New research, led by a team of scientists from the University of Cambridge, has demonstrated a way to rejuvenate old, dysfunctional brain stem cells, making them act young again. The technique points to potential new treatments for multiple sclerosis (MS), but also broader ways to reverse general age-related brain changes.
The research focused on a type of brain cell called oligodendrocyte progenitor cells (OPCs). As the name suggests, these kinds of brain stem cells are precursors to mature oligodendrocyte cells, which are vital for healthy brain function.
One of the key physiological characteristics of MS is the loss of functional oligodendrocytes. This results in a breakdown of the axons of neurons, causing many of the degenerative symptoms associated with the disease. We know, alongside the acute conditions of MS, age is another factor that disrupts the effective transformation of OPCs into active oligodendrocyte cells. Exactly why, or how, OPCs become dysfunctional has been a mystery to scientists.
The new research set out to investigate whether external cellular environmental conditions could influence the loss of function in aging OPCs, and the team indeed found that age-related brain stiffening seemed to directly influence OPC function. Transplanting OPCs from old rats into the softer brains of younger animals seemed to rejuvenate their cellular activity. Further experiments growing OPCs on different kinds of materials revealed the cellular surface environments were key to the OPCs' functionality.
"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," explains Kevin Chalut, co-lead on the new research. "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."
The researchers then asked how these OPCs were sensing their external environment. They discovered a key protein, called Piezo1, sat on the surface of OPCs and signaled to the cell whether the surrounding environment was stiff or soft. Instead of trying to fundamentally change the cellular environment of the brain, the researchers wondered if they could trick the OPCs into acting young by messing with the Piezo1 signaling protein.
"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," says Robin Franklin, the other co-leader on the new research. "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."
One of the most fundamentally fascinating implications of the research is that it shows how the behavior of certain stem cells can be significantly affected by their surrounding tissue environment. In this particular instance it seems like the age-related dysfunction in OPCs is not due to anything intrinsic in the stem cells, which means that functionality can be kickstarted back into action relatively easily.
While the research has impressively broad implications for many age-related brain degenerative disorders, the most immediate outcome is a novel MS treatment. MS is very specifically related to a loss of function in these kinds of brain stem cells, and Susan Kohlhaas, from the MS Society, says the research opens up new pathways for future treatments.
"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 says.
The new research was published in the journal Nature
Source: University of Cambridge
