of cytokine signaling, while in maturation we identified changes in ionic transport with implications for calcium signaling. In addition, we identified subtle sexual dimorphism in human cortical astrocytes, which has implications for observed sex differences across many neurologic disorders. Overall, genes involved in synaptic function exhibit dynamic changes in the peritumor microenvironment and aging. These data provide powerful new insights into human astrocyte biology in several biologically relevant states that will aid in generating novel testable hypotheses about homeostatic and reactive astrocytes in humans. SIGNIFICANCE STATEMENT Astrocytes are an abundant class of cells playing integral roles at synapses. Astrocyte dysfunction is implicated in a variety of human neurologic diseases. Yet our knowledge of astrocytes is largely based on mouse studies. Direct knowledge of human astrocyte biology remains limited. Here, we present transcriptomic profiles of human cortical astrocytes, and we identified molecular differences associated with age, sex, and disease state. We found that peritumor and aging astrocytes downregulate genes involved in astrocyte-synapse interactions. These data provide necessary insight into human astrocyte biology that will improve our understanding of human disease. (Copyright © 2022 the authors.)
Databáze:	MEDLINE
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