Brain cells from an unlikely source

This article appeared in the Spring 2013 issue of Current Exchange Magazine.

At this moment, millions of toilets are flushing. Whirling down the drains is something that might one day be used to treat Parkinson’s disease and ALS – urine. That is, the cells in urine. It turns out that living cells found in human urine can be programmed to generate a steady stream of brain cells. Researchers at Guangzhou Institute in China found a quick and relatively efficient method that converts urine cells into a parental cell type that gives birth to a variety of nerve cells. The hope is that that one day, a patient could submit a simple urine sample and get back the neurons he or she has lost to neurodegenerative disease.

It might be surprising that urine contains living cells in the first place. They come from the kidneys, where they line the tubules, until they detach, get excreted and become so-called urine cells. The key to transforming these simple epithelial cells into bona fide neurons is to turn back their developmental clocks. Through a process called reprogramming, scientists push adult cells to revert to an earlier, less specialized form. This process essentially takes cells through the plotline of The Curious Case of Benjamin Button. Their fixed identities unravel until a small fraction of cells ultimately resemble what they were in their infancy: embryonic stem cells.

Embryonic stem cells have limitless potential for self-renewal and can give rise to any cell type. Similarly, we begin life with myriad possibilities of who we will become, but as we go through life we make decisions that set us on a more defined path. The same goes for cells as they develop: embryonic stem cells commit to lineages that give rise to mature cell types, and normally after fate decisions are made, there’s no going back.

This made the breakthrough discovery of reprogramming factors by 2012 Noble Prize winner Shinya Yamanaka so surprising. He found that merely four gene products, called transcription factors, were sufficient to turn back the clock and reprogram mature cells to stem cells. Transcription factors are proteins that bind DNA and recruit machinery that transcribes the DNA code into mRNA that then serves as the template for protein production. The idea is that Yamanaka factors must turn on gene products that give stem cells their unique abilities. Only recently scientists have begun to carry out detailed molecular studies that track how cells change during reprogramming. It appears that cells go through distinct intermediate steps, so that like the Benjamin Button story, reprogramming really does look like development in reverse.

Reprogramming efficiency is very low in general: only a tiny fraction of the cells end up resembling embryonic stem cells. These fully reprogrammed cells are called induced pluripotent stem cells, or iPSCs. Apart from the amniotic sac and placenta (only made by embryonic stem cells) they can become any type of cell in the body – from the bone cells that form your elbow to the nerve cells that respond when you whack it. Reprogramming adult cells – be it from a cheek swab or a urine sample – into iPSCs skirts the ethical issue of harvesting stem cells from human embryos. In addition, they don’t cause immune rejection like embryonic stem cells do, because they come from the patient’s own tissue. What makes urine cells a great cell source for reprogramming experiments is that it’s plentiful and easy to collect. More commonly used cell sources require invasive procedures such as skin biopsies and blood draws. The Chinese researchers were studying methods to increase the efficiency of reprogramming when they made a surprising observation.

The gee whiz moment came when Wang and colleagues noticed that urine cells grown in a specially-defined media clumped together in a flower-like shape. This rosette pattern was reminiscent of the way that neuronal progenitors, the parental cell type that gives rise to all types of nerve cells, grow. They had stumbled on a shortcut for producing brain cells: the cells picked from the rosette expressed genetic markers that were characteristic of neuronal progenitors, not iPSCs. The urine cells acquired the ability to grow and self renew without ever becoming iPSCs. By repeating the same steps, the scientists made the same progenitor cells from three men. While reprogramming efficiency was only a fraction of a percent (.2%) they could produce enough progenitors to generate many types of mature cells found in the brain.

Besides being faster, this shortcut method is also safer than previous methods used to make brain cells. Before, scientists made brain cells by forcing mouse connective tissue cells to make proteins and RNAs normally found in neurons. This method required that viruses insert foreign DNA into the mouse cell’s genome. Unfortunately, viral integration can lead to the unwanted side effects of genomic instability and cancer. Instead, Wang and colleagues introduced a small circular piece of bacterial DNA that served as a platform for reprogramming factor delivery. Bacterial platforms multiply in the cytoplasm, and reprogramming factor expression is driven directly off of them, no integration into the host cell’s genome required.

It’s all well that urine cells could produce brain cells in a dish, but in order for replacement therapy to work, they would have to convert and survive in a living brain. To test this, researchers transplanted neuronal progenitors made from human urine into the brains of newborn mice. They saw that the urine-made neuronal progenitors produced mature brain cells that survived for at least a month in the mice brains. Follow up studies are needed to test if these neurons actually participate in brain function. Importantly, there was no evidence of tumor formation, indicating that the virus-free system could be safe for therapeutic applications.

Overall, the ability to convert excreted urine cells directly into brain cells is faster and safer than older methods that first require reprogramming to iPSCs. The higher efficiency of reprogramming mature cells directly to neuronal progenitors plus the abundance of source material, make pee-made brain cells an exciting tool for the study and treatment of nervous system disorders

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