Our brains — much like our joints — stiffen with age, causing brain stem cells called oligodendrocyte progenitor cells (OPCs) to lose their ability to proliferate and transform into oligodendrocytes, the cells that produce myelin, an essential component for nerve cell communication, a study found.
But tricking OPCs into sensing a surrounding environment that’s less stiff can help rejuvenate the brain, its researchers said. These findings open the potential for new therapies for neurodegenerative diseases like multiple sclerosis (MS).
The study “Niche stiffness underlies the ageing of central nervous system progenitor cells” was published in the journal Nature.
Researchers at the Wellcome-MRC Cambridge Stem Cell Institute at University of Cambridge investigated whether they could rescue aging OPCs that were no longer proliferating and differentiating into oligodendrocytes.
The team transplanted aged OPCs from older rats into the brains of younger rats, which are softer. The transplanted OPCs regained their ability to proliferate and to generate mature oligodendrocytes, acting much like younger OPCs. These findings suggested that the younger brain microenvironment could promote the rejuvenating potential of aged OPCs.
Researchers then cultured aged OPCs in a brain extracellular matrix — the mesh-like scaffold surrounding cells — from younger and older brains. Results showed that the proliferation of aged OPCs increased by 10 times in the younger and softer matrix.
To determine if mechanical properties were the cues that OPCs were responding to, the team also created scaffolds with specific stiffness, and tested how a stiffer environment affected OPC behavior. Results showed that stiffer scaffolds led to a slower OPC proliferation rates compared to softer scaffolds.
“We were fascinated to see that when we grew young, functioning rat brain stem cells on the stiff material, the cells became dysfunctional and lost their ability to regenerate, and in fact began to function like aged cells,” Kevin Chalut, one of the study’s co-lead authors, said in a press release.
“What was especially interesting, however, was that when the old brain cells were grown on the soft material, they began to function like young cells — in other words, they were rejuvenated,” Chalut added.
Next, researchers focused their attention on a cellular sensor that senses whether the surrounding environment is soft or stiff, called Piezo1. They first saw that the levels of Piezo1 rose with age, and that the protein was highly present in OPCs, including in humans.
By genetically silencing the expression of Piezo1, they were able to maintain young OPC proliferation in an older brain microenvironment.
“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,” said Robin Franklin, the study’s co-lead author.
The team then mimicked the myelin damage seen in MS in the brain of aged animals, and lowered the levels of Piezo1 in OPCs. Compared to control animals, the OPCs with lesser Piezo1 were found at the lesion site, promoting remyelination (the formation of new myelin sheaths).
“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,” Franklin said.
The results suggest that therapies favoring OPC rejuvenation and transformation could promote myelin regeneration in MS.
Furthermore, these “findings could be important not only for the development of regenerative therapies, but also for understanding the ageing process itself,” the researchers wrote.
“MS is relentless, painful, and disabling, and treatments that can slow and prevent the accumulation of disability over time are desperately needed,” said Susan Kohlhaas, director of research at the MS Society, which provided funding for this research.
“The Cambridge team’s discoveries on how brain stem cells age and how this process might be reversed have important implications for future treatment, because it gives us a new target to address issues associated with aging and MS, including how to potentially regain lost function in the brain,” Kohlhaas added.