Abstract
Astrocyte reactivation has been discovered to be an important contributor to several neurological diseases. In vitro models involving human astrocytes have the potential to reveal disease-specific mechanisms of these cells and to advance research on neuropathological conditions. Here, we induced a reactive phenotype in human induced pluripotent stem cell (hiPSC)-derived astrocytes and studied the inflammatory natures and effects of these cells on human neurons. Astrocytes responded to interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) treatment with a typical transition to polygonal morphology and a shift to an inflammatory phenotype characterized by altered gene and protein expression profiles. Astrocyte-secreted factors did not exert neurotoxic effects, whereas they transiently promoted the functional activity of neurons. Importantly, we engineered a novel microfluidic platform designed for investigating interactions between neuronal axons and reactive astrocytes that also enables the implementation of a controlled inflammatory environment. In this platform, selective stimulation of astrocytes resulted in an inflammatory niche that sustained axonal growth, further suggesting that treatment induces a reactive astrocyte phenotype with neurosupportive characteristics. Our findings show that hiPSC-derived astrocytes are suitable for modeling astrogliosis, and the developed in vitro platform provides promising novel tools for studying neuron-astrocyte crosstalk and human brain disease in a dish.
Highlights
Astrocyte reactivation has been discovered to be an important contributor to several neurological diseases
To confirm that the astrocytes were mostly negative for neuronal markers, the cells were stained for microtubule-associated protein 2 (MAP2) (Supplementary Fig. S1)
Astrocytes were treated with a combination of the cytokines IL-1β and tumor necrosis factor-α (TNF-α), which are typically released by activated microglia during neuroinflammation and are capable of stimulating astrogliosis in vivo[5,44,45] and in vitro[18,46,47,48]
Summary
Astrocyte reactivation has been discovered to be an important contributor to several neurological diseases. We induced a reactive phenotype in human induced pluripotent stem cell (hiPSC)-derived astrocytes and studied the inflammatory natures and effects of these cells on human neurons. We engineered a novel microfluidic platform designed for investigating interactions between neuronal axons and reactive astrocytes that enables the implementation of a controlled inflammatory environment. During CNS injury and disease, astrocytes transform into a reactive phenotype with changed morphology and altered gene expression and secretion profiles[4,5] These astrocytes are regarded as immunocompetent cells that can respond to complex inflammatory events by secreting cytokines and chemokines, thereby controlling immune cell activation and migration to sites of damage[5,6]. Understanding the complex cellular interplay among several neural cell types can help to reveal underlying mechanisms in neurodegenerative diseases and create opportunities for drug discovery
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