Top row: Untreated stem cells contain a protein (orange) marking its ability to mature into many different kinds of cells. Bottom row: Stem cells given a cocktail of transcription factors to coax them to become microglia-like cells express an array of proteins characteristic of human microglia. Images: Wyss Institute
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.
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 of researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard Medical School have developed 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.
Authorship, funding, disclosures
Li Li, Fan Zhang, and Mariana Garcia-Corral are co-first authors with Liu. Additional authors include Katharina Meyer, Patrick R. J. Fortuna, Björn van Sambeek, Evan Appleton, 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, and Soumya Raychaudhuri.
The study was funded by the National Human Genome Research Institute of the National Institutes of Health (grant RM1HG008525) and the Lipper Foundation.
Liu and Church are listed as inventors on a patent related to work in this article. Church, Khoshakhlagh, and Ng are cofounders/employees/advisors at, and have equity in, GC Therapeutics, Inc., and are inventors on patents filed by the President and Fellows of Harvard College. Full disclosure for Church is available at arep.med.harvard.edu/gmc/tech.html. The remaining authors declare no competing interests.
