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Going more than skin deep
by Kelsey Kaustinen  |  Email the author


SAN FRANCISCO—A new development in the field of cell reprogramming might provide researchers with not only a safer method of reprogramming cells, but also access to more accurate human testing models.  
Dr. Sheng Ding, a scientist at the Gladstone Institutes, has discovered a way to transform adult skin cells into brain cells, neurons fully capable of transmitting brain signals. Ding's work, detailed in the July 28 issue of Cell Stem Cell, builds on the cell-reprogramming research of the study's senior investigator, Dr. Shinya Yamanaka, another scientist at Gladstone, who discovered a way to convert adult skin cells into cells that mimicked embryonic stem cells. Ding, a leading chemical biologist in stem cell science, is a senior investigator at the Gladstone Institute of Cardiovascular Disease and a University of California San Francisco (UCSF) professor of pharmaceutical chemistry.  
For this experiment, Ding converted skin cells from a 55-year-old woman into working brain cells using two genes and a microRNA, which are strands of genetic material responsible for regulating cellular processes throughout the entire body. The cells were capable of exchanging electrical impulses as regular brain cells do to convey thoughts.  
The process, Ding explains, begins with adult human skin fibroblast cells. The cells are grown in culture dishes, and when introduced with a microRNA molecule and two genes, the cells' morphology changes within a couple weeks to form functional neurons. The use of microRNA rather than gene modification to reprogram cells is safer, and Ding hopes to use only microRNAs and pharmaceutical compounds to covert skin cells to brain cells in future experiments, something he says will help researchers avoid genome modifications.
"The introduced molecules basically rewire the fibroblast cells' memory at the so-called epigenetic level," Ding explains, "and change the cell fate/identity from fibroblasts to neurons."  
Unlike pluripotent stem cells, the reprogrammed cells do not carry with them a risk of tumor, since the "generated neurons come directly from fibroblasts," skipping the pluripotent stem cell stage, says Ding. The resulting cells are mature and functional, as well as non-proliferative, or tumorgenic, he adds.  
Reprogramming cells is a method with a great deal of potential. Since the skin cells would come from each individual patient, they would contain a complete set of the genes that resulted in the individual's disease in the first place. Such samples would provide much more accurate human models for studying illnesses, testing drugs and determining the safety and efficacy of treatments, including neurological disorders.  
Dr. Stuart Lipton, who collaborated on this work with Ding, noted in a press release that the technology provides researchers the ability to "very rapidly model neurodegenerative diseases in a dish by making nerve cells from individual patients in just a matter of days—rather than the months required previously." Lipton directs the Del E. Webb Neuroscience, Aging and Stem Cell Research Center at Sanford-Burnham Medical Research Institute.  
"This work could have important ramifications for patients and families who suffer at the hands of neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease," Dr. Lennart Mucke, director of neurological research at Gladstone, added in a press release about the discovery. "Dr. Ding's latest research offers new hope for the process of developing medications for these diseases, as well as for the possibility of cell- replacement therapy to reduce the trauma of millions of people affected by these devastating and irreversible conditions."  
Ding says the next step for this research is to develop a more efficient method of reprogramming the cells, one that is scalable and "allows manufacture of these reprogrammed cells safely under GMP conditions." Researchers will also need to further study the process and test the cells in animal models to determine their safety and efficacy in vivo, he says, in addition to determining which diseases or injuries the reprogrammed cells are best suited for as potential treatments.  
The reprogrammed cells are not ready for transplantation, Ding noted in a press release, but this development "removes some of the major technical hurdles to using reprogrammed cells to create transplant-ready cells for a host of diseases."  
"I think with any early stage/breakthrough biomedical discovery, it will typically take at least 10 years to mature into safe medicine," says Ding. "But with the unprecedented pace in biomedical research, especially significant enthusiasm and investment in stem cell research and therapeutic development, it may take shorter to mature this type of technology."  
The research detailed in the paper, entitled "Direct Reprogramming of Adult Human Fibroblasts to Functional Neurons under Defined Conditions," was performed at The Scripps Research Institute. The authors of the paper include, in addition to Ding and Lipton, Rajesh Ambasudhan of the Department of Chemistry at Scripps and the Del E. Webb Center for Neuroscience, Aging and Stem Cell Research at Sanford-Burnham Medical Research Institute; Maria Talantova of the Del E. Webb Center; Ronald Coleman and Xu Yuan of the Department of Chemistry at Scripps; and Saiyong Zhu of the Department of Chemistry at Scripps and the Department of Pharmaceutical Chemistry at Gladstone.
Gladstone, which is affiliated with the University of California San Francisco (UCSF), is an independent biomedical-research organization that furthers its work in its three major areas of focus—neurodegenerative disease, cardiovascular disease and viral infections—through stem cell research.

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