CIRM grantees directly create neuronal stem cells for research and therapies

CIRM grantees at the Scripps Research Institute, University of California, San Diego and Sanford-Burnham Research Institute have taken an intriguing step toward producing neural progenitor cells for research or therapies. The team, led by Sheng Ding who has recently moved to the Gladstone Institutes in San Francisco, started with mouse skin cells and converted them directly to an early stage of neural cell. The work was published in the April 26 online issue of Proceedings of the National Academy of Sciences.

This work falls somewhere between two other pieces of research starting with skin cells. Since 2006 it has been possible to convert mouse skin cells into reprogrammed iPS cells that are similar to embryonic stem cells in their ability to create all cell types. Scientists could then mature those cells into whatever cell type they are interested in studying.

Over the past year, other groups have started with skin and converted those cells directly to neurons or heart cells.

Ding and his colleagues fall somewhere in the middle, sidestepping some issues with both direct reprogramming and generating iPS cells.

• Converting skin directly into neurons has the major limitation that neurons can't divide. The number of neuronal cells available for research or therapies is limited by the number of starting skin cells.
• Going all the way back to iPS cells has limitations of its own. The cells multiply in a lab dish to create as many cells as a scientist might need for therapies or research uses, but maturing those cells into the appropriate cell type can be an arduous task any traces of the original iPS cells could lead to tumors.

Converting skin to these neural precursors avoids both problems. Those neural cells are already pushed down the pathway to become neurons, and they can multiply. The researchers also showed that the cells can integrate into a mouse brain without developing tumors.
In a press release from the Gladstone Institutes, Ding says:

“These cells are not ready yet for transplantation,” Dr. Ding said. “But this work removes some of the major technical hurdles to using embryonic stem cells and iPS cells to create transplant-ready cells for a host of diseases.”

That's all good, but the work is a long way from ending the need for iPS cells. First, it's in mice. There's no evidence yet that the protocol will work with human cells. Also, the resulting neural progenitors can only divide a few times, so they aren't an unlimited source of cells.

Those caveats aside, it's exciting to watch how quickly the field is evolving. Not long ago, the idea of converting one cell type into another was nothing but a dream. Now, scientists (many of them CIRM grantees) are finding ever more ingenious ways of converting skin, fat and other starting tissues into embryonic-like stem cells, adult cell types, and now in-between progenitors, each of which could be useful in their own way for understanding and treating disease.

PNAS, April 26, 2011
CIRM Funding: Sheng Ding (RN1-00536-1); Stuart Lipton (RC1-00125-1); Maria Talantova (T2-00004)

- A.A.

Skin cells to beating heart cells in just 11 days

(Comment: it appears that we already blogged about this study back in February. It's interesting work, though, so this second blog entry gets to remain.)

CIRM grantee Sheng Ding at Scripps Research Institute has converted mouse skin cells into beating heart cells. If this sounds familiar, it's because Deepak Srivastava at the Gladstone Institute for Cardiovascular Disease did something similar last year, but there are a few key differences.

• Ding worked with skin cells whereas Srivastava worked with cells from the heart.
• Srivastava used a group of heart-related factors to push the cells directly into becoming heart tissue. By contrast Ding began by directing the skin cells to become reprogrammed iPS cells, then did a quick change and drove those partially reprogrammed cells to become heart.

The biggest difference is in speed and efficiency. Ding's approach produced beating heart cells in 11-12 days as opposed to 4-5 weeks, and produced those cells in much higher numbers.

In his Nature Cell Biology paper, Ding did point out a few flaws with his approach. First, they need to figure out how to achieve the conversion using transient factors rather than with permanent genetic modifications. Because when it comes to therapies in humans, permanent changes to the DNA — especially with know cancer-causing genes — are frowned upon. They also need to test whether the beating cells can still function when transplanted and don't cause tumors.

Despite these hurdles, Ding and his team say their approach could be effective for a wide variety of cell types. The initial step of partially reprograming the cells would be universal, then it's just a matter of finding which factors push the partially naïve cells to form a new cell type.

In a press release, Scripps Research Institute quotes Ding as saying:

“This work represents a new paradigm in stem cell reprogramming. We hope it helps overcome major safety and other technical hurdles currently associated with some types of stem cell therapies.”

This latest paper is one more indication that it could be possible to switch one type of cell into another as a way of repairing tissue damage. However, as with so much in the field of stem cell biology and regenerative medicine, how that approach fits in with ongoing research using adult, embryonic or iPS cells is still anyone's guess.

CIRM funding: Sheng Ding (RN1-00536-1)
Nature Cell Biology, January 30, 2011

- A.A.

Skin cells become beating heart cells in a lab dish

Scripps Research scientists have
created mature heart muscle cells
directly from skin cells.

Eventually, directly reprogramming one type of adult cell into another is going to be old news. For now, the entire field is new enough that each time scientists pluck one adult cell type and coerce it to become another, it’s exciting.

The most recent example comes from CIRM grantees at Scripps Research Institute, who converted mouse skin cells into beating heart cells in just 11 days. A press release quotes senior author Sheng Ding:

“It is like launching a rocket," he said. "Until now, people thought you needed to first land the rocket on the moon and then from there you could go to other planets. But here we show that just after the launch you can redirect the rocket to another planet without having to first go to the moon. This is a totally new paradigm.”

Since 2006, scientists have been able to convert skin cells into embryonic-like iPS cells, which they could then mature into different cell types including heart. Directly converting skin to heart saves time, and could result in more effective therapies. According to the Scripps press release:

When, for example, scientists induce iPS cells to become heart cells, the resulting cells are a mix of heart cells and some lingering iPS cells. Scientists are concerned that giving these new heart cells (along with the remaining pluripotent cells) to patients might be dangerous. When pluripotent cells are injected in mice, they cause cancer-like growths.

Other CIRM grantees who have succeed in direct reprogramming include Marius Wernig at Stanford, who converted skin to nerve, and Deepak Srivastava, who converted heart fibroblasts into heart muscle cells.


Nature Cell Biology, January 30, 2011
CIRM funding: Sheng Ding (RN1-00536-1)

- A.A.