How can cells be returned to their initial and most powerful state?
Embryonic stem cells arouse quite a bit of enthusiasm, and to a large extent rightfully so - their ability to transform into any type of tissue has tremendous medical and research potential. And yet, in the "Almighty cell" competition, they would not have reached first place. This title is reserved for earlier cells - those that make up the embryo in the first day or two of its formation. They recently found out Scientists of the Weizmann Institute of Science how the early cells lose their super abilities, and just as importantly - how they can be restored. "We found a new way to take cells the farthest back in time, to the first stage of the embryo's life," says Dr Yifat Marble from the department of systemic immunology at the institute, who headed the research team alongside Prof. Yaakov Hana from the Department of Molecular Genetics.
At the stage when the embryo consists of only two cells, its cells are characterized by a feature called "totipotency", meaning "capacity for anything". In other words, they can become not only all types of cells in the embryo, but also extraembryonic tissues. But as soon as the cells divide and become two to four, some of them gradually lose the "ability to do anything" and have to settle for a slightly less impressive feature, "pluripotency", that is, "ability to do many things". These are the glorified embryonic stem cells that can produce any tissue in the body, but not the placenta.
Like life itself, the process of embryo development always progresses in one direction: from a single cell, the fertilized egg, to billions of cells that specialize in different roles - from muscle to nerve - and make up our body. Amazingly, in the laboratory the direction can be reversed: return mature cells to a pluripotent state. This sensational discovery even earned the scientists behind it the Nobel Prize for 2012.
Now the scientists of the Weizmann Institute of Science have discovered a new mechanism, by means of which it is possible to make cells go back even further, that is, to return pluripotent stem cells to a totipotent state, this is the characteristic of a day-old embryo. In fact, the researchers discovered that the cell loses its totipotency and begins its journey to form a distinct self-identity simultaneously with the activation of a mechanism that changes the spatial arrangement of the chromatin - the material in which the DNA is packaged.
"It is a mechanism that acts like a type of lock, and it ensures that the development of the fetus will progress in one direction only and will not go back," says Dr. Daoud Shiban, who led the research as part of his doctoral studies in the laboratories of Dr. Marble and Prof. Hana. "This locking mechanism physically compresses the chromatin, i.e. changes its spatial arrangement, thus preventing the expression of genes associated with totipotency. As soon as the compression is removed, the chromatin opens and the lock is released."
Experiments in mice have revealed what exactly causes chromatin to change shape and undergo compaction. This happens when another protein from the SUMO family (small ubiquitin-like modifiers) is attached to one of the building blocks of chromatin, the protein called histone 1H. Unlike its famous cousin, ubiquitin, SUMO does not mark proteins for degradation but changes their activity. This marking is one of a long line of markings that change the activity of proteins after they have already been formed. "These late changes are actually a control mechanism that has a decisive effect on the activity of these essential molecules," explains Dr. Marble.
But is it possible to cancel the check and release the lock? To test this, the scientists engineered embryonic stem cells to be without histone H1 or without the enzyme responsible for attaching SUMO to proteins. They saw that these cells went back in time: their chromatin opened up, they returned to expressing more than 100 genes involved in totipotency and were able to produce cells capable of differentiating into extra-embryonic tissues, including the placenta.
The ability to restore mature cells to an earlier state has implications far beyond the laboratory. For example, the chromatin compaction mechanism may be involved in various disease states, including cancer, since disruptions in this mechanism may allow malignant cells to return to an earlier developmental state, characterized by rapid growth. In addition, increased control over the maturation process of the cell may greatly advance the promising field of tissue engineering and growing organs for transplantation. "Unlocking the chromatin and reorganizing its spatial arrangement may prove to be a powerful tool for tissue regeneration and creation for healing purposes," explains Dr. Shiban.
Also participating in the study were: Dr. Thom Shani, Alejandro Aguilera, Dr. Nofer Moore, Dr. Bernardo Oldek, Dr. Jonathan Beyrel, Sergey Vyukov, Dr. Vladislav Krupelnik, Valeria Chogaba, Shadi Terzi, Alejandra Rodríguez de la Rosa, Mary Zerbiv and Dr. Noa Noverstern from Prof. Hana's lab; Roi Mor, Dr. Merav Shmoeli, Dr. Avital Eisenberg Lerner, Goyon Shen, Dr. Assaf Kasan, Dr. Adi Ullman and Suleiman Masraui from Dr. Marble's laboratory; Jacob Herbert and Dr. Yael David from Memorial Sloan Kettering Cancer Center; Dr. Mittal Cooperser and Dr. Yishai Levin from the Israeli National Center for Personalized Medicine named after Nancy and Steven Grand; and Dr. Efrat Shema from the department of immunology and biological regeneration of the institute.
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