As people age or get sick, their immune systems can become depleted and less able to fight off viruses like the flu or COVID-19. In a new mouse study funded in part by the National Institutes of Health and published in Advances in Scienceresearchers from Rong Lu’s USC stem cell lab describe how specific gene activity could potentially boost immune cell production.
“Hematopoietic stem cells, or HSCs, produce blood and immune cells, but not all HSCs are equally productive,” said study corresponding author Rong Lu, PhD, who is an associate professor of stem cell biology and regenerative medicine, biomedical engineering, medicine. and gerontology at USC, and a fellow of the Leukemia & Lymphoma Society. “We wanted to understand the mechanism of why some stem cells produce more immune cells, while other stem cells produce less.”
With this goal in mind, first author Du Jiang, PhD, and colleagues in the Lu lab at USC’s Keck School of Medicine pioneered new techniques to understand the quantitative correlation between immune cell production and gene expression in mice laboratory. The scientists tagged individual stem cells with genetic “barcodes” to monitor their immune cell production. They then correlated barcode tracking with measurements of gene expression activity. They also developed innovative bioinformatics approaches to characterize their quantitative relationship.
By leveraging these technical advances, scientists have identified nearly 40 genes — including genes associated with diseases such as myelodysplastic syndrome, a type of cancer caused by abnormal blood-forming cells — related to the production of immune cells. They discovered correlations between the activity of these genes and both the amount and variety of immune cells produced. For example, some genes are associated with the production of lymph cells, others with myeloid cells, and others with a healthy balance of different types of immune cells.
Some of the genes showed what the scientists described as a “consistent association” with the production of only lymphocytes. In other words, at any level of lymphocyte production, gene expression always correlated with lymphocyte production.
A few other genes were “significantly associated” only with lymphocyte production. This means that gene activity was associated with lymphocyte production within a certain range of lymphocyte production levels.
More commonly, the genes would have either a “unimodal or multimodal” relationship with immune cell production. In these cases, involving both lymphoid and myeloid cells, gene activity was only associated with immune cell production at either one or multiple specific levels of immune cell production.
“In this study, we show that most genes associated with immune cell production are only associated at specific levels of immune cell production,” said Jiang, who earned his Ph.D. in the Lu lab. Our findings can inform strategies to optimize bone marrow transplantation — for example, by selecting donor bone marrow cells with gene activity associated with high and balanced levels of immune cell production.”
Additional authors include Adnan Y. Chowdhury, Anna Nogalska, Jorge Contreras, Yeachan Lee, Mary Vergel-Rodriguez, and Melissa Valenzuela from the Lu Lab.
The project was supported by federal funding from the National Institutes of Health (grants R00HL113104, R01HL138225, R01HL135292, R01HL135292-S1, R35HL150826, and R01AG080982 National Institute of Cancer (04). Additional support came from the Leukemia & Lymphoma Society (grant LLS-1370-20 ), the California Institute for Regenerative Medicine, and the Hearst Foundations.