Researchers from the Laboratory of Mathematical Oncology (MOLAB) at the University of Castilla-La Mancha (UCLM), on developing a mathematical model based on complex network techniques and artificial intelligence, and in collaboration with researchers from the Carlos III National Centre for Cardiovascular Research (CNIC), headed by Andrés Hidalgo, have discovered that neutrophils, a type of immune cells "behave" differently in the blood during inflamation. The study, published in the high-standing journal, Nature, was able to identify a conduct associated with cardiovascular diseases.

The work, which has combined mathematical modelling and the mass analysis of morphological and dynamic data from 4D  in vivo images of over one hundred thousand immune cells obtained by the CNIC, is of great significance in terms of therapy. This is because it enables new treatments to be designed for minimising  sequelas caused by  heart attacks, as  Gabriel Fernández Calvo, profesor at the UCLM Department of Mathematics,  MOLAB  researcher and coauthor of this study, explains.

Neutrophils are a type of immune cell which are the main line of defence for the organism, but may also damage healthy cells, especially in the cardiovascular system. Various studies have associated a high presence of neutrophils in the blood with a greater risk and severity of suffering from cardiovascular problems. However, it is not possible to remove neutrophils to protect the cardiovascular system, since this would create a a state of defencelessness against different pathogens and this would be counterproductive for the organism.

To resolve this paradox, the authors aimed to identify specific types of neutrophils responsible for   vessel damage. To do so, they analysed the behaviour of cells using high resolution intravital microscopy (a technology which enables cells to be visualised in capillaries in live animals). For this purpose, they designed a highly original computer system capable of analysing how immune cells behave in blood vessels by making simple measurements of changes in size, shape and in cell movements. They thereby discoverered that immune cells  had three patterns of behaviour during  inflammation, but just one of these, characterised by a greater size and proximity to the vessel walls, was associated with cardiovascular vessels.

By means of a  mass genetic analysis in animal models, they used this computer system to find the molecules responsible for these pathological behaviours in neutrophils which led to cardiovascular damage. One of the main findings of this study was the identification of a molecule called Fgr, which is responsible for this pathological behaviour of the neutrophils, which, in turn, were key to selecting a highly effective pharmaceutical for preventing inflamation and cell death after a heart attack. 

“One of the more original aspects of the study is that, by means of combining a technology for extracting 4D in vivo images  from thousands of cells and mathematical techniques for a mass  data analysis, this has paved the way  for using this methodological strategy in the future to identify new molecular targets. With this,  more specific treatments for patients can be designed”, just as indicated by David G. Aragonés González, doctorate student at the UCLM Department of Mathematics and researcher at MOLAB.

"The idea now is to apply it to other situations, not just infectious ones, but also to tumours. As regards the latter, there is a strong interaction between the cells in the immune system and tumour cells. Due to the vast heterogeneity shown by many cancers, it would be of great interest to   dynamically characterise the key processes in play and do so with an unprecedented space-time resolution”, states Gabriel Fernández Calvo.

In this multidisciplinary study  Behavioral immune landscapes of inflammation, the  Carlos III National Centre for Cardiovascular Research (CNIC),the Singapour Agency for Science and Technology (ASTAR), Vithas Hospitals in Madrid, and the universities of Yale, Harvard, Baylor and Carlos III collaborated. At the UCLM, the MOLAB researchers,David G. Aragonés González, doctorate student, and Gabriel Fernández Calvo, professor at the Department of mathematics were co-authors.

This research was published on 5th of January 2022 in the journal Nature, which belongs to the Multidisciplinary Sciences category with an impact rating of 49,962 and position Q1 (1/72). 

UCLM Communication Office Ciudad Real, 7th of January 2022