In a groundbreaking advancement that promises to accelerate neurological disease research and therapeutic development, scientists at Harvard University’s Wyss Institute and Harvard Medical School (HMS) have devised a rapid, efficient method to generate human microglia-like cells from induced pluripotent stem cells (iPSCs). This novel approach condenses a traditionally lengthy and costly differentiation process—once spanning over a month—into an astonishing four-day protocol. Leveraging a sophisticated transcription factor-based technology dubbed TFome™, the team achieved cellular conversion that faithfully mimics native microglia, the brain’s specialized immune cells pivotal to neural health and disease.
Microglia constitute approximately 10% of the cells within the central nervous system, where they serve multifaceted roles from clearing infectious agents and cellular debris to sculpting neural circuits during brain development. Dysregulation of microglial function is increasingly recognized as a driver of neuroinflammation, which precedes and exacerbates hallmark protein aggregation in devastating disorders such as Alzheimer’s, Parkinson’s, Huntington’s diseases, amyotrophic lateral sclerosis (ALS), and multiple sclerosis. Understanding microglial biology and manipulating their activity therapeutically has long been hampered by the scarcity of human cells and significant interspecies differences that limit rodent models’ translational reliability.
The core breakthrough rests on the use of TFome™—an innovative synthetic biology platform that systematically screens and applies combinations of human transcription factors (TFs) to steer iPSC fate decisions with remarkable precision and speed. Transcription factors are proteins that act as master regulators driving entire gene expression networks, thereby orchestrating cellular identity and function. Prior to this study, attempts to cultivate microglia-like cells from stem cells were inefficient, protracted, and often yielded immature or functionally limited cells. Employing iterative rounds of TF screening and single-cell RNA sequencing (scRNA-seq), the Wyss-HMS team distilled a potent sextet of microglia-specifying TFs that unlock rapid differentiation and maturation in only four days.
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The researchers initiated the process by curating a smartly selected panel of 40 candidate TFs, informed by developmental biology and disease-specific expression profiles characteristic of primary human microglia. By randomly expressing combinations of five to seven TFs in single iPSCs and assessing their genetic profiles through scRNA-seq, the team identified a triumvirate of TFs—SPI1, CEBPA, and FLI1—that induced partial microglial programming. Recognizing that this initial combination was insufficient for full functional maturation, the group supplemented the cocktail with three additional TFs—MEF2C, CEBPB, and IRF8—elevating the cellular phenotype to closely match native microglia both transcriptionally and morphologically.
Crucially, these engineered microglia-like cells exhibited hallmark responses to neuroinflammatory stimuli, a fundamental functional test. Exposure to interferon gamma (IFNγ), a cytokine elevated during brain infections and neurodegenerative states, provoked activation of microglia-specific gene expression programs. Remarkably, the aggregates of TDP-43 protein—a pathological feature in ALS—similarly elicited microglial gene expression changes, underscoring the physiological relevance of these stem cell-derived microglia surrogates.
The implications of this technology extend far beyond mere cell culture convenience. By expediting the derivation of highly functional human microglia, the TFome™ platform empowers researchers to faithfully model neuroinflammatory processes implicated in myriad neurological diseases. It paves the way for high-throughput drug screening, mechanistic exploration, and personalized medicine interventions with patient-specific iPSC lines. Moreover, the modularity and adaptability of TFome™ technology portend its application to other elusive cell types, potentially revolutionizing regenerative medicine and cell therapy product development.
This advance builds upon prior work in which the Wyss Institute team developed a comprehensive library of 1,732 human transcription factors and variants, laying the foundation for precision control of stem cell fates. Notably, the founders also established GC Therapeutics, a biotechnology startup aiming to translate transcription factor-based cell engineering into commercially viable cell therapies. The current study signifies a major refinement of their platform, showcasing iterative design and data-driven optimization harnessed by single-cell transcriptomics to achieve rapid and target-specific cellular identity.
Underlying this cellular engineering feat is an integrated interdisciplinary effort combining synthetic biology, computational genomics, bioinformatics, and neural cell biology. Collaborators included experts in statistics and single-cell data analysis who developed algorithms to rank TF combinations by their effectiveness in recapitulating authentic microglial gene expression signatures. Such iterative screening—cycling through design, experimental testing, and computational validation—proved essential to identifying the optimal transcriptional code for human microglia induction.
The team’s focus on microglia originated from a longstanding interest in creating complex brain organoids—three-dimensional miniaturized tissue models—which aim to recapitulate cellular diversity and functional intercellular interactions present in the human brain. While TFome™ technology had allowed generation of neuronal, oligodendrocyte, stromal, and vascular components of brain organoids, microglia presented a tougher challenge due to their unique developmental origins and transcriptional programs. Addressing this gap enhances the physiological relevance of brain organoids, expanding their utility in modeling neurodevelopment, neurodegeneration, and neuroinflammation.
Looking forward, the researchers envision fine-tuning TF expression dynamics—varying timing, dosage, and sequence—to engineer microglia subtypes with specialized activities. This precision could unravel cell-type-specific contributions to brain pathologies and enable targeted interventions that modulate particular microglial functions. Their approach exemplifies a synthetic biology paradigm in which modular genetic parts enable custom design of complex cellular phenotypes within unprecedented timeframes.
In sum, this iterative transcription factor screening method exemplifies a leap forward in stem cell biology and neuroimmunology. By successfully producing microglia-like cells that combine rapid generation with mature, functionally relevant profiles, investigators have unlocked a promising new avenue for studying brain immune cells and their roles in health and disease. As neurodegenerative disorders continue to exact a growing global toll, innovative tools such as this offer fresh hope for decoding disease mechanisms and discovering effective therapeutics.
Subject of Research: Cells
Article Title: Iterative transcription factor screening enables rapid generation of microglia-like cells from human iPSC
News Publication Date: 10-Jun-2025
Web References:
Wyss Institute at Harvard University: https://wyss.harvard.edu/
Harvard Medical School: https://hms.harvard.edu/
GC Therapeutics: https://www.gc-tx.com/
TFome™ technology Nature publication: https://www.nature.com/articles/s41587-020-0742-6
CircaVent drug discovery platform: https://wyss.harvard.edu/technology/circavent-a-drug-discovery-platform-for-mental-health-conditions/
References:
Liu, S., Zhang, F., Li, L., et al. Iterative transcription factor screening enables rapid generation of microglia-like cells from human iPSC. Nature Communications. 2025 Jun 10.
Image Credits: Wyss Institute at Harvard University
Tags: advanced cellular conversion methodsbrain immune system recreationHarvard Wyss Institute researchhuman cell scarcity in researchhuman microglia-like cellsinduced pluripotent stem cells differentiationmicroglial function in neuroinflammationneurobiology and immune responseneurological disease researchprotein aggregation in neurological disordersTFome technologytherapeutic development for neurodegenerative diseases