The Pluripotent

Research led by Dr. Steven McKnight of UT Southwestern Medical Center has demonstrated that the activation of a particular gene encoding threonine dehydrogenase (TDH) may be a key component of why mouse embryonic stem cells are easily grown in a laboratory while other mammalian ES cells are difficult, if not impossible, to maintain.

Here’s the abstract:

Measurements of the abundance of common metabolites in cultured embryonic stem (ES) cells revealed an unusual state with respect to one-carbon metabolism. These findings led to the discovery of copious expression of the gene encoding threonine dehydrogenase (TDH) in ES cells. TDH-mediated catabolism of threonine takes place in mitochondria to generate glycine and acetyl-CoA, with glycine facilitating one-carbon metabolism via the glycine cleavage system and acetyl-CoA feeding the tricarboxcylic acid (TCA) cycle. Culture media individually deprived of each of the 20 amino acids were applied to ES cells, leading to the discovery that ES cells are critically dependent upon but one amino acid—threonine. These observations show that ES cells exist in a unique, high-flux backbone metabolic state comparable to that of rapidly growing bacterial cells.

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Todd Ransom of UC Riverside reports:

A new development in stem cell research has resulted from a completed study by a collaboration of scientists using the drug Rapamycin to inhibit mTOR, an intracellular protein necessary in cell proliferation. UCR’s Jiayu Liao, assistant professor in the Department of Bioengineering at Bourns College of Engineering, recently published a paper on the results in the Proceeding of the National Academy of Sciences dealing with human embryonic stem cell pluripotency.

His team inhibited mTOR using Rapamycin, a drug approved by the Food and Drug Administration, and found that pluripotency (the ability to create all cell types) was impaired, stem cell self-renew was prevented, and endodermal and mesodermal differentiation were enhanced.

“Stem cells can potentially develop into cancer,” Liao said. “That’s why it is important to be certain that any stem cells introduced into patients do not remain pluripotent, which has the potential to form tumors. The use of Rapamycin could potentially prevent this problem.”

Stem cells can differentiate into and of the three germ layers: the endoderm (interior stomach lining, gastrointestinal tract, the lungs), the mesoderm (muscle, bone, blood, urogenital), or the ectoderm (epidermal tissues and nervous system). Pluripotent stem cells can give rise to any fetal or adult cell type. However, alone they cannot develop into a fetal or adult animal because they lack the potential to contribute to extra embryonic tissue, such as the placenta.

“You don’t want to maintain pluropotency when using stem cells for treatment,” Liao said. “You want them all to differentiate into one of the three germ layers.”

The discovery could have a significant impact on the future use of stem cells in regenerative medicine, he added. Rapamycin itself is also an immunosuppressant which prevents rejection of organ transplantation from the host.

“It really opens the door for stem cell research towards translational medicine” he said.

In addition, because the drug is FDA approved, there is no need to order clinical trials for safety so the method can be placed into treatment immediately.

Here’s the abstract:

“Despite the recent identification of the transcriptional regulatory circuitry involving SOX2, NANOG, and OCT-4, the intracellular signaling networks that control pluripotency of human embryonic stem cells (hESCs) remain largely undefined. Here, we demonstrate an essential role for the serine/threonine protein kinase mammalian target of rapamycin (mTOR) in regulating hESC long-term undifferentiated growth. Inhibition of mTOR impairs pluripotency, prevents cell proliferation, and enhances mesoderm and endoderm activities in hESCs. At the molecular level, mTOR integrates signals from extrinsic pluripotency-supporting factors and represses the transcriptional activities of a subset of developmental and growth-inhibitory genes, as revealed by genome-wide microarray analyses. Repression of the developmental genes by mTOR is necessary for the maintenance of hESC pluripotency. These results uncover a novel signaling mechanism by which mTOR controls fate decisions in hESCs. Our findings may contribute to effective strategies for tissue repair and regeneration.”

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[Via UC Riverside PR]

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Linda Hemphill reports on the 87th General Session of the International Association for Dental Research:

Human embryonic stem cells (hESC) provide a potentially unlimited source of oral mucosal tissues that may revolutionize the treatment of oral diseases. When fully exploited in the future, this source of cells will be able to produce functional tissues to treat a broad variety of oral diseases. However, little is known about how hESC can be developed into complex, multilayer oral tissues that line the gums, cheeks, lips, and other intra-oral sites. However, the use of hES cells for oral application faces numerous obstacles that must be overcome before their therapeutic potential can be realized.

During the 87th General Session of the International Association for Dental Research, investigators from Tufts University in Boston report on their research to optimize the potential of hESC cells to generate complex, functional multilayer tissues, such as the oral mucosa and skin, and to understand how tissue fabrication is controlled and directed.

The Garlick lab has used tissue engineering principles to produce complex oral-lining tissues that mimic many features of their counterparts found in the oral cavity. Making these tissues was a two-step process. With a combination of chemical signals and specialized surfaces on which these cells attach, an hESC cell line (H9) was directed toward two divergent cell populations. The first population comprises the surface layer (epithelial cells) of complex tissues, while the other is found beneath these cells (mesenchymal cells). Following their isolation and characterization, the team incorporated these two distinct cell populations into the two tissue compartments that comprise these tissue types. The populations were then grown at an air-liquid interface to mimic their growth environment in the oral cavity. Within two weeks, tissues developed that shared many features in common with normal tissues that were constructed with mature cells that are the “gold standard” of normal tissue generation in our lab.

For the first time, researchers have established proof of concept that a single, common source of pluripotent hESC could provide the multiple cell types needed to be recombined within different, but interactive, tissue compartments to generate complex, multilayer tissues. In addition to providing oral mucosal tissues for future transplantation, the tissues generated in these studies can now be used to answer questions regarding the stability and safety of hESC-derived cells and tissues by providing information that will predict how they will respond after therapeutic transplantation in the future.

This is a summary of abstract #3021, “Microenvironmental Cues Direct 3D Tissues from Human Embryonic Stem Cells”, by J. Garlick et al. of Tufts University (Boston, Mass., USA), which was presented at 11:45 a.m. on Saturday, April 4, 2009, in Room D235 of the Miami Beach Convention Center, during the 87th General Session of the International Association for Dental Research.

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While I’ve been busy getting ready for tomorrow’s lab meeting over the weekend, Dayo texted me news that Obama is expected to reverse (or has signed legislation?) Bush’s limitations on embryonic stem cell research today.  If the lift of Bush ban happens, the NIH would be allowed to fund studies using embryos discarded from IVF clinics.  News sources say: The move is part of a broader effort to separate science and politics and “restore scientific integrity in governmental decision-making,” White House domestic policy adviser Melody Barnes said Sunday.  Harold Varmus, co-chair of Obama’s science advisory council, said Obama’s order will direct the National Institutes of Health to develop revised guidelines on federal funding for embryonic stem cell research within 120 days.

All this seems to be in good timing (better late than later) since the NIH portion of the stimulus package was recently announced to scientists.  Allowing hESCs would expand the possible projects to be funded by the NIH.

Update:  Pres Obama signed today legislation allowing federal funding for human embryonic stem cell research.  Here’s the full text of the executive order.

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I just read on local news that the New Mexico Senate passed a bill today (Thursday) to allow the University of New Mexico to perform embryonic stem cell research.  So hESC research supporters gain a point over pro-lifers here.  Senators voted 27-14 in favor of Senate Bill 77 , which now heads to the House.  Researchers can’t use any embryos for research.  They could only use embryos that had been discarded from in-vitro fertilization clinics and only with the consent of the original owner of the embryo.  And the obvious things are prohibited: selling embryos, cloning embryos, or created them just for the sake of research. Watch the video!

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Reuters is reporting that President Barack Obama will soon issue an executive order lifting an eight-year ban embryonic stem cell research imposed by former President George W. Bush.  This was announced by Senior Adviser David Axelrod on Sunday, “We’re going to be doing something on that soon, I think. The president is considering that right now.”

It’s good to know to hear from a senior adviser that Pres. Obama is currently considering the issue, especially after he vowed to reverse Bush’s ban during his campaign and inaugural address to “return science to its proper place.”

More news:
Washington Post

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The guy in the picture is Ge Lin, a postdoc in UConn’s Stem Cell Core Laboratory in Farmington.  He and fellow researchers developed two new lines of embryonic stem cells that are expected to boost work seeking treatments for a variety of diseases.  The new stem cell lines, named CT1 and CT2, were derived from embryos from a fertility clinic, donated with the consent of the patients.  Why is this news?  The breakthrough is significant because it will allow UConn to supply researchers in Connecticut and elsewhere the material necessary for research that scientists believe could lead to advances ranging from the repair of bones shattered in war to cures for diseases like diabetes and Parkinson’s.

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