Researchers from the University of California-San Francisco report a new stem cell discovery that might eventually lead to a more streamlined process for obtaining stem cells, which, in turn, could be used in the development of replacement tissue for failing body parts.
The scientists say their finding builds on a strategy that involves reprogramming adult cells back to an embryonic state in which they again have the potential to become any type of cell. The team published its study (“Systematic Identification of Barriers to Human iPSC Generation”) in Cell. They believe the efficiency of this process may soon increase because of the identification of biochemical pathways that can inhibit the necessary reprogramming of gene activity in adult human cells. Removing these barriers increased the efficiency of stem cell production, the researchers pointed out.
"Our new work has important implications for both regenerative medicine and cancer research," said Miguel Ramalho-Santos, Ph,D,, 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.
The earlier discovery that it was possible to take specialized adult cells and reverse the developmental clock to strip the mature cells of their distinctive identities and characteristics—and to make them immortal, reprogrammable cells that theoretically can be used to replace any tissue type—led to a share of the Nobel Prize in Physiology or Medicine being awarded to UCSF, Gladstone Institutes, and Kyoto University researcher Shinya Yamanaka, M.D., in 2012.
These induced pluripotent stem (iPS) cells are regarded as an alternative experimental approach to ongoing efforts to develop tissue from stem cells obtained from early-stage human embryos. However, despite the promise of iPS cells and the excitement surrounding iPS research, the percentage of adult cells successfully converted to iPS cells is typically low, and the resultant cells often retain traces of their earlier lives as specialized cells.
As Dr. Ramalho-Santos notes, "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 the nature of what exactly was getting in the way of reprogramming remained poorly understood. "Now, by genetically removing multiple barriers to reprogramming, we have found that the efficiency of generation of iPS cells can be greatly increased," he said. The discovery will contribute to accelerating the safe and efficient use of iPS cells and other reprogrammed cells, according to Dr. Ramalho-Santos.
“We identify reprogramming barriers, including genes involved in transcription, chromatin regulation, ubiquitination, dephosphorylation, vesicular transport, and cell adhesion. Specific a disintegrin and metalloproteinase (ADAM) proteins inhibit reprogramming, and the disintegrin domain of ADAM29 is necessary and sufficient for this function,” wrote the investigators. “Clathrin-mediated endocytosis can be targeted with small molecules and opposes reprogramming by positively regulating TGF-β signaling. Genetic interaction studies of endocytosis or ubiquitination reveal that barrier pathways can act in linear, parallel, or feedforward loop architectures to antagonize reprogramming. These results provide a global view of barriers to human cellular reprogramming.”
Apart from maintaining the integrity of our adult tissues, the barrier genes probably serve important roles in other diseases, including in the prevention of certain cancers, explained Dr. Ramalho-Santos.