Contrary to medical convention, a mathematical model predicted two different mechanisms of scar tissue formation in the heart – hot and cold. Findings in human heart tissue confirmed the model and may lead to new therapeutic approaches
Injury or aging processes can lead to the formation of scar tissue (fibrosis) in internal organs such as the heart, lungs, kidneys, or liver, but contrary to popular belief in the medical world, not all scars are the same – this is the conclusion emerging from a new study by scientists at the Weizmann Institute of Science. The findings which are published today in the scientific journal Cell Systems It is revealed that two different types of scar tissue are formed in different heart diseases – “hot fibrosis” and “cold fibrosis” – and that each requires a different therapeutic approach. The discovery may lead to innovative cardiological treatments and even paves the way for studies on fibrosis in other organs.
The research began as a collaboration between neighbors at the Weizmann Institute. Prof. Eldad Tzhor, whose research focuses on the heart and its diseases, heard about a mathematical model created in a nearby laboratory headed by Prof. Uri AlonProf. Alon's model proposed classifying scar tissue in different organs based on the presence of only two types of cells: fibroblasts – collagen-producing cells that provide tissue with support and structure – and immune system cells called macrophages.
"At first it sounded too simplistic to me – after all, we all know how complex biological systems are. But the idea intrigued me, and maybe it was just an excuse to collaborate with Uri," confesses Prof. Tzahor. "So I suggested to him that we try to apply the model to heart disease."
Scar tissue forms in the heart when heart muscle cells are damaged, such as after a heart attack. Like a patch that repairs a hole in clothing, the scar tissue that replaces damaged cells allows the heart to continue to function as the body's blood pump. However, this tissue does not contract effectively, and it can even expand and eventually lead to impaired heart function. Since there is currently no effective treatment for heart scars, medicine is trying to prevent their formation or reduce their size.
"Scar tissue in the heart may seem relatively simple on the surface, but the process of its formation is extremely complex and involves many types of cells and molecules," says Shoval Miyara, a joint doctoral student of Professors Tzahor and Alon, who led the study together with Dr. Miri Adler from the Hebrew University of Jerusalem, a former student of Prof. Alon. "To deal with biological complexity and get to the heart of the matter, we approached the challenge like an artist trying to distill the essence from the noisy world around us – like Picasso's famous bull that remains a bull even when drawn with a few single lines."
The "bull" that the researchers drew using Prof. Alon's mathematical model ultimately ran afoul of the medical convention that views all scars in the heart as equal. The model predicted two different mechanisms for the formation of heart scars. One, a mechanism in which scar tissue develops as a result of the interactions and communication between myofibroblasts - fibroblasts with the ability to contract that characterize scar tissue in the heart - and macrophages of the immune system, and the other, a closed-loop mechanism in which the myofibroblasts manage on their own without partners and encourage scar development through molecules that they themselves secrete. Because immune system involvement is often associated with fever and inflammation, the first mechanism was called "hot fibrosis" - while the other mechanism was called "cold fibrosis."
When Miara and his team put the model to the test of reality – first in cell cultures and in mice – they were given confirmation of its surprising predictions. The researchers saw that while chronic heart failure leads to warm fibrosis with a high presence of macrophages, acute injury, such as a heart attack, leads to cold fibrosis. Although immune cells are present immediately after a heart attack, within a few weeks there are almost no macrophages left in the scar tissue. In the next step, these findings were also reproduced in human samples of heart tissue.
But the researchers didn't stop at the model validation stage – they were able to identify a key molecule that influences scar development in cold fibrosis: a protein called TIMP-1, which was known in other contexts, but was discovered here for the first time as a growth factor that promotes myofibroblast division and the formation of scar tissue in the heart. When the scientists blocked TIMP-1 in mice after a heart attack, the scar tissue that formed in their heart muscle was smaller compared to untreated mice.
"We have shown that TIMP-1 is a potential target for future anti-fibrosis drugs, but it is clearly not the only one," says Miara. "Further research could reveal additional targets, and show which ones can be targeted most effectively to prevent or minimize damage to the heart muscle after a heart attack."
"In medical textbooks, microscopic images of pathologies in the heart muscle look the same – they usually show the collagen fibers that make up the scar tissue, but we have shown that hot fibrosis and cold fibrosis are the result of different biological mechanisms. In other words, these are two different heart diseases, and therefore they must also be treated and drugs developed for them differently." Concludes Prof. Tzahor. "The collaboration opened my heart to the fascinating biology of the heart," says Prof. Alon. "Future studies will be able to apply our approach, which combines mathematical models, basic biology and medical needs, to other organs and test whether the division into hot and cold fibrosis applies to scars in other tissues – in the lung, kidneys or liver – and even to scars that develop following cancer or stroke."
Also participating in the study were Dr. Kfir-Baruch Umansky, Yelin Divinsky, Yaakov Elkahel, Dr. David Keen, Dr. Daria Landengoltz, Dr. Hanna Bueno-Levi, Dr. Alexander Genzling, Daniel Kimchi, Dr. Avraham Shaked, Dr. Lingling Zhang, Zacharia Petrover, Dr. Rachel Serig and Dr. Avi Mayo from the Institute's Department of Molecular Cell Biology; Daniel Hausler and Prof. Achim Kruger from the Technical University of Munich; Dr. Elad Bashet, Dr. Jingkui Wang and Prof. Eli Tanaka from the Vienna Biocenter; Dr. Ricardo Ramirez Flores and Prof. Julio Sez-Rodriguez from the University of Heidelberg; Dr. Ofra Golani from the Institute's Department of Life Sciences Research Infrastructures; Dr. Tali Shalit, Michael Gershovitz and Aviatar Weizmann from the Nancy and Stephen Grand Israel National Center for Personalized Medicine; Dr. Andrea Bar, Dr. Tatiana Dorn, Prof. Alessandra Moretti and Prof. Christian Kopf from the German Center for Cardiovascular Research (DZHK) and Prof. Ruslan Medzhitov from the Yale University School of Medicine.
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