Drug Discovery 2022: driving the next life science revolution
Poster
154

Fast, reproducible and scalable generation of functional microglia from hiPSCs for neuroinflammation and neurodegenerative disease research & drug development

Authors

C Fairbairn1; E Yates1; P Barton1; R Hickman1; P Parac1; B Klapholz1; S Milde1; R O’Reilly1; H Garnett1; M Raman1; F Patell-Socha1; T Moreau1; W Bernard1; M Kotter1
1 bit.bio, UK

Abstract

Microglia are the tissue-resident macrophages of the brain, accounting for 10-15% of total cells within the central nervous system (CNS). These cells survey neuronal function, play roles in neurogenesis & synaptic remodelling, are the first responders to infection, and are thereby implicated in various CNS diseases. The life sciences sector relies predominantly on animal models to mimic disease states for drug discovery although they do not always recapitulate human cell and disease phenotypes. To bridge this translational gap, several in vitro human models have been developed for the study of microglia, most typically primary microglia extracted directly from either embryonic, neonatal or adult tissue. However, primary cells are limited in supply, difficult to source, and often show donor-to-donor and user variability.

 

There is a need for functional, consistent, & scalable disease-relevant human cells for both neuroimmune research and the development of therapeutics against neurodegenerative diseases. bit.bio’s opti-ox™ (optimised inducible overexpression) technology enables the highly controlled expression of transcription factors to rapidly reprogram human iPSCs (hiPSCs) into somatic cell types, in a scalable manner. Using opti-ox precision reprogramming we have generated hiPSC-derived microglia, termed ioMicroglia, that within days are converted from hiPSCs to functional microglia. ioMicroglia, 10 days post-revival, display typical morphology and express key phenotypic markers (TMEM119, P2RY12, IBA1, CD11b, CD45, and CD14). RNA sequencing demonstrates that ioMicroglia have a transcriptomic signature similar to primary adult and foetal microglia. Functionally, ioMicroglia can perform phagocytosis, secrete proinflammatory cytokines upon stimulation, and can be co-cultured with glutamatergic neurons. Therefore, ioMicroglia provide a rapidly maturing, functional, consistent, and scalable hiPSC-based model system for neurodegenera

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