Transmission electron micrograph (TEM) of neutrophils, magnified 10,000 times. Credit: Segalen/Phanie/Alamy Stock Photo.
The researchers at IRCCS Ospedale San Raffaele characterized1 around 20 different gene activation states, analysing at the single-cell level more than 100,000 neutrophils from healthy donors, patients with viral infections, those with pancreatic cancer, and recipients of hematopoietic stem cell transplantation. Their findings pave the way for the use of neutrophils as biomarkers, or as tools for cell therapy.
Neutrophils are generated in the bone marrow and originate from hematopoietic stem cells. They circulate in blood stream, pass through endothelia and enter tissues. When a tissue is under stress because of damage or a pathogen attack, it produces chemical inflammatory signals that trigger the bone marrow to release more neutrophils and guide mature ones from the blood stream to the damaged site.
Neutrophils live between 7 and 10 hours in blood circulation, and a few days in tissues. “Because of their short lifespan, they were traditionally viewed as crude and scarcely plastic”, says Renato Ostuni, group leader of the Genomics of the Innate Immune System Unit at San Raffaele and senior author of the study. “It now appears that functional diversity is their strong suit.” They have a round shape while moving in blood stream, but migrating in tissues they change to resemble amoebas, equipped with sorts of pseudopodia. They have a specialized arsenal to attack pathogens: they can eat up small ones, release toxic chemicals or engulf larger ones in a net of fibres.
The cells’ shapeshifting ability comes from RNA transcription of selected genes on environmental cue. The researchers found that neutrophils from patients receiving hematopoietic stem cell transplantation display an interferon-response signature, those from COVID-19 patients up-regulate antiviral genes, while neutrophils from cancer patients activate an inflammatory signature. “It suggests that these cells promote tumour formation in pancreatic cancer,” Ostuni says. Previous research2 co-authored by Ostuni and colleagues, found that neutrophils in healthy lung tissue express genes promoting angiogenesis and they probably have a role in healthy liver metabolism too.
“So far, we have analysed neutrophils in blood, but we need to do it in different human tissues, including tumours”, says Ostuni. “Then we’ll have enough information to use these cells as a biomarker for early cancer diagnosis, for instance, or for prognosis after stem cell transplantation”.
The ultimate goal is to use neutrophils for cell therapy. Scientists plan to collect hematopoietic stem cells from patient’s bone marrow, differentiate them into neutrophils and induce tailored gene expression to make them reach a specific tissue and perform a specific task. “They could be great smart bullets,” Ostuni says.
