Movies on Nature Reports Stem Cells
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Archive by date: July 2008
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Cell fate: Instead of ‘transdifferentiated’ or `reprogrammed’, try `converted’
In our write-up of the last ISSCR meeting, Natalie DeWitt and I described Thomas Graf’s, Doug Melton’s, and others’ work to change cell fate. We asked people to weigh in on preferred terms.
Graf sent us this thoughtful response:
Dear Monya, Dear Natalie,
I would like to comment on the issue that you brought up in the last edition of Nature Report Stem Cells.
‘Are the terms reprogramming or trans-differentiation appropriate in describing the transition from one differentiated cell type into another? Should another term be used instead? ‘
In my opinion, this discussion comes too early. We simply don't know enough about what happens when a differentiated cells acquires a new fate. If, unlike during induction of iPS cell formation, the cells directly transit from one phenotype into another probably a term other than 'reprogramming' would be more appropriate. Indeed, the frequency and timing by which transcription factor induced lineage conversions can be observed makes it unlikely that the cells transiently acquire an ES like state. However, it is still possible that when one lineage turns into another the cells go back to the stage of a common precursor before they re-commit. If this would be the case- should it be called 'reprogramming'? The other possibility is that we will increasingly see induced cell fate conversions in which the new phenotypes generated only partially recapitulate known stages of differentiation. Would it make sense to coin different terms to distinguish these diverse processes?
For the time being the non committal term 'conversion' seems appropriate in all instances that do not involve iPS cell reprogramming.
Thomas Graf
Center for Genomic Regulation, CRG
Carrer Dr. Aiguader 88
E 08003 Barcelona
Spain
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Web round-up: Stem cell business news
Shortly after the announcement that stem-cell pioneer (and promoter) Advanced Cell Technology was going broke, a venture capital firm has announced that it is looking for investors to pour $225 million dollars into the technology. Here’s the story in the San Francisco Business Times. The firm, Proteus Ventures, is no stranger to stem cell endeavors, including making investments in Saudi Arabia. (See Gulf states embrace stem cell technologies at home and abroad .)
Big pharma has also backed stem cell research, with the latest announcement of a five-year $25 million deal between GSK and Harvard. For the most part, drug companies have been interested in using embryonic stem cells for drug screening (See New tools for drug screening), but Pfizer has made a tiny investment in a cell-therapy startup as well.
And finally, adult-stem cell company Osiris has raised some money for future stem-cell products by selling its current one. The product, Osteocel, is currently sold not as a drug but as a surgical product, which does not have to meet the FDA requirements for an approved drug or cell therapy. According to the Baltimore Sun, Osiris has sold its stem-cell product Osteocel for $137 million and plans to use the money to finance development of biologic products as well as mesenchymal stem cells. These are in clinical trials for heart failure and graft versus heart disease (See Questioning the self cell and Stem cells for the heart, a new wave of clinical trials ).
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Some NIH Registry Lines Fall Outside Informed Consent Guidelines
UPDATE: When reporting this last week, I was told that Stanford had made a decision to disallow certain lines but had not announced it. On Monday, I received a note that Stanford had not reached a final decision. Please see the end of the blog for this full notice.
Research oversight committees across the country will need to rethink what experiments they will allow on human embryonic stem cell lines, following revelations that several lines eligible for federal funding do not meet standards of informed consent. Stanford University has decided not to allow experiments to be conducted on five of the 21 lines approved for federal funding, according to some prvy to the school's oversight committee. The official announcement should come once affected scientists have been notified.
The analysis follows research by University of Wisconsin bioethicist Robert Strieffer, who published his analysis of informed consent forms in the Hastings Center Report this May. In 2001, President George Bush declared that federal monies could only be used to support research on embryonic stem cell lines that had been derived before his declaration and that came from donated embryos originally created for reproduction.
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Ian Wilmut's move from cloning: getting practical with iPS
The scientist that helped clone Dolly the sheep has moved away from cloning and toward making embryonic-like stem cells without eggs. The shift is described in an article and interview in Scientific American. Wilmut (and others) think that iPS cells might one day replace ES cells for clinical applications and drug-testing applications, but no one thinks that day is now here. Bits of the SciAm articles are floating around the blogosphere, but these (willfully?) strip away some of the nuances, so it’s worth reading the full articles from the source. I also think that the article conflated and neglected a few ideas, which I’ll outline below.
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Fly guts and lessons for humans
Here's an account of a recent Nature paper. This will be an official article on Nature Reports on July 24.
Stretched out to its full length, your small intestine would be about five metres taller than you. It would take some 7,000 fruit flies, each standing on top of another, to reach that height.
That image is not quite as odd as it seems. Work led by Volker Hartenstein at the University of California, Los Angeles, shows that cell development within the hindgut of Drosophila is strikingly similar to that within the crypts and villi of the mammalian gut. Indeed, even the movement and differentiation of stem cells in the fly hindgut seem to mirror those seen within villi, the finger-like projections lining the small intestine. Thus, Drosophila could become a powerful model organism for studying this stem cell system.
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Advanced Cell Technology going broke
News reports today say that embryonic-stem cell company Advanced Cell Technology is running out of money and won't be able to keep up its operations past the end of the month. The company is well known for its efforts to clone human embryonic stem cells and also for its efforts use embryonic stem cells to treat blindness.
Here’s the story as first reported in the Boston Globe.
Though often accused of hype, ACT has been considered one of the leaders in bringing embryonic-stem cell derived cells to the clinic. In April this year, it was one of only three companies asked to testify to the FDA about ways to safely test embryonic-stem-cell products in patients. (See my account of the questions raised and an overview from that meeting.)
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Head of California stem cell institute resigns from advocacy group
UPDATE: Since I wrote this, Americans for Cures contacted me to say that Bob Klein will remain on the board of the organization but has resigned from the presidency.
The head of California’s stem cell funding agency has resigned from the presidency of a stem-cell advocacy group, according to a public interest group that monitors the government agency . Consumer Watchdog, a non-profit taxpayer advocacy group, has repeatedly denounced Robert Klein, the chair of the governing board of the California Institute of Regenerative Medicine (CIRM), for conflicts of interest.
In 2004, Klein largely drafted and campaigned for Proposition 71, the legislation that led to the creation of CIRM, which is funded through $3 billion in state bonds to promote stem-cell research. Since then, Klein, a real-estate developer, has headed the boards both for CIRM and for the Americans for Cures Foundation, a stem-cell research advocacy group.
Consumer Watchdog’s John Simpson called for Klein’s resignation from either group after Americans for Cures derided a state legislator. Americans for Cures lambasted Senator Sheila Kuehl for sponsoring a bill that could limit the prices that CIRM-funded companies could charge for therapies. Advocates of SB 1565 say the legislation will ensure access to medical benefits from stem-cell research; critics believe it will discourage companies from developing cures. This has been chronicled extensively in the blog, California Stem Cells Report, which reports that both Klein and Americans for Cures have apologized. (See posts from July 10 to July 15.)
Staff at Americans for Cures would not officially confirm or deny that Klein had left the organization, nor would the group’s vice president for public policy, Don Reed. However, Reed did imply that the research-advocacy group would soon have a new president. “Bob is the flame of our faith, but he has to face the reality that he has so much work to do,” he said.
The most recent flap is not the first time that Simpson has called on Klein to resign. In November last year, Simpson said Klein demonstrated extremely poor judgment by encouraging John Reed, president of the Burnham Institute and a CIRM board member, to speak with CIRM staff when a Burnham researcher’s grant was denied.
(See my account of the incident here )
CIRM is an unprecedented organization with an unusual governing structure. Coverage of the agency by Nature and Nature Reports Stem Cell is nicely summed up at this posting on the Niche.
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Cell papers: purified skeletal muscles help mice; packaging DNA for pluripotency
There are a couple cool stem cell papers in this month’s Cell.
Using a screen of chromatin regulating proteins in embryonic stem cells, UCSF’s Barbara Panning discovers something surprising. (See below)
Also see another cool article by Amy Wagers at Harvard, where her team was able to identify skeletal stem cells from look-alike cells and then show that these stem cells could rescue the phenotype of a mouse model of muscular dystrophy. It was written up in the Washington Post. and ScienceNews.
Packaging DNA for pluripotency
An RNA interference screen reveals a surprising player
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Two ways to leave your lab on someone else’s dime
Here are a couple grant opportunities to spend some time in another institution’s lab studying stem cells.
CIRM’s “bridges” award works only for folks in California. It funds internships for undergraduates and Master’s level students at for-profit companies and academic institutions. Funds totaling $18 million will be awarded to 10 California institutions, where they will cover a program director, ten interns a year, and other activities. Letters of intent are due on July 31. It’s available to accredited academic institutions that didn’t get CIRM’s shared laboratory grants. More details are available at CIRM.
(BTW: There’s also $48 million coming in funds for CIRM trainee grants, which are geared for more specialized young scientists for one to three years. It’s similar to the NIH program; letters of intent are due at the end of July.)
Another award will foster collaborations between the United Kingdom and the U.S. It pays up to 5000 pounds ($10,000 dollars) for travel and expenses. The funding is primarily available for group leaders and principal investigators, but “exceptional” postdocs will be considered. (All awardees have to fly economy class) Funds are being offered through the British consulate in San Francisco, but scientists based in anywhere in the US or the UK can apply. (I looked for and didn’t find eligibility requirements based on citizenship. Let me know if I missed something.) You need to apply by September 14th for notification on October 14th, and your travel needs to be concluded by February.
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Growing blood in a dish; using stem cells to screen for breast cancer
Below is a summary of a couple Cell Stem Cell papers that offer map-fragments to one of stem cells Holy Grails: culturing the cells that give rise to blood. This could lead to more broadly applicable alternatives to treatments that now use cord blood or bone marrow transplants. This will become a formal highlight next week.
Also, an article published yesterday in Nature Medicine shows how embryonic stem cells can be used to evauluate mutations implicated in breast cancer.
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Developing a way to reliably produce hematopoietic stem cells (HSCs) is a bloody tough problem. Unlike most tissues, cells of the hematopoietic system emerge from several embryonic sites and then circulate through the body. This mobility has perplexed researchers who hope that mimicking the in vivo environment will help them culture HSCs. Now though, two British research teams report complementary techniques for isolating HSCs in Cell Stem Cell. These could form the lifeblood of techniques creating easier alternatives to bone marrow transplantation.
Alexander Medvinsky and his colleagues at the University of Edinburgh went straight to the heart of HSC development — the aorta-gonad-mesonephros (AGM) region, where the first multipotent HSCs are thought to arise in the embryo. By dissociating and reconstructing the mouse AGM's three-dimensional structure, they developed a new method to expand and track the development of HSCs, and tracked down a population of cells containing markers (VE-cadherin and CD45) generally found on separate types of cells1.
"Medvinsky characterized a cell that's wearing two hats: It's an endothelial cell and a blood cell," says M. William Lensch, of Children's Hospital Boston and the Harvard Medical School. "When you see a cell like this, it lends credibility that they develop directly from the vasculature," rather than from elsewhere in the developing embryo.
Medvinsky’s population of cells contained one marker associated with the inner lining of blood vessels and another specific to blood cells themselves, and he thought that these cells might constitute “pre-HSC” progenitors capable of acquiring stem cell function. Indeed, when he injected the VE-cadherin+CD45+ cells in irradiated mice, they rapidly developed into a large pool of definitive HSCs that that restored hematopoiesis. Since these cells mature within the AGM microenvironment, this constitutes an active niche that drives the specification of fully mature HSCs, says Medvinsky.
Rather than trying to isolate HSCs directly, a team led by Majlinda Lako of Newcastle University developed a relatively efficient way of coaxing hematopoietic differentiation from human embryonic stem cells (hESCs). They co-cultured hESCs with AGM-derived stromal cell lines, and found that hematopoietic activity increased at least 31-fold compared to previous co-culturing methods2. They then injected the induced-hESCs into the femurs of immunocompromised mice, and found substantially greater engraftment efficiencies than previously reported — up to 16% for cells co-cultured with the best cell line. Finally, Lako’s group screened around 40 signaling molecules for positive enhancers of hematopoietic differentiation, and flagged the transcription factors TGF-β1 and TGF-β3 as the most efficient inducers of hematopoiesis.
Together, the studies show that nascent cells must mature within the proper context to become definitive HSCs, regardless of whether you start with pre-HSCs or hESCs, says Hanna Mikkola, of the University of California, Los Angeles. “The message from both papers is you really need to have the correct embryonic environment for functional maturation in culture.”
The question of how that maturation occurs remains unanswered. The TGF family members identified by Lako are probably involved, Mikkola says, but she doubts these factors tell the whole story. Lako agrees. As a follow-up, Lako's group is currently sifting through a library of other candidate factors, including calcium signaling molecules and insulin-like growth factors, for other key regulators of HSC development.
Lako’s results are impressive, says Medvinsky. But he thinks that co-culturing hESCs with his VE-cadherin+CD45+ cells could be even more successful. “With our system we might be able to produce a better outcome.” Lako, however, suspects her stromal cell lines may already contain some of Medvinsky’s “niche” factors. “It’s very likely that we’re using the same signals to induce our human ES cells,” she says. In either case, both authors recognize that more work will be needed to nail down the molecular cues before fully transplantable HSCs can be cultured. "Because you can do this all in a lab dish now, you have the ability to really focus on what the molecules are," notes Lensch. These two studies now inject new blood into achieving that goal.
References
1. Taoudi, S. et al. Extensive hematopoietic stem cell generation in the AGM region via maturation of VE-cadherin+CD45+ pre-definitive HSCs. Cell Stem Cell 3: 99–108 (July 2008).
2. Ledran, M.H. et al. Efficient hematopoietic differentiation of human embryonic stem cells on stromal cells derived from hematopoietic niches. Cell Stem Cell 3: 85–98 (July 2008).
Author affiliation
Elie Dolgin is a Canadian science writer currently residing in Milwaukee, Wisconsin.
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What got funded: statistics on California’s new stem cell line grants
The California scientists most likely to receive state grants for making new cell lines were those who proposed comparing embryonic stem cell lines and induced pluripotent stem (iPS) cell lines. Overall, thirty-two percent of all grant applications (16 of 50) were funded. Four of the five grants that proposed comparisons got funds. The unfunded grant application crossed into less favored categories, as it also proposed making lines from parthenotes and through nuclear transfer. None of the grant applications that sought to make cell lines using human oocytes were funded. Two proposed cloning through nuclear transfer, one proposed stimulating unfertilized eggs to divide into parthenotes, and one application proposed using both methods.
Success rates for grants proposing the derivation of only ES or only iPS cells were each 33%, but there were twice as many grants for iPS cells. That’s astounding considering that the grant program was announced in October 2007, a month before the first publications that human cells could be successfully reprogrammed.
Four proposals to make pluripotent lines using cells derived from the placenta, testes, or amniotic fluid were rejected. But a proposal to make spermatagonial stem cells, ES cells, and iPS cells was funded and highly praised, with reviewers particularly keen to see a comparison of iPS and spermatagonial stem cells from the same individual.
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‘Reprogramming ready’ mice offer a source of genetically identically induced pluripotent stem cells
An edited version will appear on the site on later this month.
Differentiated cells can be reset to an embryonic-stem-cell-like state, but doing so requires using retroviruses to insert a suite of genes into a culture of cells. Because the viruses insert their cargo at random into the genome, infected cell populations from the same individual are genetically different, and it’s hard to know whether differences between the resulting stem cell lines are due to this genetic variation, the epigenetic state of the original cells, or chance events. Worse, the current use of retroviruses renders the cells unusable for clinical applications.
Now researchers led by Rudolf Jaenisch at the Whitehead Institute in Cambridge Massachusetts show a convenient way to generate genetically identical cell populations that can be converted to induced pluripotent stem (iPS) cells by adding a drug . What’s more, they show that cells from multiple organs can be successfully reprogrammed.
In previous work, Jaenisch and other laboratories had reprogrammed cells using genes that turn on in the presence of a drug called doxycycline. This allowed them to study how long transgenes need to stay active for reprogramming to occur. To prove that the cells with drug-inducible reprogramming genes were pluripotent, researchers mixed the cells with mouse embryos to create chimeric mice.
In this paper, the researchers show that cells from multiple organs within these chimeric mice can be efficiently reprogrammed with the addition of doxycycline: reprogrammed cells include neural progenitors, mesenchymal stem cells, and keratinocytes as well as cells taken from muscle, intestinal epithelium, the adrenal gland, and the hematopoietic lineage.
iPS cells generated from different tissues taken from the same mouse are genetically identical, allowing researchers to examine the effects of cell types and retroviral insertion sites. For example, the researchers were able to reprogram intestinal epithelium derived from one iPS cell line, but not another, suggesting that reprogramming requirements vary between cell types. In particular, the expression of transgenes seemed to vary with both cell type and site of insertion in the genome.
The reprogramming rate for `secondary iPS cells’ was 4 to 8 fold higher than for the production of primary iPS cells, presumably because cells in the mice already had the favorable number of proviruses inserted at appropriate sites of the genomes. Still the overall reprogramming rate is low, only between 2% and 4%.
The researchers believe this could be because the drug-inducible transgenes may be more or less responsive to doxycycline even within genetically identical cells and also because reprogramming depends on stochastic events, several of which are required for complete reprogramming.
A source of genetically identical cells will help researchers home in on these and other variables and greatly simplify the search for methods to create clinically acceptable reprogrammed cells.
Wernig, M. et al. A drug-inducible transgenic system for direct reprogramming of multiple somatic cell types. Nat. Biotechnol. doi:10.1038/nbt1483 (Advance online publication July 1, 2008)