Going more than skin deep
Gladstone scientist successfully reprograms skin cells into brain cells
SAN FRANCISCO—A new development in the field of cellreprogramming might provide researchers with not only a safer method ofreprogramming 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, neuronsfully capable of transmitting brain signals. Ding's work, detailed in the July28 issue of Cell Stem Cell, builds onthe cell-reprogramming research of the study's senior investigator, Dr. Shinya Yamanaka, another scientist at Gladstone, who discovered a way to convert adultskin cells into cells that mimicked embryonic stem cells. Ding, a leadingchemical biologist in stem cell science, is a senior investigator at theGladstone Institute of Cardiovascular Disease and a University of CaliforniaSan Francisco (UCSF) professor of pharmaceutical chemistry.
For this experiment, Ding converted skin cells from a55-year-old woman into working brain cells using two genes and a microRNA, whichare strands of genetic material responsible for regulating cellular processesthroughout the entire body. The cells were capable of exchanging electricalimpulses as regular brain cells do to convey thoughts.
The process, Ding explains, begins with adult human skinfibroblast cells. The cells are grown in culture dishes, and when introducedwith a microRNA molecule and two genes, the cells' morphology changes within acouple weeks to form functional neurons. The use of microRNA rather than genemodification to reprogram cells is safer, and Ding hopes to use only microRNAsand pharmaceutical compounds to covert skin cells to brain cells in futureexperiments, something he says will help researchers avoid genomemodifications.
"The introduced molecules basically rewire the fibroblastcells' memory at the so-called epigenetic level," Ding explains, "and changethe cell fate/identity from fibroblasts to neurons."
Unlike pluripotent stem cells, the reprogrammed cells do notcarry with them a risk of tumor, since the "generated neurons come directlyfrom fibroblasts," skipping the pluripotent stem cell stage, says Ding. Theresulting cells are mature and functional, as well as non-proliferative, ortumorgenic, he adds.
Reprogramming cells is a method with a great deal ofpotential. Since the skin cells would come from each individual patient, theywould contain a complete set of the genes that resulted in the individual'sdisease in the first place. Such samples would provide much more accurate humanmodels for studying illnesses, testing drugs and determining the safety andefficacy of treatments, including neurological disorders.
Dr. Stuart Lipton, who collaborated on this workwith Ding, noted in a press release that the technology provides researchersthe ability to "very rapidly model neurodegenerative diseases in a dish bymaking nerve cells from individual patients in just a matter of days—ratherthan the months required previously." Lipton directs the Del E. WebbNeuroscience, Aging and Stem Cell Research Center at Sanford-Burnham MedicalResearch Institute.
"This work could have important ramifications for patientsand families who suffer at the hands of neurodegenerative diseases such asAlzheimer's, Parkinson's and Huntington's disease," Dr. Lennart Mucke, director of neurological research at Gladstone, added in a press release aboutthe discovery. "Dr. Ding's latest research offers new hope for the process ofdeveloping medications for these diseases, as well as for the possibility ofcell-replacement therapy to reduce the trauma of millions of people affected bythese devastating and irreversible conditions."
Ding says the next step for this research is to develop amore 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 inanimal models to determine their safety and efficacy in vivo, he says, in addition to determining which diseases orinjuries 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 majortechnical hurdles to using reprogrammed cells to create transplant-ready cellsfor a host of diseases."
"I think with any early stage/breakthrough biomedicaldiscovery, it will typically take at least 10 years to mature into safemedicine," says Ding. "But with the unprecedented pace in biomedical research,especially significant enthusiasm and investment in stem cell research andtherapeutic development, it may take shorter to mature this type oftechnology."
The research detailed in the paper, entitled "DirectReprogramming of Adult Human Fibroblasts to Functional Neurons under DefinedConditions," was performed at The Scripps Research Institute. The authors ofthe paper include, in addition to Ding and Lipton, Rajesh Ambasudhan of theDepartment 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 theDepartment of Chemistry at Scripps; and Saiyong Zhu of the Department ofChemistry at Scripps and the Department of Pharmaceutical Chemistry atGladstone.
Gladstone, which is affiliated with the University ofCalifornia San Francisco (UCSF), is an independent biomedical-researchorganization that furthers its work in its three major areas offocus—neurodegenerative disease, cardiovascular disease and viralinfections—through stem cell research.