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Stiffness in Brain Tissue Niches Causes Declining Stem Cell Activity and Myelination


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Posted 15 August 2019 - 07:28 PM


Loss of the myelin layer that sheathes nerves is the proximate cause of severe conditions such as multiple sclerosis, but this sort of loss occurs to a lesser degree in the course of normal aging, and contributes to cognitive decline. In today's open access research materials, scientists draw a line of cause and effect between (a) increasing stiffness of the brain tissue that hosts niches where stem cells reside, (b) dysfunction of those stem cells mediated by the specific stiffness-sensing mechanism of Piezo1, a process that may exist in other stem cell populations as well, © the loss of myelin-generating cells normally produced by the stem cells, and (d) the consequent degradation of myelin and nervous system function.

Without looking into underlying causes of increasing stiffness of brain tissue in stem cell niches, the researchers here demonstrate restored stem cell function via blocking the mechanism by which the stem cells sense stiffness. This is an interesting demonstration, but I'd tend to regard it as more of a strong hint to further investigate the causes of tissue stiffness in the aging brain rather than as a basis for therapies. There is some work in the literature on stiffness of brain tissue, but not an enormous amount; most of it is correlational in nature, rather than a search for deeper mechanisms. Stiffness of brain tissue shows distinct patterns for different age-related neurodegenerative conditions, for example. The use of brain magnetic resonance elastography allows living brains to be mapped for stiffness, which should allow for greater progress towards understanding in the years ahead.

Why does brain tissue stiffen with age? This may or may not have anything to do with the mechanisms of tissue stiffening that are better studied in skin and blood vessels. These include cross-linking of the extracellular matrix, wherein persistent byproducts of metabolism link together the complex extracellular matrix molecules, restricting their movement and altering the structural properties of the tissue, particularly elasticity. There is also the loss of elastin molecules, accumulation of inflammatory senescent cells, and so forth. Perhaps none of that is all that relevant in the brain, however. Research indicates that the water content of brain tissue is important to tissue stiffness, as is the pH of the tissue. One can speculate on what age-related changes in blood flow to the brain, or loss of capillary networks, might do to these measures of the environment.

Cambridge scientists reverse ageing process in rat brain stem cells

As our bodies age, our muscles and joints can become stiff, making everyday movements more difficult. This study shows the same is true in our brains, and that age-related brain stiffening has a significant impact on the function of brain stem cells. Researchers studied young and old rat brains to understand the impact of age-related brain stiffening on the function of oligodendrocyte progenitor cells (OPCs). These cells are a type of brain stem cell important for maintaining normal brain function, and for the regeneration of myelin - the fatty sheath that surrounds our nerves, which is damaged in multiple sclerosis (MS). The effects of age on these cells contributes to MS, but their function also declines with age in healthy people.

To determine whether the loss of function in aged OPCs was reversible, the researchers transplanted older OPCs from aged rats into the soft, spongy brains of younger animals. Remarkably, the older brain cells were rejuvenated, and began to behave like the younger, more vigorous cells. To fully understand how brain softness and stiffness influences cell behavior, the researchers investigated Piezo1 - a protein found on the cell surface, which informs the cell whether the surrounding environment is soft or stiff. "When we removed Piezo1 from the surface of aged brain stem cells, we were able to trick the cells into perceiving a soft surrounding environment, even when they were growing on the stiff material. What's more, we were able to delete Piezo1 in the OPCs within the aged rat brains, which lead to the cells becoming rejuvenated and once again able to assume their normal regenerative function."

Niche stiffness underlies the ageing of central nervous system progenitor cells

Ageing causes a decline in tissue regeneration owing to a loss of function of adult stem cell and progenitor cell populations. One example is the deterioration of the regenerative capacity of the widespread and abundant population of central nervous system (CNS) multipotent stem cells known as oligodendrocyte progenitor cells (OPCs). A relatively overlooked potential source of this loss of function is the stem cell 'niche' - a set of cell-extrinsic cues that include chemical and mechanical signals. Here we show that the OPC microenvironment stiffens with age, and that this mechanical change is sufficient to cause age-related loss of function of OPCs.

Using biological and synthetic scaffolds to mimic the stiffness of young brains, we find that isolated aged OPCs cultured on these scaffolds are molecularly and functionally rejuvenated. When we disrupt mechanical signalling, the proliferation and differentiation rates of OPCs are increased. We identify the mechanoresponsive ion channel PIEZO1 as a key mediator of OPC mechanical signalling. Inhibiting PIEZO1 overrides mechanical signals in vivo and allows OPCs to maintain activity in the ageing CNS. We also show that PIEZO1 is important in regulating cell number during CNS development. Thus we show that tissue stiffness is a crucial regulator of ageing in OPCs, and provide insights into how the function of adult stem and progenitor cells changes with age. Our findings could be important not only for the development of regenerative therapies, but also for understanding the ageing process itself.


View the full article at FightAging




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