Stem Cell Advance May Enhance the Process of Tissue Regeneration

The research builds on a strategy exploited by scientists from the University of California, San Francisco (UCSF; USA) that involves reprogramming adult cells back to an embryonic state in which they again have the potential to become any type of cell. They reported their findings July 17, 2014, issue of the journal Cell.

The efficiency of this process may soon increase due to the scientists’ identification of biochemical pathways that can suppress the necessary reprogramming of gene activity in adult human cells. Taking away these hurdles was shown to increase the efficiency of stem-cell production.

“Our new work has important implications for both regenerative medicine and cancer research,” said Miguel Ramalho-Santos, PhD, an associate professor of obstetrics, gynecology and reproductive sciences and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, who led the research, funded in part by a NIH Director’s New Innovator Award.

The earlier discovery that it was possible to take specialized adult cells and reverse the developmental clock to strip the mature cells of their distinguishing identities and characteristics, and to make them immortal, reprogrammable cells that theoretically can be used to substitute for any tissue type, led to a share of the Nobel Prize in Physiology or Medicine being awarded to UCSF, Gladstone Institutes and Kyoto University (Japan) researcher Shinya Yamanaka, MD, in 2012.

These induced pluripotent stem (iPS) cells are regarded as an alternative research strategy to ongoing efforts to develop tissue from stem cells obtained from early-stage human embryos. However, in spite of the potential of iPS cells and the enthusiasm surrounding iPS research, the percentage of adult cells effectively transformed to iPS cells is typically low, and the resulting cells often retain indications of their earlier lives as specialized cells.

Researchers generate stem cells by forcing the activation within adult cells of pluripotency-inducing genes, beginning with the so-called “Yamanaka factors,” a process that turns back the clock on cellular maturation. However, as Dr. Ramalho-Santos noted, “from the time of the discovery of iPS cells, it was appreciated that the specialized cells from which they are derived are not a blank slate. They express their own genes that may resist or counter reprogramming.”

But as to what precisely was getting in the way of reprogramming remained little understood. “Now, by genetically removing multiple barriers to reprogramming, we have found that the efficiency of generation of iPS cells can be greatly increased,” Dr. Ramalho-Santos said. The discovery, he reported, will contribute to accelerating the safe and effective use of iPS cells and other reprogrammed cells.

The researchers found not only isolated genes acting as barriers, but rather sets of genes acting together through different mechanisms to create roadblocks to reprogramming. “At practically every level of a cell’s functions there are genes that act in an intricately coordinated fashion to antagonize reprogramming,” Dr. Ramalho-Santos said.

These processes are likely to help adult cells maintain their characteristics and functional roles. “Much like the Red Queen running constantly to remain in the same place in Lewis Carroll’s ‘Through the Looking-Glass,’ adult cells appear to put a lot of effort into remaining in the same state,” he said.

To uncover this earlier unidentified busy biochemical environment of inhibitory gene activity, the scientists had to simultaneously master a few different technical coups in the lab. They combined advanced cellular, genetic, and bioinformatics technologies to comprehensively identify genes that act as barriers to the generation of human iPS cells, and examined how these distinctive barriers work.

Apart from maintaining the stability of adult tissues, the barrier genes most likely serve important roles in other diseases—including in the prevention of various cancers, according to Dr. Ramalho-Santos.


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