Work described in this story was made possible in part by federal funding supported by taxpayers. At Harvard Medical School, the future of efforts like this - done in service to humanity - now hangs in the balance due to the government's decision to terminate large numbers of federally funded grants and contracts across Harvard University.
- By WYSS INSTITUTE COMMUNICATIONS
Microglia - immune cells in the brain and spinal cord - play crucial roles in keeping the brain healthy, including helping shape neural circuits as well as getting rid of infectious bacteria and viruses, dead cells, and abnormal protein clumps.
Accordingly, when microglia malfunction, they can contribute to inflammation in the nervous system; neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's disease; and amyotrophic lateral sclerosis (ALS) and multiple sclerosis.
Researchers have been striving to better understand microglia and develop drugs that target them to safeguard brain health and combat these diseases. But conducting such research is difficult. Human microglia can only be obtained through biopsies, and rodents' microglia differ from their human counterparts in many critical features. Reprogramming human stem cells to become microglia in a lab dish offers another strategy, but to date the process has required weeks to complete, entails significant costs, and results in cells that only partially behave like true human microglia.
A team at the Wyss Institute for Biologically Inspired Engineering at Harvard University now reports a faster and cheaper way to turn stem cells into more authentic microglia-like cells.
The researchers report June 10 in Nature Communications that they have devised a way to create microglia with "strong functional similarities" to human microglia in four days, compared to the 35 days it takes to obtain less fine-tuned cells in a conventional stem-cell differentiation process.
Their approach builds on a previously developed technology known as TFome, which draws from a comprehensive library of proteins called transcription factors to "instruct" induced pluripotent stem cells (iPSCs) to mature into specific cells of the human body. Transcription factors change cell identity and function by altering patterns of gene activity.
Senior author George Church, the Robert Winthrop Professor of Genetics in the Blavatnik Institute at Harvard Medical School and Wyss Institute founding core faculty member, and colleagues used TFome to design microglia-specific libraries of transcription factors and performed iterative rounds of screening to identify the ones that worked best. They used single-cell RNA sequencing (scRNA-seq) technology to determine how similar the resulting cells' gene expression was to that of actual microglia.
They identified a potent cocktail of six transcription factors, enabling the ultrafast production of microglia-like cells. The cells showed expected responses to molecular stimuli typical of pathogens that infect the brain or of ALS.
The new method allows researchers to better incorporate microglia-like cells into sophisticated models of human brain diseases, such as brain organoids at the Wyss Institute being used to study mental health conditions like bipolar disorder.
"This cell differentiation approach can open many avenues of brain disease-focused research and new therapeutic perspectives," said Church. "Equally relevant, it can be applied to the generation of other hard-to-get and therapeutically relevant cell types that require complex transcriptional scenarios."
Church, co-authors Alex Ng and Parastoo Khoshakhlagh, and former HMS researcher Cory Smith previously founded the startup GC Therapeutics to commercialize TFome to create next-generation cell therapy products.
The new findings advance transcription factor libraries as a platform technology, Church said.
The study also provides proof of concept that identifying additional transcription factors and developing ways to further fine-tune their expression can continue to advance microglia production, allowing researchers to "hone specific microglia identities and even create microglia subtypes with dedicated functions in the brain," said study co-first author Songlei Liu, former graduate student in the Church Lab.
