Editors' ChoiceCellular Models of Disease

Neurons Are Only Skin Deep

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Science Translational Medicine  07 Sep 2011:
Vol. 3, Issue 99, pp. 99ec144
DOI: 10.1126/scitranslmed.3003138

One day, stem cells may provide replacement tissues and cures for a host of human diseases, but controversy around the use of embryonic stem cells in research has led to a search for alternative sources of pluripotent cells. In a new study, Qiang et al. report that human skin cells can be directly transformed into functional nerve cells.

Skin cells can be induced to form stem-like cells, known as induced pluripotent stem (iPS) cells. However, making iPS cells is not easy, because they have exceedingly low conversion rates and can show DNA alterations and tumorigenesis. By transfecting human fibroblasts from skin with the key transcription regulatory genes Ascl1, Brn2, Zic1, and Myt1, the researchers were able to bypass the iPS cell state and directly reprogram skin cells to neurons with a conversion rate of 85%. Gene expression profiling and electrophysiological testing demonstrated that the reprogrammed cells were phenotypically similar to neuronal cells. More important, after transplantation into the brains of embryonic mice, the new cells were functionally integrated into the mouse neural circuitry.

The researchers then repeated the experiment with skin cells from individuals with an inherited form of Alzheimer’s disease who carried mutations in the presenilin-1 (PSEN-1) or PSEN-2 genes. Although these cells also behaved like neurons, they differed significantly from those generated from healthy individuals. The Alzheimer’s neurons abnormally processed and localized the amyloid precursor protein (APP) and exhibited increased concentrations of amyloid-β, which is consistent with the neuropathology of Alzheimer’s disease.

These results point to numerous scientific and therapeutic opportunities: Easier access to disease-specific iPS cells will enable researchers to further delineate the underlying mechanisms that contribute to neurodegenerative disease, to examine potential therapeutic targets, and to investigate possible cell replacement therapies for conditions such as Alzheimer’s disease.

L. Qiang et al., Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons. Cell 146, 359–371 (2011). [Abstract]

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