CD49f Is a Novel Marker of Functional and Reactive Human iPSC-Derived Astrocytes.

New methods for investigating human astrocytes are urgently needed, given their critical role in the central nervous system. Here we show that CD49f is a novel marker for human astrocytes, expressed in fetal and adult brains from healthy and diseased individuals. CD49f can be used to purify fetal astrocytes and human induced pluripotent stem cell (hiPSC)-derived astrocytes. We provide single-cell and bulk transcriptome analyses of CD49f+ hiPSC-astrocytes and demonstrate that they perform key astrocytic functions in vitro , including trophic support of neurons, glutamate uptake, and phagocytosis. Notably, CD49f+ hiPSC-astrocytes respond to inflammatory stimuli, acquiring an A1-like reactive state, in which they display impaired phagocytosis and glutamate uptake and fail to support neuronal maturation. Most importantly, we show that conditioned medium from human reactive A1-like astrocytes is toxic to human and rodent neurons. CD49f+ hiPSC-astrocytes are thus a valuable resource for investigating human astrocyte function and dysfunction in health and disease. • CD49f is a novel, reactivity-independent marker for human astrocytes • CD49f can be used to purify human fetal astrocytes and iPSC-derived astrocytes • CD49f+ hiPSC-astrocytes acquire an A1-like reactive state upon cytokine stimulation • CD49f+ A1-like reactive astrocytes are dysfunctional and toxic to neurons in vitro Barbar et al. identify CD49f as a novel surface marker expressed by human astrocytes that can purify hiPSC-astrocytes and primary fetal astrocytes. CD49f+ hiPSC-astrocytes respond to pro-inflammatory stimuli and become A1 reactive astrocytes, which are dysfunctional and secrete neurotoxic factors that induce apoptosis in human and rodent neurons. [ABSTRACT FROM AUTHOR]