Cancer can derail neutrophil development. Source: Daniel Araujo, La Jolla Institute for Immunology

Neutrophils are a type of immune cell that is one of the first cell types to travel to the site of an infection. Neutrophils help fight infection by ingesting microorganisms and releasing enzymes that kill the microorganisms. However, immature neutrophils can be dangerous as the accumulation of neutrophils has been linked to cancer and may even be a biomarker for COVID-19. Immature neutrophils are primarily distinguished from each other by nuclear features, such as a lack of nuclear segmentation, with decreasing indentation with more immaturity.

Neutrophils are the most abundant peripheral immune cells and are continually replenished by bone marrow-derived progenitors. Yet, it is unclear how newly identified neutrophil subsets fit into the bone marrow neutrophil lineage. Now researchers at La Jolla Institute for Immunology (LJI) report they have tracked down the rare stem cells that generate neutrophils in human bone marrow.

Their study, “Coexpression of CD71 and CD117 Identifies an Early Unipotent Neutrophil Progenitor Population in Human Bone Marrow,” is published in Immunity and provides a potential path for intervening in diseases where neutrophil development is disrupted.

“We have identified the stem cells that are the early origins of neutrophils, the most abundant blood cell type in humans,” said Huy Dinh, PhD, a former LJI postdoctoral associate who is currently at the University of Wisconsin-Madison.

“Knowing how human neutrophils develop is especially relevant today because immature neutrophils have been found to be elevated in both the blood and lungs of severe COVID-19 patients.”

In 2018, the lab of LJI professor Catherine C. Hedrick, PhD, reported the discovery of a group of “progenitor” stem cells that give rise to mature neutrophils. The researchers believed that detecting these progenitors could give doctors a better way to catch early cancer cases. The researchers decided to get a closer look at neutrophil development.

The new research revealed a progenitor cell type that exists earlier in human neutrophil development. The team used a tool called cytometry by time-of-flight (CyTOF) to distinguish these rare cells from other types of immune progenitor cells, which made it possible for the researchers to identify more specific protein markers.

“Here, we use mass cytometry to show that two recently defined human neutrophil progenitor populations contain a homogeneous progenitor subset we term ‘early neutrophil progenitors’ (eNePs; Lin CD66b +CD117 +CD71 +). Surface marker- and RNA-expression analyses, together with in vitro colony formation and in vivo adoptive humanized mouse transfers, indicate that eNePs are the earliest human neutrophil progenitors,” noted the researchers. “Furthermore, we identified CD71 as a marker associated with the earliest neutrophil developmental stages.”

The researchers have used a few markers to track neutrophils over time, but the new research provides specific markers for tracking neutrophil development from the beginning.

They also discovered that cases of skin and lung cancers are often accompanied by a flood of immature neutrophils including the early progenitor cells into the bloodstream. “Expression of CD71 marks proliferating neutrophils, which were expanded in the blood of melanoma patients and detectable in blood and tumors from lung cancer patients,” the researchers noted.

“It’s like the train is falling apart,” Dinh commented, comparing the development of neutrophils to the cars on a train.

Recent studies have shown immature neutrophils are also more abundant in some patients with COVID-19, and the researchers are determined to study if neutrophils can be tied to case prognosis or if they can be a drug target for COVID-19.

The researchers are looking forward to continuing their work to discover the exact mechanisms that stop neutrophils from reaching maturity, and stress knowing the earliest cells that give rise to neutrophils is critical for targeting the cells.

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