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

Abstract

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.

Astrocyte heterogeneity and interactions with local neural circuits

“…The underlying message appears to be that astrocytes are plastic and respond to their local environment. Such changes can even be deleterious, as in human astrocytes associated with tumor margins, which downregulate genes involved in synaptic function, suggesting the involvement of peritumor astrocytes in tumor-associated neural circuit dysfunction [69]. At the extreme, it appears that striatal astrocytes may be so plastic that they are able to engage a latent neurogenic program following injury [70].…”

How expensive is the astrocyte?

“…31 For example, astrocytes located near human tumors showed a 60-70% reduction in the mRNA expression of the three transport proteins that link the buffering of K þ to energy metabolism (a2b2 NKA, Kir4.1 and NBCe1). 76 Glial K þ buffering is also downregulated in a Drosophila seizure model, 77 whereas its reactivation by genetic means suppressed neuronal hyperactivity and seizures, and increased the life span of the fly. 77 The role of K þ buffering and associated energy demand in neuroprotection is complex.…”

HepaCAM Suppresses Glioblastoma Stem Cell Invasion in the Brain

“…GBM cells expressing low levels of hepaCAM may have defective contact communication with astrocytes. The roles for astrocytes in the GBM microenvironment remain uncertain, with some publications supporting tumor promoting functions whereas other studies show tumor suppressive roles (43). It will be important to determine if levels of hepaCAM in GBM cells control interactions with different sub-populations of astrocytes or other glial cell types such as microglia that impact tumor malignancy.…”

“…The roles for astrocytes in the GBM microenvironment remain uncertain, with some publications supporting tumor promoting functions whereas other studies show tumor suppressive roles (43).…”