Innovative Stem Cell Platform Rapidly Cultures Human Microglia Cells

In a groundbreaking study published on June 11, 2025, researchers at the Wyss Institute at Harvard University and Harvard Medical School have developed an innovative stem cell-based platform capable of generating human microglia cells, significantly enhancing disease modeling and therapeutic research. Microglia, which comprise approximately 10% of the cells in the brain and spinal cord, play a critical role in the central nervous system's immune response—eliminating dead cells, infectious microbes, and aggregated proteins that could jeopardize brain health. Dysfunctional microglia are implicated in various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis (ALS).

The conventional method of obtaining human microglia relies on biopsies, which are not only invasive but also yield limited quantities and may not accurately represent the behavior of microglia in vivo. Rodent microglia, often used as substitutes, differ significantly from their human counterparts, posing challenges for researchers in understanding human-specific neuroinflammatory processes. This situation necessitated the development of alternative approaches for microglia generation, leading to the creation of the new stem cell platform.

The research team, led by Dr. George Church, a prominent figure in genetics at Harvard, has successfully demonstrated that induced pluripotent stem cells (iPSCs) can be transformed into microglia-like cells in just four days, a significant reduction from the previous standard of 35 days. This efficiency is achieved through a novel technology known as TFome™, which utilizes transcription factors (TFs) to drive cell differentiation processes more effectively than traditional methods.

In their study, the team created specialized libraries of microglia-specific transcription factors and employed iterative screening to determine the optimal combinations for inducing iPSC differentiation into microglia. The results revealed a potent cocktail of six transcription factors that not only accelerated the production of microglia-like cells but also ensured they closely resembled authentic human microglia in gene expression profiles.

Dr. Church emphasized the implications of this breakthrough, stating, "This cell differentiation approach can open many avenues for brain disease-focused research and new therapeutic perspectives. Equally relevant, it can be applied to the generation of other hard-to-get and therapeutically relevant cell types that require complex transcriptional scenarios."

The study's co-authors, Dr. Alex Ng and Dr. Parastoo Khoshakhlagh, previously established a comprehensive library of 1,732 human transcription factors, which laid the groundwork for the TFome™ platform. They, alongside Dr. Church, co-founded the startup GC Therapeutics to commercialize this advanced cell engineering technology.

The research also highlights the potential for creating brain organoids—miniature, simplified versions of the brain—using iPSC-derived cells, which could incorporate microglia to study neuroinflammatory responses in various brain disorders. Dr. Jenny Tam, Director of the Synthetic Biology platform at the Wyss Institute, noted that the incorporation of microglia is crucial for capturing aspects of neuroinflammation in organoid studies.

In subsequent rounds of experimentation, the researchers identified additional transcription factors that further enhanced the functionality and maturity of the microglia-like cells. They demonstrated that these cells could react to stimuli typically associated with brain infections, affirming their utility in studying neurodegenerative diseases.

As the research progresses, the team aims to refine their methods further, potentially leading to the creation of diverse microglia subtypes with specific roles in brain health and disease. This advancement not only holds promise for understanding the underlying mechanisms of neuroinflammatory diseases but also paves the way for developing targeted therapies that could mitigate their effects on patients.

The findings of this research are published in *Nature Communications*, and the study signifies a major step forward in the fields of neuroscience and regenerative medicine. With continued refinement and application of the TFome™ technology, researchers expect to revolutionize the approach to studying microglia and their role in brain diseases, ultimately contributing to improved therapeutic strategies for neurodegenerative conditions.

Reference: Liu, S., Li, L., Zhang, F., et al. (2025). Iterative transcription factor screening enables rapid generation of microglia-like cells from human iPSC. *Nature Communications*, 16(1), 5136. doi: 10.1038/s41467-025-59596-3