Iterative transcription factor screening enables rapid generation of microglia-like cells from human iPSC

Songlei Liu, Li Li, Fan Zhang, Mariana Garcia-Corral, Katharina Meyer, Patrick R. J. Fortuna, Björn Sambeek, Evan Appleton, Alex H. M. Ng, Parastoo Khoshakhlagh, Yuancheng Ryan Lu, James Cameron, Ricardo N. Ramirez, Yuting Chen, Chun-Ting Wu, Jeremy Y. Huang, Yuqi Tan, George Chao, John Aach, Elaine T. Lim, Jenny M. Tam (), Soumya Raychaudhuri () and George M. Church ()
Additional contact information
Songlei Liu: Harvard Medical School
Li Li: Harvard Medical School
Fan Zhang: Brigham and Women’s Hospital
Mariana Garcia-Corral: Harvard Medical School
Katharina Meyer: Harvard Medical School
Patrick R. J. Fortuna: Harvard Medical School
Björn Sambeek: Harvard Medical School
Evan Appleton: Harvard Medical School
Alex H. M. Ng: Harvard Medical School
Parastoo Khoshakhlagh: Harvard Medical School
Yuancheng Ryan Lu: Whitehead Institute for Biomedical Research
James Cameron: Whitehead Institute for Biomedical Research
Ricardo N. Ramirez: Harvard Medical School
Yuting Chen: Harvard Medical School
Chun-Ting Wu: Harvard Medical School
Jeremy Y. Huang: Harvard Medical School
Yuqi Tan: Johns Hopkins University School of Medicine
George Chao: Harvard Medical School
John Aach: Harvard Medical School
Elaine T. Lim: Division of Innate Immunity University of Massachusetts Chan Medical School
Jenny M. Tam: Harvard Medical School
Soumya Raychaudhuri: Brigham and Women’s Hospital
George M. Church: Harvard Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Differentiation of induced pluripotent stem cells (iPSCs) into specialized cell types is essential for uncovering cell-type specific molecular mechanisms and interrogating cellular function. Transcription factor screens have enabled efficient production of a few cell types; however, engineering cell types that require complex transcription factor combinations remains challenging. Here, we report an iterative, high-throughput single-cell transcription factor screening method that enables the identification of transcription factor combinations for specialized cell differentiation, which we validated by differentiating human microglia-like cells. We found that the expression of six transcription factors, SPI1, CEBPA, FLI1, MEF2C, CEBPB, and IRF8, is sufficient to differentiate human iPSC into cells with transcriptional and functional similarity to primary human microglia within 4 days. Through this screening method, we also describe a novel computational method allowing the exploration of single-cell RNA sequencing data derived from transcription factor perturbation assays to construct causal gene regulatory networks for future cell fate engineering.

Date: 2025
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DOI: 10.1038/s41467-025-59596-3

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