Not just stem cells
"Softening of the brain" restored youth to rat stem cells
And the stiffness of the nervous tissue, on the contrary, turned out to be a sign of old age
Polina Loseva, "The Attic"
The life of stem cells is influenced not only by their chronological age, but also by the environment. Scientists from Cambridge have found out that in the brain of rats, the fibers of the intercellular substance become tougher over time. When they were partially split, the stem cells began to multiply better and repair the damaged tissue. The researchers achieved a similar effect by turning off the mechanoreceptor in cells that responds to tissue stiffness. Apparently, the sensitivity of stem cells to signals from outside saves the developing brain from overpopulation, but subsequently only accelerates its aging.
Most tissues in the animal body rely on an extracellular matrix, or intercellular substance, a three–dimensional network of protein fibers. In young tissue, these fibers are long and flexible, but they shorten with age. The fact is that, like any molecules, protein filaments wear out, and the cells that produce them age with them. At the same time, cross–linking occurs between the matrix fibers - the result of reactions with glucose and other random substances. Thus, with age, the protein network between cells becomes tougher and stronger. However, this strength does not benefit the cells themselves, which react to the state of the matrix.
A group of researchers from Cambridge suggested that changes in the structure of the intercellular substance also affect the activity of neural stem cells. They worked with the precursors of oligodendrocytes – auxiliary cells that form a protective shell around neurons and nerve fibers. Stem cells obtained from the brains of old rats multiplied much worse in the laboratory than the cells of young animals. However, these properties were lost if scientists transplanted them into the body of an animal of a different age: the "young" cells stopped dividing in the old tissue, and, on the contrary, youth returned to the "elderly" cells when they were injected into the brain of a newborn baby rat.
To check whether it's really the extracellular matrix, scientists decided to soften it. To do this, they partially "digested" hard intercellular fibers with the help of the enzyme chondroitinase, and then damaged a section of tissue to start regeneration. In rats with a "softened" brain, injuries healed better because the cells multiplied faster. The researchers reproduced the same effect in the laboratory: growing cells on gels of different stiffness, they confirmed that the fate of cells does not depend on specific molecules, but only on the tension in the tissue.
Stem cells from the brains of old rats grow better on a soft surface (left) than on a hard one (right). Figure from the press release of Cambridge scientists reverse aging process in rat brain stem cells – VM.
Then the scientists tested whether it was possible to disable such mechanosensitivity in stem cells. Their target was the mechanoreceptor protein PIEZO, and the new model object was mice. Animals in which scientists were able to block its work recovered better from injuries even in old age. Their stem cells multiplied more actively and formed a protective shell around the neurons. But if you turn off the PIEZO operation in newborn mice, then pandemonium began in the nervous tissue: stem cells multiplied five times more than in control animals. Apparently, the main function of PIEZO is to inhibit cell division in the growing brain. But after the tissue has formed, this protein begins to do more harm than good, forbidding stem cells to make up for losses.
The relationship between cells and intercellular matter can be an important obstacle to prolonging life. Oligodendrocyte precursors are not the only cells that decrease activity in response to matrix aging. Connective tissue cells, for example, have a similar property. And this calls into question the idea of tissue rejuvenation by stem cells: once trapped inside an aged matrix, they can fall under its influence and lose their ability to regenerate.
Article by Segel et al. Niche stiffness underlies the aging of central nervous system progenitor cells published in the journal Nature.
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