When it comes to defending the body against invading pathogens, there is strength in diversity. Different types of immune cells specialize in different functions, playing complementary—and occasionally contrasting—roles. For example, granulocytes are usually the ‘first responders” at a site of infection while monocytes are important for activating a secondary immune response. Despite their diverging functions, both types of cells were believed to originate from the same ‘parent’ cells: granulocyte-monocyte progenitors (GMPs).
In recent years, new techniques have cast doubt on this classical understanding of how granulocytes and monocytes differentiate. “It is becoming increasingly clear that GMPs might be a heterogeneous group with specific programming cues that dictate their differentiation fate,” said Lai Guan Ng, a Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN).
To tease out the differences between granulocyte and monocyte progenitors, Ng and his team first used single-cell transcriptomics to identify distinctive mRNA signatures for each type of cell. They then validated their data at the protein level, screening the levels of over 260 proteins found on the surface of mouse bone marrow cells. “To understand and analyze the enormous amount of single-cell protein data generated, we used a supervised machine learning approach that allowed us to profile the proteomic signature of each cell type,” Ng said.
The result of this combined approach was the identification of proNeu1, the earliest progenitor of a subset of granulocytes known as neutrophils. When the researchers experimentally caused sepsis in mice, they saw the number of proNeu1 cells rapidly expand, skewing towards neutrophils at the expense of monocytes.
“Septic mice whose GMPs were unable to switch towards monocyte differentiation had a high inflammatory cytokine profile and died shortly after. Finding a way to modulate how GMPs differentiate may thus lead to better treatments for septic patients,” Ng said. “This understanding of how the balance between neutrophil and monocyte commitment may impact the outcome of sepsis was only possible after identifying proNeu1 cells so that they could be isolated and studied further.”
The identification of proNeu1 could also lead to treatments for patients with low neutrophil counts such as those undergoing chemotherapy. Ng and his team are currently looking into how proNeu1 cells localize in the bone marrow and what signals are required for the production of the large numbers of neutrophils required each day. “These findings will allow us to expand neutrophil production in vitro for therapeutic purposes,” he said.
The A*STAR researchers contributing to this study are from Singapore Immunology Network (SIgN).
