Gene activity plays key role in immune cell production, study shows

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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. A new mouse study funded in part by the National Institutes of Health and published Science advancesResearchers in Rong Lu’s USC Stem Cell Lab describe how specific gene activity can potentially increase immune cell production.

Hematopoietic stem cells, or HSCs, produce blood and immune cells, but not all HSCs are equally productive. “We wanted to understand the mechanism why some stem cells produce more immune cells, while other stem cells produce less.”


Rong Lu, PhD, corresponding author of the study, is an associate professor of stem cell biology and regenerative medicine, biomedical engineering, medicine and gerontology at USC and a Leukemia and Lymphoma Society Scholar.

With this goal in mind, first author Du Jiang, PhD, and his colleagues in the Lu lab at USC’s Keck School of Medicine pioneered new techniques to understand the quantitative relationship between immune cell production and gene expression in lab mice. Scientists labeled individual stem cells with genetic “barcodes” to track their immune cell production. They then correlate barcode tracking with measurements of gene expression activity. They developed innovative bioinformatics methods to characterize their quantitative relationships.

Using these technological advances, scientists have identified about 40 genes — including genes associated with myelodysplastic syndrome, a type of cancer caused by abnormal blood-forming cells — that are related to immune cell production. They discovered a link between the activity of these genes and both the quantity and variety of immune cells produced. For example, certain genes are associated with the production of lymphoid cells, others with myeloid cells, and others with a healthy balance of different immune cells.

Some genes have shown what scientists only describe as a “constant relationship” with the production of lymphocytes. In other words, at any level of lymphocyte output, gene expression was always associated with lymphocyte production.

A few other genes had a “discrete association” only with the production of lymphocytes. This means that gene activity was associated with lymphocyte production within a certain range of lymphocyte output levels.

Generally, genes have a “unimodal or multimodal” relationship with immune cell production. In these instances, which involved both lymphoid and myeloid cells, gene activity was only associated with immune cell production at one or more specific levels of immune cell production.

“In this study, we show that most of the genes associated with immune cell production are only associated with certain levels of immune cell production,” said Jiang, who earned his PhD in Lu’s lab. “Our findings may 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, Yechan Lee, Mary Vergel-Rodriguez, and Melissa Valenzuela from the Lou lab.

The project was supported by federal funding from the National Institutes of Health (grants R00HL113104, R01HL138225, R01HL135292, R01HL135292-S1, R35HL150826, and R01AG0809826 and R01AG080982 from the National Cancer Institute). Additional support came from the Leukemia and Lymphoma Society (grant LLS-1370-20), the California Institute for Regenerative Medicine, and the Hearst Foundation.

Source:

Journal Reference:

Jiang, D., etc. (2024). Quantitative correlation between gene expression and hematopoietic production of differentiated hematopoietic stem cells in mice. Science advances. doi.org/10.1126/sciadv.adk2132.



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