Human microglia maturation is underpinned by specific gene regulatory networks

Claudia Z Han; Rick Z Li; Emily Hansen; Samantha Trescott; Bethany R Fixsen; Celina T Nguyen; Cristina M Mora; Nathanael J Spann; Hunter R Bennett; Olivier Poirion; Justin Buchanan; Anna S Warden; Bing Xia; Johannes C M Schlachetzki; Martina P Pasillas; Sebastian Preissl; Allen Wang; Carolyn O'Connor; Shreya Shriram; Roy Kim; Danielle Schafer; Gabriela Ramirez; Jean Challacombe; Samuel A Anavim; Avalon Johnson; Mihir Gupta; Ian A Glass; Birth Defects Research Laboratory; Michael L Levy; Sharona Ben Haim; David D Gonda; Louise Laurent; Jennifer F Hughes; David C Page; Mathew Blurton-Jones; Christopher K Glass; Nicole G Coufal

doi:10.1016/j.immuni.2023.07.016

Human microglia maturation is underpinned by specific gene regulatory networks

Immunity. 2023 Sep 12;56(9):2152-2171.e13. doi: 10.1016/j.immuni.2023.07.016. Epub 2023 Aug 14.

Authors

Claudia Z Han¹, Rick Z Li¹, Emily Hansen², Samantha Trescott², Bethany R Fixsen¹, Celina T Nguyen³, Cristina M Mora², Nathanael J Spann¹, Hunter R Bennett¹, Olivier Poirion⁴, Justin Buchanan⁴, Anna S Warden³, Bing Xia², Johannes C M Schlachetzki¹, Martina P Pasillas¹, Sebastian Preissl⁴, Allen Wang⁴, Carolyn O'Connor⁵, Shreya Shriram², Roy Kim², Danielle Schafer², Gabriela Ramirez², Jean Challacombe¹, Samuel A Anavim², Avalon Johnson², Mihir Gupta⁶, Ian A Glass⁷; Birth Defects Research Laboratory⁷; Michael L Levy⁸, Sharona Ben Haim⁶, David D Gonda⁸, Louise Laurent⁹, Jennifer F Hughes¹⁰, David C Page¹¹, Mathew Blurton-Jones¹², Christopher K Glass¹³, Nicole G Coufal¹⁴

Affiliations

¹ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
² Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
³ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
⁴ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Center for Epigenomics, University of California, San Diego, La Jolla, CA 92093, USA.
⁵ Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁶ Department of Neurosurgery, University of California, San Diego, La Jolla, CA 92037, USA.
⁷ Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, WA, USA.
⁸ Department of Neurosurgery, University of California, San Diego-Rady Children's Hospital, San Diego, CA 92123, USA.
⁹ Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁰ Whitehead Institute, Cambridge, MA 02142, USA.
¹¹ Whitehead Institute, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142, USA.
¹² Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92696, USA.
¹³ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: ckg@ucsd.edu.
¹⁴ Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: ncoufal@health.ucsd.edu.

PMID: 37582369
PMCID: PMC10529991 (available on 2024-09-12)
DOI: 10.1016/j.immuni.2023.07.016

Abstract

Microglia phenotypes are highly regulated by the brain environment, but the transcriptional networks that specify the maturation of human microglia are poorly understood. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia and acquired corresponding data in induced pluripotent stem cell (iPSC)-derived microglia, in cerebral organoids, and following engraftment into humanized mice. Parallel development of computational approaches that considered transcription factor (TF) co-occurrence and enhancer activity allowed prediction of shared and state-specific gene regulatory networks associated with fetal and postnatal microglia. Additionally, many features of the human fetal-to-postnatal transition were recapitulated in a time-dependent manner following the engraftment of iPSC cells into humanized mice. These data and accompanying computational approaches will facilitate further efforts to elucidate mechanisms by which human microglia acquire stage- and disease-specific phenotypes.

Keywords: epigenomics; humanized; microglia; neurodevelopment; neurological disorders; stem cells; transcription factors; transcriptomics.

Publication types

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

MeSH terms

Animals
Brain
Gene Expression Regulation
Gene Regulatory Networks
Humans
Induced Pluripotent Stem Cells*
Mice
Microglia*

Abstract

Publication types

MeSH terms

Grants and funding