Human Neurons from Skin Cells

By David Prentice

Editor’s note. The following appeared last week at Dr. Prentice’s great blog. The second part–the precursor to the good news at Stanford—is taken from an entry Dr. Prentice wrote last year.

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Dr. David Prentice

Scientists at Stanford report that they can turn human skin cells directly into functioning nerve cells in the lab dish. Last year this group showed that they could accomplish this direct conversion with mouse cells.

The process, called “direct reprogramming,” directly converts skin cells into neurons rather than first forming a stem cell. The new results, reported in the journal Nature, accomplished this conversion for the first time with human cells by adding four genes to skin cells. Other researchers have obtained similar direct conversion results in the formation of blood, heart, and insulin-secreting cells.

The direct conversion technique is similar in some respects to the method used to create induced pluripotent stem cells. iPS cells are created when genes are added to normal cells to convert them to stem cells that behave similarly to embryonic stem cells.

By contrast the scientists at Stanford added a few tissue-specific genes to a cell to target the conversion of that cell directly into another tissue type, rather than go through the intermediary step of turning first into a pluripotent stem cell. 

But pluripotent stem cells such as embryonic stem cells also have a significant risk of tumor formation. This out-of-control growth problem with pluripotent stem cells makes the direct conversion technique preferable when it comes to deriving new cells from normal cells. Likewise, using native adult stem cells is both safer and effective, e.g., in repair of stroke damage.

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Go Directly to Nerves, Do Not Pass Pluripotency

By David Prentice

A new report published online in Nature describes how Stanford scientists turned mouse skin cells directly into nerve cells, without any intermediate stem cell step. Starting with mouse skin cells in the lab dish, they added three nerve-specific genes using viruses. According to senior author Marius Wernig, the “induced neuronal cells” are fully functional.

“We actively and directly induced one cell type to become a completely different cell type. These are fully functional neurons. They can do all the principal things that neurons in the brain do. That includes making connections with and signaling to other nerve cells.”

Wernig’s group took a page from Dr. Shinya Yamanaka’s book in discovering the right mix of factors to add. [Dr. Yamanaka is credited with first showing how to add a few gene factors to any cell, to reprogram a normal cell into a stem cell.  Yamanaka discovered the successful mixture of a few factors by testing multiple combinations of different gene factor.]

Wernig’s group started with 19 genes expressed in neural tissue, testing various 5-gene and 3-gene sets until finally narrowing down to just three genes that worked to convert the skin fibroblasts to neurons. The change took a week with an efficiency of almost 20 percent, faster and better than the reprogramming seen with iPS cells. Wernig said:

“We were very surprised by both the timing and the efficiency. This is much more straightforward than going through iPS cells, and it’s likely to be a very viable alternative. That means reprogramming doesn’t only go backward, but can occur in any direction. If you extrapolate from this, you could probably turn any cell in your body into any other cell if you just know the right factors.”

Wernig and his colleagues are now trying to do the same direct reprogramming with human cells and Stanford has applied for a patent on the process.

In 2008, Doug Melton’s team at Harvard used a similar technique to directly reprogram adult mouse pancreas cells, turning them into insulin-secreting beta cells. That cell reprogramming was accomplished within the bodies of the mice by infecting their pancreas with viruses containing three transcription factors; the newly-formed beta cells could ameliorate hypoglycemia in the mice. In his Nature paper, Melton noted that the new direct reprogramming method

“suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.”

Commenting on the latest Stanford results, Melton thought it was a major advance because it used cells that could be easily obtained from a person, and takes a more direct route to changing cells than Yamanaka’s iPS cell method, which creates undifferentiated embryonic-like stem cells.

“Instead of trying to turn them back into pluripotent stem cells and then make those into differentiated cells, he’s short-circuiting that process and saying let’s go right from one readily available cell to another cell of interest.”

Perhaps the most significant fact is that the cells make the change without first becoming a pluripotent type of stem cell, like an embryonic stem cell. Given that pluripotent stem cells are notoriously difficult to control, bypassing that step with direct reprogramming becomes an extremely attractive method to transform cells

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