Histones may hold the key to the generation of totipotent stem cells

1 hour ago This image shows iPS cells (green) generated using histone variants TH2A and TH2B and two Yamanaka factors (Oct3/4 and Klf4). Credit: RIKEN

One major challenge in stem cell research has been to reprogram differentiated cells to a totipotent state. Researchers from RIKEN in Japan have identified a duo of histone proteins that dramatically enhance the generation of induced pluripotent stem cells (iPS cells) and may be the key to generating induced totipotent stem cells.

Differentiated cells can be coaxed into returning to a stem-like pluripotent state either by artificially inducing the expression of four factors called the Yamanaka factors, or as recently shown by shocking them with sublethal stress, such as low pH or pressure. However, attempts to create totipotent stem cells capable of giving rise to a fully formed organism, from differentiated cells, have failed.

The study, published today in the journal Cell Stem Cell and led by Dr. Shunsuke Ishii from RIKEN, sought to identify the molecule in the mammalian oocyte that induces the complete reprograming of the genome leading to the generation of totipotent embryonic stem cells. This is the mechanism underlying normal fertilization, as well as the cloning technique called Somatic-Cell Nuclear Transfer (SCNT).

SCNT has been used successfully to clone various species of mammals, but the technique has serious limitations and its use on human cells has been controversial for ethical reasons.

Ishii and his team chose to focus on two histone variants named TH2A and TH2B, known to be specific to the testes where they bind tightly to DNA and affect gene expression.

The study demonstrates that, when added to the Yamanaka cocktail to reprogram mouse fibroblasts, the duo TH2A/TH2B increases the efficiency of iPSC cell generation about twentyfold and the speed of the process two- to threefold. And TH2A and TH2B function as substitutes for two of the Yamanaka factors (Sox2 and c-Myc).

By creating knockout mice lacking both proteins, the researchers show that TH2A and TH2B function as a pair, are highly expressed in oocytes and fertilized eggs and are needed for the development of the embryo after fertilization, although their levels decrease as the embryo grows.

In the early embryo, TH2A and TH2B bind to DNA and induce an open chromatin structure in the paternal genome, thereby contributing to its activation after fertilization.

These results indicate that TH2A/TH2B might induce reprogramming by regulating a different set of genes than the Yamanaka factors, and that these genes are involved in the generation of totipotent cells in oocyte-based reprogramming as seen in SCNT.

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Histones may hold the key to the generation of totipotent stem cells

Stem Cell Research at the 2014 NJ Symposium on Biomaterials Science

Piscataway, NJ (PRWEB) February 06, 2014

Mahendra Rao, MD, PhD, the Director of the Center for Regenerative Medicine (CRM) at the National Institutes of Health (NIH) has agreed to be a keynote speaker at the 12th edition of the New Jersey Symposium Biomaterials Science. Dr. Rao is internationally renowned for his research involving human embryonic stem cells and other somatic stem cells. He has worked in the stem cell field for more than 20 years with stints in academia, government and regulatory affairs, and industry. Dr. Rao will address the role of biomaterials for stem cell therapies in a session devoted to scientific breakthroughs leading to clinical applications.

Along with Dr. Rao, the 12th edition of the New Jersey Symposium on Biomaterials Science will feature a roster of presentations by 30 leading scientists, many with global reputations for their work in academia and industry in the areas of biomaterials, bioengineering and clinical practice.

Detailed information about the symposium and registration links will be found at http://www.njbiomaterials.org/biomaterials-symposia.htm.

The New Jersey Center for Biomaterials (NJCBM) was founded in 1997. Based at Rutgers, the State University of New Jersey, the center spans academia, industry and government. Staffed by biomaterial scientists, the Center works to improve health care and quality of life by developing advanced biomedical products for tissue repair and replacement as well as the delivery of pharmaceutical agents. The Centers technologies have been translated into clinical and pre-clinical products including surgical meshes, cardiovascular stents, bone regeneration scaffolds, and ocular drug delivery systems.

Media Contact:

Louli Kourkounakis (732) 445 0488 ext. 40001 symposium(at)dls(dot)rutgers(dot)edu

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Stem Cell Research at the 2014 NJ Symposium on Biomaterials Science

Extraordinary stem cell method tested in human tissue

(Image: Charles Vacanti and Koji Kojima, Harvard Medical School)

Talk about speedy work. Hot on the heels of the news that simply dipping adult mouse cells in acid could turn them into cells with the potential to turn into any cell in the body, it appears that the same thing may have been done using human cells.

The picture above, given to New Scientist by Charles Vacanti at Harvard Medical School, is said to be images of the first human "STAP cell" experiments.

Last week, the scientific world was bowled over by a study in Nature showing that an acidic environment turned adult mouse cells into "totipotent" stem cells which can turn into any cell in the body or placenta. The researchers called these new totipotent cells stimulus-triggered acquisition of pluripotency (STAP) cells.

"If they can do this in human cells, it changes everything," Rob Lanza of Advanced Cell Technologies in Marlborough, Massachusetts, said at the time. The technique promises cheaper, quicker and potentially more flexible cells for regenerative medicine, cancer therapy and cloning.

Now, Vacanti and his colleagues say they have taken human fibroblast cells and tested several environmental stressors on them in an attempt to recreate human STAP cells. He won't reveal what type of stressors were applied but he says the resulting cells appears similar in form to the mouse STAP cells. His team is in the process of testing to see just how stem-cell-like these cells are.

Vacanti says that the human cells took about a week to resemble STAP cells, and formed spherical clusters just like their mouse counterparts. Using a similar experimental set-up with green monkey (Chlorocebus sabaeus) cells, Vacanti says the resulting cells are behaving slightly differently. He says that may be due to the fact that the researchers used slightly different techniques. Both Vacanti and his Harvard colleague Koji Kojima emphasise that these results are only preliminary and much further analysis and validation is required.

"Even if these are STAP cells they may not necessarily have the same potential as mouse ones they may not have the totipotency which is one of the most interesting features of the mouse cells," says Sally Cowley, head of the James Martin Stem Cell Facility at the University of Oxford.

Pluripotent cells, such as embryonic stem cells, can form any cell in an embryo but not a placenta. Totipotent cells, however, can form any cell in an embryo and a placenta meaning they have the potential to create life. The only cells known to be naturally totipotent are in embryos that have only undergone the first couple of cell divisions immediately after fertilisation.

Research using totipotent cells would have to be under very strict regulatory surveillance, says Cowley. "It would actually be ideal if the human cells could be pluripotent and not totipotent it would make everyone's life a lot easier."

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Extraordinary stem cell method tested in human tissue