“Transdifferentiation” refers to the conversion of adult cells that are already committed to a particular cell fate to another cell fate. Transdifferentiation is an alternative to the cellular reprogramming that involves converting a mature cell into a pluripotent stem cell — one capable of becoming many types of cell — then coaxing the pluripotent cell into becoming a particular type of cell, such as neurons. In the past year, scientists have been able to convert connective tissue-specific cells called fibroblasts into heart cells (Ieda, M. et al. Cell 142, 375-386 (2010)), blood cells (Szabo, E. et al. Nature 468, 521-526 (2010)), and liver cells (Huang, P. et al. Nature advance online publication doi:10.1038/nature10116 (2011)). Clearly transdifferentiation is a very fast-moving field.
Now researchers have succeeded in converting fibroblasts into neurons, the cells that are responsible for the conduction of nerve impulses. This might generate a model system for nervous-system diseases and even regenerative therapies based on cell transplants.
Stanford University stem-cell researcher Marius Wernig, says that skipping the pluripotency step could avoid some of the problems of making tissues from induced pluripotent stem cells (iPSCs). Also, making iPSCs can also take months to complete. Wernig’s team sparked the imaginations of stem cell scientists last year when he and his research team managed to convert adult mouse cells into iPSCs in only two weeks (Vierbuchen, T. et al. Nature 463, 1035-1041 (2010)). That feat took just three foreign genes that were delivered into tail cells with a virus. “We thought that as it worked so great for the mouse, it should be no problem to work it out in humans,” Wernig says. “That turned out to be wrong.”
Instead those three genes also made human cells that looked like nerve cells but did not fire the electric pulses characteristic of neurons. However, the addition of a fourth virus-delivered gene, found through trial and error, pushed fibroblast cells to become bona fide neurons. After a couple of weeks in culture, many of the neurons responded to electric jolts by pumping ions across their membranes. A few weeks later still, these neurons started to form connections, or synapses, with the mouse neurons they were grown alongside.
This transdifferentiation procedure is rather inefficient. Only 2–4% of the treated fibroblasts became neurons. This is lower than the ~8% efficiency achieved with the mouse tail cells. Also most of the resulting neurons communicated using a chemical called glutamate, which limits their use for understanding or treating neurodegenerative diseases. Given all these caveats, Wernig admits that there are still kinks to work out. However, he and his team are trying to improve the efficiency of transdifferentiation and also to make neurons that communicate using other chemicals.
Evan Snyder, a stem-cell biologist at the Sanford Burnham Medical Research Institute in San Diego, California stated that neurons forged through transdifferentation offer advantages over brain cells made from iPSCs. In addition to being made more quickly, they are less likely to form tumors when they implanted into tissue. There are disadvantages, however. The signs of disease usually appear when a cell develops naturally, from a pluripotent stem cell into a differentiated neuron. Forcing a cell into becoming a neuron could cause scientists to miss aspects of a disease. Also fibroblasts that are the starting material for transdifferentiation do not divide as readily as iPSCs, which limits their use in applications that require lots of cells, such as drug screening, according to Wernig.