OHSU research team successfully converts human skin cells into embryonic stem cells

(Press-News.org) PORTAND, Ore. – Scientists at Oregon Health & Science University and the Oregon National Primate Research Center (ONPRC) have successfully reprogrammed human skin cells to become embryonic stem cells capable of transforming into any other cell type in the body. It is believed that stem cell therapies hold the promise of replacing cells damaged through injury or illness. Diseases or conditions that might be treated through stem cell therapy include Parkinson's disease, multiple sclerosis, cardiac disease and spinal cord injuries.

The research breakthrough, led by Shoukhrat Mitalipov, Ph.D., a senior scientist at ONPRC, follows previous success in transforming monkey skin cells into embryonic stem cells in 2007. This latest research will be published in the journal Cell online May 15 and in print June 6.

The technique used by Drs. Mitalipov, Paula Amato, M.D., and their colleagues in OHSU's Division of Reproductive Endocrinology and Infertility, Department of Obstetrics & Gynecology, is a variation of a commonly used method called somatic cell nuclear transfer, or SCNT. It involves transplanting the nucleus of one cell, containing an individual's DNA, into an egg cell that has had its genetic material removed. The unfertilized egg cell then develops and eventually produces stem cells.

"A thorough examination of the stem cells derived through this technique demonstrated their ability to convert just like normal embryonic stem cells, into several different cell types, including nerve cells, liver cells and heart cells. Furthermore, because these reprogrammed cells can be generated with nuclear genetic material from a patient, there is no concern of transplant rejection," explained Dr. Mitalipov. "While there is much work to be done in developing safe and effective stem cell treatments, we believe this is a significant step forward in developing the cells that could be used in regenerative medicine."

Another noteworthy aspect of this research is that it does not involve the use of fertilized embryos, a topic that has been the source of a significant ethical debate.

The Mitalipov team's success in reprogramming human skin cells came through a series of studies in both human and monkey cells. Previous unsuccessful attempts by several labs showed that human egg cells appear to be more fragile than eggs from other species. Therefore, known reprogramming methods stalled before stem cells were produced. To solve this problem, the OHSU group studied various alternative approaches first developed in monkey cells and then applied to human cells. Through moving findings between monkey cells and human cells, the researchers were able to develop a successful method.

The key to this success was finding a way to prompt egg cells to stay in a state called "metaphase" during the nuclear transfer process. Metaphase is a stage in the cell's natural division process (meiosis) when genetic material aligns in the middle of the cell before the cell divides. The research team found that chemically maintaining metaphase throughout the transfer process prevented the process from stalling and allowed the cells to develop and produce stem cells.

"This is a remarkable accomplishment by the Mitalipov lab that will fuel the development of stem cell therapies to combat several diseases and conditions for which there are currently no treatments or cures," said Dr. Dan Dorsa, Ph.D., OHSU Vice President for Research. "The achievement also highlights OHSU's deep reproductive expertise across our campuses. A key component to this success was the translation of basic science findings at the OHSU primate center paired with privately funded human cell studies."

One important distinction is that while the method might be considered a technique for cloning stem cells, commonly called therapeutic cloning, the same method would not likely be successful in producing human clones otherwise known as reproductive cloning. Several years of monkey studies that utilize somatic cell nuclear transfer have never successfully produced monkey clones. It is expected that this is also the case with humans. Furthermore, the comparative fragility of human cells as noted during this study, is a significant factor that would likely prevent the development of clones.

"Our research is directed toward generating stem cells for use in future treatments to combat disease," added Dr. Mitalipov. "While nuclear transfer breakthroughs often lead to a public discussion about the ethics of human cloning, this is not our focus, nor do we believe our findings might be used by others to advance the possibility of human reproductive cloning."

### The human studies were funded by OHSU and a grant from Leducq Foundation. The nonhuman primate studies were funded by the following grants from the National Institutes of Health: HD063276, HD057121, HD059946, EY021214 and OD011092.

Illustrations, Photos and Videos

Link to graphic illustrating the cell reprogramming process
http://www.ohsu.edu/news/media/images/stem-cell-breakthrough-2013.jpg

Link to sound bites from Dr. Shoukhrat Mitalipov, Ph.D.
Password: stemcell33
https://vimeo.com/66009914

Link to video of the cell manipulation process filmed using a microscope equipped with a video camera
Password: stemcell33
https://vimeo.com/66012007

Link to video of beating heart cells from stem cells derived from skin cells
Password: stemcell33
https://vimeo.com/66012006

Link to animation of cell reprogramming process
Password: stemcell33
https://vimeo.com/66012008

Link to cell photos
http://www.flickr.com/photos/ohsunews/sets/72157633449241885/

Link to photos of Dr. Shoukhrat Mitalipov, Ph.D.
http://www.flickr.com/photos/ohsunews/sets/72157633478865988/

Particulars: Dr. Shoukhrat Mitalipov, Ph.D. Senior Scientist and Professor in the Division of Reproductive & Developmental Sciences at ONPRC, Oregon Stem Cell Center and OHSU School of Medicine departments of Obstetrics & Gynecology and Molecular & Medical Genetics.

About ONPRC The ONPRC is one of the eight National Primate Research Centers supported by NIH. ONPRC is a registered research institution, inspected regularly by the United States Department of Agriculture. It operates in compliance with the Animal Welfare Act and has an assurance of regulatory compliance on file with the National Institutes of Health. The ONPRC also participates in the voluntary accreditation program overseen by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC).

About OHSU Oregon Health & Science University is the state's only academic health and research university. As Portland's largest employer with approximately 14,000 employees, OHSU's size contributes to its ability to provide many services and community support not found anywhere else in the state. OHSU serves patients from every corner of Oregon and is a conduit for learning for more than 4,300 students and trainees. OHSU is the source of more than 200 community outreach programs that bring health and education services to each county in the state. END