How to make new neurons

By Bruce Lieberman
August 31, 2011

Imagine the ability to take skin cells from a patient with Alzheimer’s disease, convert them directly into brain cells, and then study how the disease progresses in those cells—which still contain the patient’s DNA—all in the lab, with minimal invasiveness on the part of the patient. Then imagine taking those same brain cells and testing novel but risky drugs that could cure the devastating disease—again, in the safety of a dish in the lab.

Researchers are on their way to achieving this remarkable milestone. Dr. Stuart Lipton at Sanford-Burnham, Dr. Sheng Ding at the Gladstone Institutes, and their collaborators recently figured out how to reprogram skin cells directly into functioning neurons. The study was published online July 28 in the journal Cell Stem Cell.

“This technology should allow us 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,” Dr. Lipton says in a statement released by the Gladstone Institutes.

The paper is one of several recent studies that are all zeroing in on a long-sought-after advance in stem cell science: the potential to obtain unlimited numbers of brain cells from an easily accessible tissue such as the skin.

The advance is important in part because it does not rely on human embryonic stem cells to study development and disease and test drugs. Stem cells are pluripotent—they have the ability to develop into almost any cell type in the body. Understanding the genetic signaling that drives this differentiation is at the heart of stem cell science. Now, many scientists are exploiting this knowledge to figure out how to essentially dial back the developmental clock, turning adult cells into a type of stem cell called an induced pluripotent stem (iPS) cells, then coaxing the iPS cells into the desired cell type (such as neurons).

In this study, the team skipped the iPS cell middleman, converting one type of adult cell directly into  another. This new approach, which begins with a patient’s own cells rather than a foreign stem cell, could lead to highly personalized medicine because it generates cells that still contain an individual’s own genetic and environmental history.

Dr. Lipton, Dr. Ding, and others had previously created large numbers of neural stem cells, which differentiate into many different types of brain cells, from human embryonic stem cells. In another paper, the team converted mouse skin cells directly into neural stem cells. This new study takes the work a step further by converting human skin cells directly into functioning adult neurons—in only a few days.

Dr. Lipton, Dr. Ding, and their colleagues took skin cells from a 55-year-old woman and inserted a combination of just two transcription factors and one microRNA. Transcription factors switch genes off and on to control which proteins are made (or not made), depending on the cell type and what it needs at that particular time. MicroRNAs are small strands of genetic material that also influence protein production. In this case, the researchers used one particular microRNA called miR-124, which is known to play a key role in neuronal development.

After exposure to this unique cocktail of transcription factors and miR-124, the reprogrammed skin cells looked like typical neurons, expressed genes that are typically activated in neurons, and displayed mature functional synapses—first steps in re-creating personalized models of Alzheimer’s disease and other neurological disorders in the laboratory.

Original paper:
Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton SA, & Ding S (2011). Direct Reprogramming of Adult Human Fibroblasts to Functional Neurons under Defined Conditions. Cell stem cell, 9 (2), 113-8 PMID: 21802386

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