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

Author

Listed:
  • Songlei Liu

    (Harvard Medical School
    Harvard University)

  • Li Li

    (Harvard Medical School
    Harvard University)

  • Fan Zhang

    (Brigham and Women’s Hospital
    Brigham and Women’s Hospital
    University of Colorado Anschutz Medical Campus)

  • Mariana Garcia-Corral

    (Harvard Medical School
    Harvard University)

  • Katharina Meyer

    (Harvard Medical School
    Harvard University)

  • Patrick R. J. Fortuna

    (Harvard Medical School
    Harvard University)

  • Björn Sambeek

    (Harvard Medical School
    Radboud University)

  • Evan Appleton

    (Harvard Medical School
    Harvard University)

  • Alex H. M. Ng

    (Harvard Medical School
    Harvard University
    Inc)

  • Parastoo Khoshakhlagh

    (Harvard Medical School
    Harvard University
    Inc)

  • 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
    Harvard University)

  • Jeremy Y. Huang

    (Harvard Medical School
    Harvard University)

  • Yuqi Tan

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • George Chao

    (Harvard Medical School
    Harvard University)

  • John Aach

    (Harvard Medical School)

  • Elaine T. Lim

    (Division of Innate Immunity University of Massachusetts Chan Medical School
    University of Massachusetts Chan Medical School)

  • Jenny M. Tam

    (Harvard Medical School
    Harvard University)

  • Soumya Raychaudhuri

    (Brigham and Women’s Hospital
    Brigham and Women’s Hospital
    Harvard Medical School
    Broad Institute of MIT and Harvard)

  • George M. Church

    (Harvard Medical School
    Harvard University)

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.

Suggested Citation

  • 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 Ca, 2025. "Iterative transcription factor screening enables rapid generation of microglia-like cells from human iPSC," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59596-3
    DOI: 10.1038/s41467-025-59596-3
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