Human microglia states are conserved across experimental models and regulate neural stem cell responses in chimeric organoids

Galina Popova; Sarah S Soliman; Chang N Kim; Matthew G Keefe; Kelsey M Hennick; Samhita Jain; Tao Li; Dario Tejera; David Shin; Bryant B Chhun; Christopher S McGinnis; Matthew Speir; Zev J Gartner; Shalin B Mehta; Maximilian Haeussler; Keith B Hengen; Richard R Ransohoff; Xianhua Piao; Tomasz J Nowakowski

doi:10.1016/j.stem.2021.08.015

Human microglia states are conserved across experimental models and regulate neural stem cell responses in chimeric organoids

Cell Stem Cell. 2021 Dec 2;28(12):2153-2166.e6. doi: 10.1016/j.stem.2021.08.015. Epub 2021 Sep 17.

Authors

Galina Popova¹, Sarah S Soliman¹, Chang N Kim¹, Matthew G Keefe¹, Kelsey M Hennick¹, Samhita Jain², Tao Li³, Dario Tejera³, David Shin¹, Bryant B Chhun⁴, Christopher S McGinnis⁵, Matthew Speir⁶, Zev J Gartner⁷, Shalin B Mehta⁴, Maximilian Haeussler⁶, Keith B Hengen⁸, Richard R Ransohoff⁹, Xianhua Piao¹⁰, Tomasz J Nowakowski¹¹

Affiliations

¹ Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
² Division of Neonatology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
³ Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
⁴ Chan Zuckerberg Biohub, San Francisco, CA, USA.
⁵ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA USA.
⁶ Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA.
⁷ Chan Zuckerberg Biohub, San Francisco, CA, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA USA; Center for Cellular Construction, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
⁸ Department of Biology, Washington University in St. Louis, St. Louis, MO, USA.
⁹ Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
¹⁰ Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Division of Neonatology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Newborn Brain Research Institute, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA. Electronic address: tomasz.nowakowski@ucsf.edu.

Abstract

Microglia are resident macrophages in the brain that emerge in early development and respond to the local environment by altering their molecular and phenotypic states. Fundamental questions about microglia diversity and function during development remain unanswered because we lack experimental strategies to interrogate their interactions with other cell types and responses to perturbations ex vivo. We compared human microglia states across culture models, including cultured primary and pluripotent stem cell-derived microglia. We developed a "report card" of gene expression signatures across these distinct models to facilitate characterization of their responses across experimental models, perturbations, and disease conditions. Xenotransplantation of human microglia into cerebral organoids allowed us to characterize key transcriptional programs of developing microglia in vitro and reveal that microglia induce transcriptional changes in neural stem cells and decrease interferon signaling response genes. Microglia additionally accelerate the emergence of synchronized oscillatory network activity in brain organoids by modulating synaptic density.

Keywords: double-stranded DNA breaks; human microglia; iPSC; induced microglia; interferon response; microglia; microglia culture; neuro-immune; organoid activity; organoids.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Brain
Cell Differentiation
Humans
Induced Pluripotent Stem Cells*
Microglia
Models, Theoretical
Neural Stem Cells*
Organoids

Abstract

Publication types

MeSH terms

Grants and funding