Monthly Archives: March 2014

These neurons derived from stem cells made from the skin of people with bipolar disorder communicated with one another differently than neurons made from the skin of people without bipolar disorder.(Credit: University of Michigan)

Bipolar disorder is known to run in families, but scientists have yet to pinpoint the genes involved. Now they have a powerful new tool in the hunt: stem cells.

In a first-of-its-kind procedure, researchers from the University of Michigan have created stem cells from the skin of people with bipolar disorder, and then coaxed the cells into neurons. This has allowed scientists, for the first time, to directly measure cellular differences between people with bipolar disorder and people without.

In the future the cells could provide a greater understanding of what causes the disease, and allow for the development of personalized medications specific to each patients cells.

The team from Michigan took skin cell samples from 22 people with bipolar disorder and 10 people without the disorder. Under carefully controlled conditions, they coaxed adult skin cells into an embryonic stem cell-like state. These cells, called induced pluripotent stem cells, then had the potential to transform into any type of cell. With further coaxing, the cells became neurons.

This gives us a model that we can use to examine how cells behave as they develop into neurons. Already, we see that cells from people with bipolar disorder are different in how often they express certain genes, how they differentiate into neurons, how they communicate, and how they respond to lithium, study co-leader Sue OShea said in a news release.

Researchers published their findings Wednesday in the journalTranslational Psychiatry.

The research team discovered intriguing differences between stem cellsand neuronsfrom bipolar individuals and those from healthy people.

For one thing, bipolar stem cells expressed more genes associated with receiving calcium signals in the brain. Calcium signals play an important role in neuron development and function. Therefore, the new findings support the idea that genetic differences expressed early in life may contribute to the development of bipolar disorder later in life.

Once the stem cells turned into neurons, researchers tested how they reacted to lithium, a typical treatment for the disorder. The tests showed that lithium normalized the behavior of neurons from bipolar patients by altering their calcium signalingfurther confirmation that this cellular pathway should be of key interest in future studies of the disease.

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Stem Cells Shed Light on Treatments for Bipolar Disorder

11 hours ago Embryonic stem cells (ESCs) established from an interphase 2-cell SCNT blastocyst (magnification 40x). Credit: Mitalipov laboratory at OHSU

An Oregon Health & Science University scientist has been able to make embryonic stem cells from adult mouse body cells using the cytoplasm of two-cell embryos that were in the "interphase" stage of the cell cycle. Scientists had previously thought the interphase stagea later stage of the cell cyclewas incapable of converting transplanted adult cell nuclei into embryonic stem cells.

The findings by OHSU's Shoukhrat Mitalipov, Ph.D., and his team could have major implications for the science of generating patient-matched human embryonic stem cells for regenerative medicine. Human embryonic stem cells are capable of transforming into any cell type in the body. Scientists believe stem cell therapies hold promise for someday curing or treating a wide range of diseases and conditionsfrom Parkinson's disease to cardiac disease to spinal cord injuriesby replacing cells damaged through injury or illness.

Mitalipov's findings will be published March 26 in the online edition of Nature. If the new findings in mice hold true for humans, it could significantly help efforts to make rejection-proof human embryonic stem cells for regenerative therapies. That's because embryonic cells that Mitalipov's team used for reprogrammingcells in the "interphase" stageare more accessible than the traditional egg cells that are in short supply. Scientists previously had believed embryonic stem cells were capable of being produced only using the metaphase stage of egg cytoplasm.

Embryonic stem cells can be made using a process called somatic cell nuclear transfer, or SCNT, in which the nucleus from an adult cell is transferred into the cytoplasm of an unfertilized egg cell. The cytoplasmic machinery then "reprograms" that nucleus and cell into becoming an embryonic stem cell capable of transforming to any type of cell in the body.

"It has always been thought that this capacity for reprogramming ended with metaphase," said Mitalipov, senior scientist at OHSU's Oregon National Primate Research Center. "Our study shows that this reprogramming capacity remains in the later embryonic cell cytoplasm even during interphase. It looks like the factors continue working and they efficiently reprogram the cellsjust as they do in metaphase."

Many scientists have attempted to reprogram cells by interphase cytoplasm. Mitalipov and his team found success by carefully synchronizing the cell cycles of the adult cell nucleus and the recipient embryonic cytoplasm. Both had to be at an almost identical point in their respective cell cycles for the process to work, Mitalipov said.

"That was the secret," Mitalipov said. "When we did that matching, then everything worked."

Mitalipov said the next step to further his research will be to test the process in rhesus macaques.

Mitalipov has become a world scientific leader in embryonic stem cell research and in somatic cell nuclear transfer. He recently was named the director of a newly created research center at OHSUthe Center for Embryonic Cell and Gene Therapy. The center will help Mitalipov and his team accelerate their research, with expanded support from private philanthropy.

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Embryonic stem cells: Reprogramming in early embryos

Just as archeologists try to decipher ancient tablets to discern their meaning, UT Southwestern Medical Center cancer biologists are working to decode the purpose of an ancient gene considered one of the most important in cancer research.

The p53 gene appears to be involved in signaling other cells instrumental in stopping tumor development. But the p53 gene predates cancer, so scientists are uncertain what its original function is.

In trying to unravel the mystery, Dr. John Abrams, Professor of Cell Biology at UT Southwestern, and his team made a crucial new discovery -- tying the p53 gene to stem cells. Specifically, his lab found that when cellular damage is present, the gene is hyperactive in stem cells, but not in other cells. The findings suggest p53's tumor suppression ability may have evolved from its more ancient ability to regulate stem cell growth.

"The discovery was that only the stem cells light up. None of the others do. The exciting implication is that we are able to understand the function of p53 in stem cells," said Dr. Abrams, Chair of the Genetics and Development program in UT Southwestern's Graduate School of Biomedical Sciences. "We may, in fact, have some important answers for how p53 suppresses tumors."

The findings appear online in the journal eLife, a joint initiative of the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust.

p53 is one of the hardest working and most effective allies in the fight against cancer, said Dr. Abrams. It regulates other genes, marshaling them to carry out an untold number of preemptive attacks and obliterate many pre-cancerous cells before they ever pose a threat. In nearly every case where there's a tumor, p53 is damaged or deranged, strongly suggesting that it is a tumor suppressant.

Stem cells are one of the body's most useful cells because of their regenerative capabilities. Stem cells produce daughter cells, one that is a stem cell and another that can become virtually any kind of cell that's needed, such as a blood cell or a kidney cell. Stem cells have received tremendous attention in cancer research because of the stem cell hypothesis. That hypothesis maintains that malignant tumors are initiated and maintained by a population of tumor cells that have properties similar to adult stem cells.

"What this new finding tells us is that an ancient functionality of p53 was hard-wired into stem cell function," said Dr. Abrams, senior author. "From the standpoint of trying to decipher cancer biology, that's a pretty profound observation."

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The above story is based on materials provided by UT Southwestern Medical Center. Note: Materials may be edited for content and length.

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Tumor suppressor gene linked to stem cells, cancer biologists report