Mechanisms underlying direct programming of stem cells into motor neurons could lead to cell-replacement therapies

December 8, 2016

A team of scientists has uncovered details of the cellular mechanisms that control the direct programming of stem cells into motor neurons. The scientists analyzed changes that occur in the cells over the course of the reprogramming process. They discovered a dynamic, multi-step process in which multiple independent changes eventually converge to change the stem cells into motor neurons.

"There is a lot of interest in generating to study basic developmental processes as well as human diseases like ALS and ," said Shaun Mahony, assistant professor of biochemistry and molecular biology at Penn State and one of the lead authors of the paper. "By detailing the mechanisms underlying the direct programing of motor neurons from , our study not only informs the study of motor neuron development and its associated diseases, but also informs our understanding of the direct programming process and may help with the development of techniques to generate other cell types."

The direct programming technique could eventually be used to regenerate missing or damaged cells by converting other cell types into the missing one. The research findings, which appear online in the journal Cell Stem Cell on December 8, 2016, show the challenges facing current cell-replacement technology, but they also outline a potential pathway to the creation of more viable methods.

"Despite having a great therapeutic potential, direct programming is generally inefficient and doesn't fully take into account molecular complexity," said Esteban Mazzoni, an assistant professor in New York University's Department of Biology and one of the lead authors of the study. "However, our findings point to possible new avenues for enhanced gene-therapy methods."

The researchers had shown previously that they can transform mouse into motor neurons by expressing three transcription factors—genes that control the expression of other genes—in the stem cells. The transformation takes about two days. In order to better understand the cellular and genetic mechanisms responsible for the transformation, the researchers analyzed how the transcription factors bound to the genome, changes in gene expression, and modifications to chromatin at 6-hour intervals during the transformation.

"We have a very efficient system in which we can transform stem cells into motor neurons with something like a 90 to 95 percent success rate by adding the cocktail of transcription factors," said Mahony. "Because of that efficiency, we were able to use our system to tease out the details of what actually happens in the cell during this transformation."

"A cell in an embryo develops by passing through several intermediate stages," noted Uwe Ohler, senior researcher at the Max Delbrück Center for Molecular Medicine (MDC) in Berlin and one of the lead authors of the work. "But in direct programming we don't have that: we replace the gene transcription network of the cell with a completely new one at once, without the progression through intermediate stages. We asked, what are the timing and kinetics of chromatin changes and transcription events that directly lead to the final cell fate?"

The research team found surprising complexity—programming of these stem cells into neurons is the result of two independent transcriptional processes that eventually converge. Early on in the process, two of the —Isl1 and Lhx3—work in tandem, binding to the genome and beginning a cascade of events including changes to chromatin structure and gene expression in the cells. The third transcription factor, Ngn2, acts independently making additional changes to gene expression. Later in the transformation process, Isl1 and Lhx3 rely on changes in the cell initiated by Ngn2 to help complete the transformation. In order for direct programming to successfully achieve cellular conversion, it must coordinate the activity of the two processes.

"Many have found direct programming to be a potentially attractive method as it can be performed either in vitro—outside of a living organism—or in vivo—inside the body and, importantly, at the site of cellular damage," said Mazzoni. "However, questions remain about its viability to repair cells—especially given the complex nature of the biological process. Looking ahead, we think it's reasonable to use this newly gained knowledge to, for instance, manipulate cells in the spinal cord to replace the neurons required for voluntary movement that are destroyed by afflictions such as ALS."

Explore further: Stem cell scientists develop more effective way to create motor neurons

Related Stories

Stem cell scientists develop more effective way to create motor neurons

April 22, 2015
Often described as the final frontier of biology, the nervous system is a complex network comprised of the brain, spinal cord and the nerves that run through the body. Published today by scientists led by Bennett Novitch, ...

New stem cell research uncovers causes of spinal muscular atrophy

July 1, 2015
New research from the Advanced Gene and Cell Therapy Lab at Royal Holloway, University of London has used pioneering stem cell techniques to better understand why certain cells are more at risk of degenerating in spinal muscular ...

Model neurons have implications for ALS and other afflictions

December 12, 2013
NYU biologists have created model neurons with greater precision and efficiency than have been achieved in the past. Their breakthrough, which appeared this fall in a pair of papers in the journal Nature Neuroscience, has ...

Zebrafish study offers insights into nerve cell repair mechanisms

October 22, 2015
Tropical fish may hold clues that could aid research into motor neuron disease and paralysis caused by spinal cord injury.

Recommended for you

Post-stroke patients reach terra firma with new exosuit technology

July 26, 2017
Upright walking on two legs is a defining trait in humans, enabling them to move very efficiently throughout their environment. This can all change in the blink of an eye when a stroke occurs. In about 80% of patients post-stroke, ...

Molecular hitchhiker on human protein signals tumors to self-destruct

July 24, 2017
Powerful molecules can hitch rides on a plentiful human protein and signal tumors to self-destruct, a team of Vanderbilt University engineers found.

Researchers develop new method to generate human antibodies

July 24, 2017
An international team of scientists has developed a method to rapidly produce specific human antibodies in the laboratory. The technique, which will be described in a paper to be published July 24 in The Journal of Experimental ...

New vaccine production could improve flu shot accuracy

July 24, 2017
A new way of producing the seasonal flu vaccine could speed up the process and provide better protection against infection.

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.