Scientists at the Weizmann Institute of Science, in collaboration with doctors at Hadassah and Rambam, present a new roadmap for the study of diseases in which the hidden is still much more visible.
Supporting actors sometimes steal the show. Fibroblasts or “fiber cells” are sub-players almost by definition – they create the “scaffolding” that keeps the body cells in place. There is no denying that they play an important role in the body’s growth process and wound healing, but the rest of the time they are considered to be particularly inactive. A new study published today in the scientific journal Cell, Challenges the heavenly image that has come out of them and reveals their involvement in a variety of vital functions – from communication with the immune system, through the effect on blood clotting and blood vessel formation to the metabolism in the body. In the study, scientists at the Weizmann Institute of Science identified no less than 10 types and 200 subtypes of fibroblasts and showed that one of the types plays a key role in the development of a rare autoimmune disease called scleroderma (connective tissue sclerosis). These findings open up a new possibility for the development of treatments for this incurable disease and outline a roadmap for the study of many other diseases.
The name of scleroderma disease (Greek: sclerosis – stiff; and drama – skin) was given to it due to its hallmark: its patients develop a stiff layer of skin, mainly on the limbs and face. However, apart from the stiffness of the skin, the disease manifests itself very differently among its patients – most of them women in their 30s to 50s. In about a third of cases, the disease will spread quickly and affect vital organs such as the lungs, heart, digestive system and kidneys. This injury can lead to significant medical complications, and mortality rates from the disease are high compared to other rheumatic diseases.
“As a physician, scleroderma is one of the most frustrating diseases,” says Prof. Hamutal Gur of the Rheumatology Unit of Hadassah University Medical Center in Jerusalem, who led the study. “We currently have a variety of very effective biological drugs for the treatment of autoimmune rheumatic diseases, but they have only a limited benefit in patients with scleroderma.” Following cases she encountered at the hospital and after two of her relatives were diagnosed with blues, Prof. Gore decided about three years ago to join Prof. Ido Amit’s laboratory in the institute’s immunology department in order to understand in depth the molecular mechanisms that cause the disease to develop.
The research led by Prof. Gore is based on innovative technologies developed in Prof. Amit’s laboratory; These methods make it possible to study living tissues at unprecedented resolution by paving the genetic material in them at the level of the individual cell and mapping the different characteristics of thousands of cells at the same time. The study was conducted in collaboration with Dr. Hagit Peleg, Dr. Fadi Karof, Dr. Anat Elazari, Dr. Suhil Amar and other rheumatologists from Hadassah University Medical Center in Jerusalem and with Prof. Alexandra Belbir-Gorman, who conducted the clinical part of the study. And Dr. Yolanda Brown-Moskowitz of the Human Health Medical Campus (Rambam) in Haifa.
Sampled her own skin
Prof. Gore’s personal involvement in the study was not limited to her family background: in order to develop an optimal technique for collecting the samples, she initially performed numerous skin biopsies on herself. After achieving the desired results and formulating the desired sampling protocol, Prof. Gore and her colleagues collected skin samples from nearly one hundred scleroderma patients (mostly women) and more than fifty samples from healthy people. This made the study the most extensive of its kind.
The findings were particularly surprising: although scleroderma was considered an autoimmune disease, no consistent patterns of immune system activity were found among patients. However, unexpected actors sneaked into the center of the stage: the researchers were amazed to find significant and noticeable differences in the fibroblast cells between the samples taken from scleroderma patients and those taken from healthy people.
In fact, the researchers identified a new subtype of fibroblasts whose incidence decreases significantly already in the early stages of the disease. These cells were attached to the researchers by the name ScAF (acronym for scleroderma-associated fibroblasts and also abbreviated scaffold – “scaffold” in English) constituted close to 30% of the fibroblasts in samples from healthy people, but their rate dropped sharply in patients’ samples, and this decrease intensified further As the disease got worse.
Changes in the level of the molecule
To understand the involvement of these cells in the development of the disease, the researchers examined what changes occur in them at the level of RNA molecules in the transition from a normal state to a disease state. In addition, they mapped the spatial layout of these cells deep into the skin tissue, examined with which cells they communicate, and identified different signaling pathways that may be a target for future development of treatments. “In the study, we also identified biological markers that have been linked to damage to certain internal organs; the use of these markers will make it possible to predict which of the patients is at high risk of developing life-threatening complications,” says Prof. Amit.
Beyond the therapeutic horizon of an incurable disease, the study presents the immense scientific and medical potential inherent in a careful comparison between diseased and healthy tissues with the help of advanced single-cell-level flooring techniques. “Our approach provides a research roadmap that can be relevant to other diseases as well,” adds Dr. Schwing-Yin Wang of Prof. Amit’s lab, who led the analysis of the research data using artificial intelligence tools.
“A close hand combination between medicine and basic science, using innovative technologies, opens the door to cracking and understanding diseases that have hitherto remained in the dark,” concludes Prof. Amit.
The study involved Paddy Shiban, Moore Zeda, Dr. Baugo Lee, Adam Yellin, Dr. Daniel Kirschenbaum, Dr. Diego Haytin, Dr. Biort K. Karjestan, Dr. Hamutal Bornstein, Shir Shlomi, Eyal David, Oren Barboy, Dr. Adi Moshe, Dr. Assaf Wiener and Dr. Amir Giladi from the Institute’s Immunology Department; Dr. Tehila Tzemach Toren, Prof. Yaakov Neferstek, Dr. Batya Avni, Dr. Sigal Grisero, Dr. Roni Sherbarak Chassidim, Dr. Vered Molcho Pesach, Dr. Dalit Amar Lisha, Dr. Tomer Tzur , Dr. Rotem Quint, Dr. Moshe Gross and Dr. Shlomit Kfir-Ehrenfeld from Hadassah University Medical Center in Jerusalem; Dr. Tomer Meir Selma, Dr. Efrat Hagai and Dr. Yosef Addi from the Department of Life Sciences Research Infrastructures; Dr. Liat Aligur and Dana Hirsch from the Department of Veterinary Resources; Dr. Moshe Bitton from the Department of Biological Control; and Dr. Reut Tzemach from the Department of Immunology of the Institute and the Tel Aviv Sourasky Medical Center.
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