Directly converted astrocytes retain the ageing features of the donor fibroblasts and elucidate the astrocytic contribution to human CNS health and disease. Issue 1 (13th December 2020)

• Record Type: Journal Article
• Authors: Gatto, Noemi; Dos Santos Souza, Cleide; Shaw, Allan C.; Bell, Simon M.; Myszczynska, Monika A.; Powers, Samantha; Meyer, Kathrin; Castelli, Lydia M.; Karyka, Evangelia; Mortiboys, Heather; Azzouz, Mimoun; Hautbergue, Guillaume M.; Márkus, Nóra M.; Shaw, Pamela J.; Ferraiuolo, Laura
• Is Part Of: Aging cell. Volume 20:Issue 1(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-13
• Subjects: ageing -- astrocytes -- direct reprogramming -- in vitro model -- neurodegeneration -- neuroinflammation -- neuron‐astrocyte crosstalk -- nuclear abnormalities -- nucleocytoplasmic transport -- oxidative stress; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.13281
• Languages: English
• ISSNs: 1474-9718

Abstract

Abstract: Astrocytes are highly specialised cells, responsible for CNS homeostasis and neuronal activity. Lack of human in vitro systems able to recapitulate the functional changes affecting astrocytes during ageing represents a major limitation to studying mechanisms and potential therapies aiming to preserve neuronal health. Here, we show that induced astrocytes from fibroblasts donors in their childhood or adulthood display age‐related transcriptional differences and functionally diverge in a spectrum of age‐associated features, such as altered nuclear compartmentalisation, nucleocytoplasmic shuttling properties, oxidative stress response and DNA damage response. Remarkably, we also show an age‐related differential response of induced neural progenitor cells derived astrocytes (iNPC‐As) in their ability to support neurons in co‐culture upon pro‐inflammatory stimuli. These results show that iNPC‐As are a renewable, readily available resource of human glia that retain the age‐related features of the donor fibroblasts, making them a unique and valuable model to interrogate human astrocyte function over time in human CNS health and disease. Abstract : iNPC‐As from fibroblasts isolated from donors of different ages retain a spectrum of age‐associated features, such as nuclear morphology and organization, as well as specific nucleo‐cytoplasm shuttling characteristics and oxidative stress response. Moreover, old donor‐derived iNPCs‐As are less supportive to neurons after pro‐inflammatory insult in human co‐culture.