Efficient and scalable generation of human midbrain astrocytes from hiPSCs

Lucy A Crompton, Sarah F. McComish, Petros Stathakos, Oscar Cordero Llana, Jon D Lane, Maeve A Caldwell

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

In Parkinson’s, progressive dysfunction and degeneration of dopamine neurons in the ventral midbrain causes life-changing symptoms. Neuronal degeneration has diverse causes in Parkinson’s, including non-cell autonomous mechanisms mediated by astrocytes. Throughout the CNS, astrocytes are essential for neuronal survival and function, as they maintain metabolic homeostasis in the neural environment. They also modulate neuroinflammation, which is present from the very earliest stages of Parkinson’s, and indeed, progression of pathology is influenced by astrocytic immunomodulation. In diseases with a chronic neuroinflammatory element, including Parkinson’s, astrocytes acquire a neurotoxic phenotype, and thus enhance neurodegeneration. Consequently, astrocytes are a potential therapeutic target to slow or halt disease, but this will require a deeper understanding of their properties and roles in Parkinson’s. Accurate models of human ventral midbrain astrocytes for in vitro study are therefore urgently required.
We have developed a protocol to generate high purity cultures of ventral midbrain-specific astrocytes (vmAstros) from hiPSCs that can be used for Parkinson’s research. vmAstros can be routinely produced from multiple hiPSC lines, and express specific astrocytic and ventral midbrain markers. Our protocol is scalable, and thus suitable for high-throughput applications including for drug screening. Crucially, the hiPSC derived-vmAstros demonstrate immunomodulatory characteristics typical of their in vivo counterparts, enabling mechanistic studies of neuroinflammatory signalling in Parkinson’s.
Original languageEnglish
JournalJournal of visualized experiments : JoVE
Publication statusSubmitted - 24 Sep 2020

Keywords

  • Astrocyte Parkinson’s disease Ventral Midbrain Neuroinflammation Reactive Human induced pluripotent stem cell Differentiation

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