Blood from stem cells?

Blood has been among the most sought after and hardest to achieve tissue that CIRM grantees are attempting to derive from embryonic stem cells. It's an obvious target. The medical system needs a constant influx of blood, which comes entirely from volunteer donors. Creating that blood in an unlimited supply from human embryonic stem cells would significantly ease concerns about blood shortages at hospitals. We blogged about a Los Angeles Times story last January that discussed the value of this type of work.

The National Blood Data Resource Center has this to say about how much blood was used in 2001:

U.S. hospitals transfused nearly 14 million units of whole blood and red blood cells to 4.9 million patients in 2001 - that's an average of 38,000 units of blood needed on any given day.

Given those needs, the findings in a Nature paper by CIRM grantee David Traver at the University of California, San Diego could prove helpful. He and his team have discovered a gene called Wnt16 that, in the lab animal zebrafish, is key to the animal eventually developing a pool of hematopoietic stem cells, which are the source of all blood in the body.

In a press release from UCSD Traver said:

“What we need is the ability to generate self-renewing [human embryonic stem cells] from patients for treatments. But accomplishing this goal means first understanding the mechanisms involved in creating HSCs during embryonic development.”

Traver's work follow that of another CIRM grantee Inder Verma of the Salk Institute, who last month published a protocol for creating blood-forming progenitor cells from human embryonic stem cells and reprogrammed iPS cells. Discussing this work in his monthly stem cell research update, CIRM President Alan Trounson wrote:

Many more cancer and blood disorder patients could benefit from stem cell transplants if large numbers of blood forming stem cells could be grown in the laboratory. Because mature hematopoietic stem cells (HSCs) don’t expand well in culture, researchers have been trying to grow these cells from pluripotent stem cells, both embryonic stem cells and reprogrammed iPS cells. Most of these attempts have generated very low numbers of bone marrow colonizing blood precursors, and none have shown robust generation of transplantable HSCs. Now, Verma’s team has shown that with five iPS cells lines and two embryonic lines that they can efficiently generate precursors and progenitors of HSCs.

This work brings up another point often made by CIRM grantee Paul Knoepfler at the University of California, Davis. In his blog and in the Sacramento Bee Knoepfler has argued that supporting stem cell research is a matter of national security. Soldiers wounded on the battlefield need a source of blood for transfusions. Knoepfler wrote in his Sacramento Bee Op-Ed:

I hope that in the future stem cell research can perhaps slightly lessen the burden on our servicepeople and their families through technologies to save the lives of wounded soldiers.

Nature, June 9, 2011
CIRM funding: David Traver (RN1-00575-1)

A.A.

iPS cell smack down

Pity the iPS cell -- it's had quite a ride this year. On the upside, cells reprogrammed from people with autism, Parkinson's disease and schizophrenia were used to create the first ever models of those diseases in a dish. Those models could provide a way of testing drugs on actual human cells. That's good.

But in the same year, a number of studies found significant genetic differences between reprogrammed iPS cells and their embryonic counterparts (here's our blog entry). Today, a paper published in Nature by CIRM grantee Yang Xu at the University of California, San Diego found that the cells can also be rejected by the body.

This finding is a bit of a blow. When Shinya Yamanaka and colleagues first reprogrammed human skin to an embryonic-like state in 2007 the stem cell world was aflutter. These cells were seen by some as a possible replacement for embryonic stem cells, with the advantage that because they could be generated from a person's own skin they would be genetically identical and not get rejected by the immune system.

It turns out the immune system is smarter than that, at least in mice. The mice were able to detect and subsequently reject genetically identical iPS cells.

A New York Times story quotes George Daley of Boston Children's Hospital:

“As with any new technology, there is always this initial phase of infatuation, and then the reality sets in,” said Dr. George Q. Daley, director of the stem cell transplantation program at Children’s Hospital Boston. “I think it goes to the heart of the issue of how ignorant we really are in understanding these cells.”

Apparently what made the cells visible to the immune system were the genes that were activated in order to reprogram the cells. The immune reaction varied depending on how the cells were made. This work isn't exactly the death knell for iPS cells, but it does mean that the path to the clinic could be a tricky one.

May 13, Nature
CIRM Funding: Yang Xu (TR1-01277)

A.A.

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.

Reducing teratoma risk from transplanted stem cells

By Paul Knoepfler

The two most serious obstacles to regenerative medicine therapies are potential immune rejection of transplanted cells and the possibility that such cells could form a type of tumor called teratoma.

CIRM grant recipient and professor of Biology at UC San Diego, Yang Xu, is tackling both of these hurdles. He and his colleagues have recently discovered a method to reduce the ability of embryonic stem cells to form teratoma. The approach involves interfering with the function of a key gene, called Nanog, that is involved in maintaining stem cells. Nanog is one of several genes known as plurpotency factors, which work together to keep cells in their embryonic state.

The paper describing this work, entitled “Phosphorylation stabilizes Nanog by promoting its interaction with Pin1”, was published this week in the Proceedings of the National Academies of Science. Xu and colleagues found that by inhibiting Nanog function in stem cells, those cells still formed teratoma, but they were only about one-third the size of tumors that formed by control cells.

Xu was quoted in a press release by UCSD as saying the method is only partially effective because “we are targeting only one pathway” and he speculates that targeting multiple pathways simultaneously might provide a more robust inhibition of teratoma formation.

Some important unanswered questions remain. Would inhibition of any key pluripotency factor, for example Oct3, produce the same effect? Are cells with reduced levels of pluripotency factors still able to give rise to normal differentiated cells of diverse types and in sufficient numbers to be useful for therapies? Could a similar effect be achieved by withdrawing growth factors, such as removing LIF from the media of mouse stem cells or FGF from the media of human stem cells?

Despite these remaining gaps in our understanding, this study provides an exciting foundation for improving the safety of regenerative medicine therapies, any area in the stem field that requires more attention.



PNAS, July 5, 2010
CIRM Funding: Yang Xu (RC1-00148)

Paul Knoepfler is assistant professor of Cell Biology and Human Anatomy at UC Davis School of Medicine. He publishes a blog about stem cell research.

Protein protects brain from damage, may prevent neurodegenerative diseases

Researchers at the University of California, San Diego and the Salk Institute for Biological Studies have found a protein that protects the brain from the kind of damage that can lead to Parkinson's disease. This protein, called Nurr1, has a long history in Parkinson's disease research. People who carry a mutation in the gene are prone to developing the disease. The new work explains how the protein prevents Parkinson's disease and could also help researchers find ways of treating of preventing the disease. The protein was especially important in two types of cells that protect and support the brain's neurons -- called microglia and astrocytes. In these cells, Nurr1 works with other proteins to limit inflammation after an immune response. Without it, these support cells produced toxic by-products that damaged the nerves in a way that could lead to Parkinson's disease or other neurodegenerative diseases.

Cell: April 3, 2009
CIRM funding: Beate Winner and Fred H. Gage (RC1-00115), Christian Carson (T3-00007), Leah Boyer (T1-00003)

Related Information: Press release, University of California, San Diego, Salk Institute for Biological Studies, Gage bio

Protein in Pancreas May Lead to New Therapy for Type II Diabetes

Researchers at the Burnham Institute for Medical Research and the University of California, San Diego have found parallels between how the pancreas develops in the embryo and type II diabetes (also known as adult diabetes). When the pancreas develops in an embryo, a protein called Wnt (pronounced “wint) helps control how the cells mature into insulin-producing cells. In most adults, the pancreas contains very little Wnt protein, but in people with type II diabetes Wnt protein is abundant in the pancreas. The authors suggest that Wnt could be a target for new type II diabetes therapies.

Experimental Diabetes Research: January 20, 2009
CIRM funding: Seung-Hee Lee (T2-00004), Carla Demeterco (T2-00003)

Related Information: Press Release, Burnham Institute for Medical Research

Genetic Profile Distinguishes Types of Stem Cells

Researchers at the The Scripps Research Institute found a new way of classifying the many cell types that fall under the category of “stem cells.” The term stem cell refers to tissue specific stem cells found in mature tissues such as blood, brain, or muscle, which are restricted to forming only cells found in those tissues, as well as to embryonic stem cells that are broadly able to form all cells of the body. The term is also used to refer to the so-called induced pluripotent stem (iPS) cells that scientists can now create out of adult skin cell and that mimic embryonic stem cells in their ability to form a variety of cell types. In this work, the researchers discovered a set of genes that are always active in the pluripotent cells – whether they were iPS cells or embryonic stem cells. As more stem cell populations become available, the gene profile discovered in this study will help researchers distinguish those cells that are truly pluripotent from those that are more restricted in the cell types they are able to form.

Nature: September 18, 2008
CIRM funding: Louise Laurent (T1-00003)

Related Information: Scripps news story, The Scripps Research Institute

Fly Stem Cells Create their Home

Researchers at the Salk Institute of Biological Studies discovered that stem cells in the testes of fruit flies are able to generate their own support cells. This work in flies could help guide researchers hoping to understand the environment surrounding resident populations of human stem cells - called the niche. The niche is difficult to study in humans but is an area of great interest because any therapy based on transplanting stem cells into a tissue will require those cells to be paced in a niche where they will thrive. This work raises the possibility that some transplanted stem cells may be able to produce their own niche.

Nature: July 20, 2008
CIRM funding: Justin Voog (T1-00003)

Related Information: Salk press release, Salk Institute for Biological Studies

Pattern of Small Genetic Factors Found to Characterize Embryonic Stem Cells

Researchers at The Scripps Research Institute discovered that human embryonic stem cells have a very specific signature when it comes to the regulators of their genes. MicroRNAs are very small, naturally occurring bits of genetic material. They don't code for specific proteins like genes do, but they regulate the activity of genes and turn on and off their protein production. In embryonic stem cells microRNAs are actively preventing the production of proteins that tell cells to differentiate into specific heart or bone tissue, for example, but are pushing hard on genes that result in self-renewal. The team hopes to use these microRNAs to reprogram any type of cell to become as pluripotent as embryonic stem cells and to do it more safely than current reprogramming called iPS.

Stem Cells: June, 2008
CIRM funding: Louise Laurent (T1-00003)

Related Information: Press release , The Scripps Research Institute

First clinical Trial Begins for a Therapy Enabled By CIRM Funding

Researchers at UC, San Diego verified a suspect gene mutation in blood-forming stem cells was by itself necessary and sufficient to cause a class of severe blood diseases called myeloproliferative disorders. They then worked with a team of researchers from other academic institutions and from the San Diego pharmaceutical company TargeGen to conduct animal tests of a compound TargeGen had already isolated and shown to inhibit that same genetic pathway. As a result of this broad collaboration, human clinical trials for this potential therapy began in February, 2008.



CIRM funding: Catriona Jamieson

Related Information: UC San Diego press release, UCSD Stem Cell Initiative

Key Protein Involved in Forming Nuclear Membrane after Division Found

Researchers at UC, San Diego found the function of a key protein involved in the cell cycle, the process by which a cell duplicates all its genes and divides. The protein is critical to the assembly of the membrane around the cell's nucleus. A fundamental understanding of the cell cycle is integral to advancing all cell-based therapies.

Proceedings of the National Academy of Sciences: April 17, 2007
CIRM funding: Youngjun Kim (T1-00003)

Related Information: UCSD Stem Cell Initiative