The scientists of the Weizmann Institute of Science and their research partners identified for the first time the cells that are responsible for one of the most basic actions of life - the production of a hormone that gives an order to produce red blood cells; The findings are expected to break new ground for innovative medical treatments in various anemia conditions
Our cells need oxygen like air to breathe. To provide them with this essential need, our body produces about 3-2 million red blood cells every second, about a quarter of all the new cells that are created in the body at any given moment. This process is dictated by a hormone called erythropoietin (or EPO for short) whose role is to bind to the parent cells of the blood cells found in the bone marrow and cause them to divide and reproduce.
Although this important hormone was identified already decades ago, until today it was not known in which cells in the body it is produced. In a new study published today in the scientific journal Nature Medicine Scientists from the research group of Prof. Ido colleague At the Weizmann Institute of Science and their research colleagues in Israel, Europe and the USA, a rare subset of kidney cells, and revealed that these cells are the main producers of the hormone in the human body. The scientists named the new cells Norn cells after the Norns - the figures in Norse mythology who weave the threads of fate in the fabric of life. Their findings are going to pave the way for innovative medical treatments for various anemia conditions.
Unfavorably, EPO became publicized mainly due to its abuse by athletes. The best known example of this is the cyclist Lance Armstrong, who used a synthetic version of the hormone to improve his endurance on the way to seven consecutive victories in the "Tour de France". However, the enormous therapeutic potential inherent in this hormone is much greater and broader than its use as a performance-enhancing drug.
As of today, more than 10% of the population in the Western world suffer from chronic kidney diseases, which in many cases lead to impairment of EPO production and potentially life-threatening anemia. Until recently, the only way to treat this type of anemia was to use EPO engineered in a lab to compensate for the lack of the natural hormone. In recent years, following new findings on the response of the body's cells to situations of lack of oxygen (hypoxia) - findings that even earned the scientists who discovered them the Nobel Prize for Medicine for 2019 - several drugs have been developed to increase the production of EPO; One of them was recently approved by the US Food and Drug Administration (FDA). However, even though this drug has been proven to be effective and safe, its development - and that of the other drugs - was done without knowing the identity of the EPO-producing cells on which they are supposed to affect.
""For decades, the identity of the producers of EPO has been controversial. It can be said that almost every cell in the kidneys is suspected at one point or another as a producer of the hormone"
"The discovery of the light cells will now make it possible to understand how these drugs work and more importantly - will make it possible to develop new drugs and treatments", says Prof. Amit and mentions how the discovery of beta cells - the producers of insulin in the pancreas - in the 50s paved the way for new treatments for diabetes. "In the longer term, new therapeutic approaches may be developed that will allow the Noren cells to be reactivated or their population replenished, similar to the groundbreaking treatments that were recently developed for diabetes and include the restoration of normal beta cells to the pancreas of patients," he says.
A brief history ofEPO
The first to document the relationship between the availability of oxygen in the environment and the production of red blood cells was the French physician and researcher François Viol, who noticed during his travels in Peru at the end of the 19th century that his and his colleagues' blood became thicker after they migrated from the capital city of Lima, which is at sea level, to a mountainous and oxygen-poor region. which is at an altitude of 4,200 meters.
About two decades later, at the beginning of the 20th century, two other French researchers, Paul Carnot and Clotilde-Cami de Flanders, first proposed the hypothesis that the production of red blood cells is regulated by factors in body fluids, which would later be called the hormonal system, but only in the years In the 70s of the same century - and after 15 years of attempts - the American biochemist Eugene Goldwasser succeeded in isolating the human EPO molecule. In doing so, Goldwasser paved the way for the synthetic production of EPO and its use as a life-saving drug for anemia patients (and an illegal way for athletes to improve their performance). Later, the gene coding for EPO was also identified and the foundations were laid for the discoveries of the 2019 Nobel laureates, William Kaelin, Peter Ratcliffe and Greg Semenza, who revealed how cells adapt to changes in oxygen levels.
The elusive hormone
Unlike insulin or other essential hormones, EPO is not stored in cells, but is produced and released rapidly in response to a lack of oxygen. "The extent of its cellular production jumps or drops sharply and quickly - which is why identifying the cells that produce it is so challenging," explains Prof. Roland Wenger from the University of Zurich, who has been researching the production process of EPO for the past 30 years and was a key partner in the current study. "For decades, the identity of the producers of EPO has been controversial. It can be said that almost every cell in the kidneys is suspected at one point or another as a producer of this hormone", he adds.
Prof. Wenger's research group has come a long way in identifying the cells. In previous studies, they genetically engineered mice in which the cells that produce EPO glow with red fluorescent light. This study was able to focus the researchers on the specific area in the kidneys where the EPO producers reside and reveal that it is a subtype of fibroblasts - cells responsible for the production of the body's connective tissue. However, the exact identity of the cells remains a mystery.
""The next challenge was to locate these cells in humans. The key to the discovery was obtaining kidney samples from people who died in fires as a result of smoke inhalation"
Now, with the help of advanced analysis technologies at the single cell level that were developed in Prof. Amit's laboratory and allow tens of thousands of individual cells to be studied at the same time and to identify rare cell types in tissues, the new study succeeded in revealing the identity of the elusive cells for the first time.
However, even with Prof. Amit's advanced methods and Prof. Wenger's engineered mice, identifying the cells was not an easy challenge. "These cells have no known markers, under normal oxygen conditions they produce a minimal amount of EPO - and under oxygen-deficient conditions, the production of the hormone is irregular," explains the difficulties Dr. Biort Kragstein, who led the research in Prof. Amit's laboratory together with Dr. Amir Giladi, Dr. Eyal David and Prof. Hamotal Gur from Hadassah Ein Kerem Hospital. Only after repeated attempts and under conditions of lack of oxygen, the researchers were finally able to identify among about 3,000 kidney cells that glowed red in the transgenic mice less than 40 cells that actively produce EPO. The researchers even deciphered the molecular pattern of these cells and showed that even under normal oxygen conditions these are the same cells that produce the EPO.
"Our next challenge was to locate these cells in humans. The key to this discovery was obtaining kidney samples taken from people who died as a result of a lack of oxygen," says Dr. Kragstein. With the help of Prof. Wenger, the researchers made contact with a German forensic scientist who has a database of kidney donations from fire victims who died from carbon monoxide poisoning. These samples allowed the researchers to identify the Noren cells in humans as well and to show that these are the same cells identified in mice.
Dr. Barak Rosenzweig, a senior urological oncologist at the Sheba Medical Center (Tel Hashomer) who participated in the study, is excited by the clinical potential of the discovery of the Noren cells, and not only in the context of patients with chronic kidney diseases. "Many cancer patients now receive blood transfusions before surgery to improve their red blood cell count. These infusions may have a negative effect on their immune system and damage their ability to fight cancer in the long term," he explains. "The new findings may allow the development of methods to stimulate the EPO-producing cells into action and improve the patients' blood count without harming their immune system."
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