Because oxygen is essential for life, cells have developed adaptation mechanisms for when levels become low – based on the HIF-1 protein. The attribution of the 2019 Nobel Prize in Physiology or Medicine to the three researchers responsible for its discovery is an opportunity to take a closer look at the Inserm teams that are also working in this field.
On Monday October 7, two US researchers, William Kaelin and Gregg Semenza, and the British researcher Peter Ratcliffe were awarded the Nobel Prize in Physiology or Medicine, honoring their research on the mechanisms used by cells to adapt to changes in their oxygenation. A decisive advance, given that oxygen is essential for tissues and organisms to function and survive. To compensate for when levels may become low − a phenomenon known as hypoxia −, cells develop adaptation strategies. But for a long time, little was known about their mechanisms until the discoveries made by the three Nobel Prize-winning researchers.
From the HIF-1 protein to the HIF-1 complex
Collectively, their research has identified Hypoxia Induced Factor-1 (HIF-1), as being the cornerstone of the system. When oxygen levels are normal (normoxia), the HIF-1 subunit that is sensitive to O2 is rapidly degraded, thereby preventing the factor from activating. However, in hypoxia, this subunit is protected from degradation and builds up in the cell. It promotes the activation of HIF-1 and the expression of genes involved in oxygen transport, as well as the expression of hundreds of genes involved in other processes, such as glucose metabolism and cell proliferation. Their interest in this protein therefore grew to encompass a much broader system, known as the HIF-1 complex. In addition to the original protein, this complex groups proteins likely to control its activation and those which will then be activated by this mechanism.
Many different reaction cascades are at play, some of which make it possible to adapt muscle function during physical activity, induce the formation of blood vessels to improve perfusion, or control cardiomyocyte metabolism during myocardial infarction. These are beneficial mechanisms which promote adaptation to hypoxia. Conversely, other processes triggered by hypoxia are harmful, due to their cardiovascular (hypertension, susceptibility to myocardial infarction or stroke) and metabolic (chronic obstructive respiratory diseases, etc.) consequences. These examples also show how the nature of hypoxia influences the outcome: "it is the intensity, duration and nature of the hypoxia − continuous or intermittent − in a particular context – healthy or pathological − that determine whether the impact on a given cell type or organ will be beneficial or harmful" explains Elise Belaidi, from the Hypoxia and Cardiovascular and Respiratory Physiopathology* laboratory in Grenoble. A postulate that explains the variety of research being conducted into the response to hypoxia.
High altitudes: where locals and travelers differ
Travel to higher altitudes is a good illustration of this: people accustomed to living in lower-lying regions may develop altitude sickness and other more serious consequences whenever they venture above 2,500 meters. Yet the majority of those who permanently live at high altitudes do not present such complications, which is a sign of their probable genetic or epigenetic adaptation! To find out more, Jean-Louis Pépin’s team from Grenoble made a novel scientific expedition to La Rinconada, a small Peruvian city located at 5,300 m altitude. A unique opportunity for the Expédition 5300 research team to study the characteristics of the local population as well as take measurements from its own members. The project will offer a better understanding of the local populations’ mechanisms of adaptation or maladaptation and of the mechanisms inherent to the various behaviors in response to such changes in O2 levels.
Sleep apnea: from disease to therapeutic avenues
Obstructive sleep apnea syndrome is characterized by the nocturnal onset of numerous recurring episodes of apnea or hypopnea (reduced breathing amplitude) that define chronic intermittent hypoxia. This hypoxia is now widely recognized as being a potent activator of HIF-1 and, above all, as responsible for many harmful effects. For a better understanding of the disease, the Grenoble laboratory has at its disposal a transversal technical platform, called Hype: "Our platform, unique in Europe, offers the means of testing a wide variety of exposure conditions − whether continuous or intermittent, acute or chronic − on cells, rodents or humans, in order to reproduce specific forms of hypoxia" describes Claire Arnaud. The results derived from using this platform, in addition to the clinical data collected in patient cohorts, offer a better understanding of the disease and its complications.
Hype is also used to study potential therapeutic avenues: "During muscular exertion, exposure to certain controlled conditions of hypoxia leads to the beneficial adaptation of the body, explains Pépin. We can therefore envisage the exploration of potential treatments for sleep apnea syndrome by conditioning the patients to situations of hypoxia different from those specific to them. But these exposure conditions still remain to be determined, depending on the mechanisms to be used". In accordance with this principle, the laboratory is currently conducting a clinical trial in which overweight or obese subjects are monitored as part of a specific hypoxia exposure protocol: the idea being to evaluate a suitable type of physical exercise, aiming to improve the cardiovascular and metabolic condition of these patients.
Optimize regenerative medicine
The regeneration of tissues and organs is another major cognitive and medical challenge. Very recent scientific research has shown the potential therapeutic role of hypoxia in cardiac regenerative medicine. At Stromalab**, a research laboratory in Toulouse, scientists are working to elucidate some of the underlying mechanisms that can improve or restore regeneration capacities in adult mammals. The maintenance of tissue integrity, just like its restoration following an aggression, involves mesenchymal stem/stromal cells (MSCs), an essential local component in all tissues. Studies conducted in the Toulouse laboratory notably concern understanding the diversity of these cells within tissues, as well as the effects of various components of their environment in vivo, such as the availability of oxygen. For that, Stromalab has a particularly innovative controlled-atmosphere closed cultivation system (XVivo). "This incubator mimics the physiological oxygenation conditions of the cells or tissues throughout the duration of their culture, with no fluctuations in the atmospheric environment. It makes it possible to study the various MSC populations under conditions close to those encountered in vivo, and particularly subject to low O2 tension. It enables accurate elucidation of the effectors and events controlled by the HIF factors in order to generate new therapeutic avenues", describes Isabelle Ader, one of the managers of this system.
Thanks to this equipment, it is possible to study how minuscule variations in cell oxygenation can modify cell behavior: "Clinical batches of MSC are usually produced at a concentration of 21% oxygen, whereas physiologically these cells are found in tissues that are much less oxygenated. Yet our research shows that MSCs cultivated under normal atmospheric conditions present differences with their in vivo counterparts: free radicals or DNA breaks are encountered which may be responsible for major discordance between the therapeutic effect sought and that actually obtained. It would appear essential to consider the conditions of cell oxygenation as a major determinant in cell production for therapeutic purposes".
Hypoxia: defense mechanism of tumor cells
"Our laboratory’s XVivo system is open to the entire scientific community of the Occitanie region. Several oncology research teams are using it to reproduce pathophysiological parameters in vitro. This should lead to new therapeutic avenues in the fight against cancer", continues Ader. In the majority of solid tumors, there is intratissular chronic hypoxia, which is reflected by high levels of HIF factors. These promote the resistance of the cells to immune effectors and chemotherapies. They also offer the tumor the means of developing its own blood vessel network whose abnormal functioning reinforces the intratumoral hypoxia and resistance to chemotherapy. Increasing oxygen levels within tumors could therefore improve cell sensitivity to anticancer agents, thereby constituting a therapeutic approach.
* unit 1042 Inserm/Université de Grenoble Alpes, Hypoxia and Cardiovascular and Respiratory Physiopathology Laboratory, Grenoble
** unit 1031 Inserm/CNRS/Université Toulouse Paul Sabatier/EFS/Ecole nationale vétérinaire, Stromalab, Toulouse