Eliminating Rejuvenation in Cellular Reprogramming

Researchers here demonstrate a method of generating reprogrammed cell lines from old patients that retain the age-related changes and damage in the cells, a useful tool for further research. The technique of induced pluripotency has in recent years been used to generate cells of arbitrary specific types from, for example, a patient skin cell sample: the skin cells are reprogrammed to be pluripotent, and then differentiated into the desired cell type. Reprogramming to pluripotency has been shown to rejuvenate some of the aspects of old cell lineages, such as by clearing out damaged mitochondria, and removing age-related epigenetic markers, possibly reflecting other forms of repair. This may be related to the early stage of embryonic development in which age-related damage is abruptly repaired, the cells reset to a youthful state. This is all very interesting to some factions of the research community, but frustrating for those scientists who are trying to build patient-matched models of old tissue to better understand what is going wrong in age-related diseases.

For the first time, scientists can use skin samples from older patients to create brain cells without rolling back the youthfulness clock in the cells first. The new technique, which yields cells resembling those found in older people's brains, will be a boon to scientists studying age-related diseases like Alzheimer's and Parkinson's. "This lets us keep age-related signatures in the cells so that we can more easily study the effects of aging on the brain. By using this powerful approach, we can begin to answer many questions about the physiology and molecular machinery of human nerve cells - not just around healthy aging but pathological aging as well."

Over the past few years, researchers have increasingly turned to stem cells to study various diseases in humans. For example, scientists can take patients' skin cells and turn them into induced pluripotent stem cells, which have the ability to become any cell in the body. From there, researchers can prompt the stem cells to turn into brain cells for further study. But this process - even when taking skin cells from an older human - doesn't guarantee stem cells with 'older' properties. "As researchers started using these cells more, it became clear that during the process of reprogramming to create stem cells the cell was also rejuvenated in other ways."

Researchers decided to try another approach, turning to an even newer technique that lets them directly convert skin cells to neurons, creating what's called an induced neuron without passing through a pluripotent state. They collected skin cells from 19 people, aged from birth to 89, and prompted them to turn into brain cells using both the induced pluripotent stem cell technique and the direct conversion approach. Then, they compared the patterns of gene expression in the resulting neurons with cells taken from autopsied brains. When the induced pluripotent stem cell method was used, as expected, the patterns in the neurons were indistinguishable between young and old derived samples. But brain cells that had been created using the direct conversion technique had different patterns of gene expression depending on whether they were created from young donors or older adults. For instance, levels of a nuclear pore protein called RanBP17 - whose decline is linked to nuclear transport defects that play a role in neurodegenerative diseases - were lower in the neurons derived from older patients.

Link: http://www.salk.edu/news/pressrelease_details.php?press_id=2119

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