How gene activity influences immune cell production in mice

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A new study by researchers from the USC Stem Cell lab of Rong Lu reveals how the activity of certain genes affects the quantity and variety of immune cells produced by hematopoietic stem cells (HSCs) in mice. The findings could have implications for understanding and treating diseases that involve immune system dysfunction, such as aging, cancer, and COVID-19.

Tracking stem cells with barcodes

HSCs are the source of all blood and immune cells in the body, but not all HSCs are equally productive. Some HSCs produce more immune cells, while others produce fewer or different types of immune cells. To understand why, the researchers used a novel technique to label individual HSCs with genetic “barcodes” and track their immune cell production over time. They then correlated the barcode tracking with measurements of gene expression activity in the HSCs. They also developed innovative bioinformatics approaches to characterize the quantitative association between gene activity and immune cell production.

Identifying genes associated with immune cell production

By leveraging these technical advances, the researchers identified nearly 40 genes that are related to immune cell production in mice. Some of these genes are known to be associated with diseases such as myelodysplastic syndrome, a type of cancer caused by abnormal blood-forming cells. The researchers discovered that the activity of these genes influences both the amount and the diversity of immune cells produced by HSCs. For example, certain genes are associated with the production of lymphoid cells, which are involved in adaptive immunity, while others are associated with the production of myeloid cells, which are involved in innate immunity. Some genes are associated with a balanced production of various immune cell types, while others are associated with a skewed or biased production.

cell production

Understanding the mechanisms of immune cell production

The researchers also found that the association between gene activity and immune cell production is not constant, but depends on the level of immune cell output. In other words, some genes are only associated with immune cell production at specific levels of output, while others are associated at any level of output. This suggests that different genes may have different roles in regulating the quantity and quality of immune cell production by HSCs.

“In this study, we show that most genes associated with immune cell production are associated only at specific levels of immune cell production,” said Du Jiang, Ph.D., the first author of the study and a former graduate student in the Lu Lab. “This reveals the complexity and diversity of the mechanisms that control immune cell production by HSCs.”

Implications for human health and disease

The study, published in Science Advances, provides new insights into how gene activity modulates the production of immune cells by HSCs in mice. This could have implications for understanding and treating human diseases that involve immune system dysfunction, such as aging, cancer, and COVID-19.

“As people age or become ill, their immune systems can become exhausted and less capable of fighting off viruses such as the flu or COVID-19,” said Rong Lu, Ph.D., the corresponding author of the study and an associate professor of stem cell biology and regenerative medicine, biomedical engineering, medicine, and gerontology at USC, and a Leukemia & Lymphoma Society Scholar. “By identifying the genes that influence immune cell production, we hope to find ways to enhance the regenerative potential of HSCs and boost the immune system in these patients.”

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