Increasing Reprogramming Efficiency by Turning Off One Gene

The removal of one genetic roadblock could improve the efficiency of adult cell reprogramming by some 10 to 30 fold, according to research by stem cell scientists at the Methodist Hospital Research Institute and two other institutions.

Rongfu Wang, the principal investigator and director of the Center for Inflammation and Epigenetics, said this about his group’s findings: “The discovery six years ago that scientist can convert adult cells into inducible pluripotent stem cells, or iPSCs, bolstered the dream that a patient’s own cells might be reprogrammed to make patient-specific iPSCs for regenerative medicine, modeling human diseases in Petri dishes, and drug screening. But reprogramming efficiency has remained very low, impeding its applications in the clinic.”

Wang and his group identified a protein encoded by a gene called Jmjd3, which is known as KDM6B, acts as an impediment to the reprogramming of adult cells into iPSCs. Jmjd3 is involved in several different biological processes, including the maturation of nerve cells and immune cell differentiation (Popov N, Gil J. Epigenetics. 2010 5(8):685-90).

These findings by Wang’s team are the first time anyone has identified a role for Jmjd3 in the reprogramming process. According to Wang, fibroblasts that lack functional Jmjd3 showed greatly enhanced reprogramming efficiency.

Helen Wang, one of the co-principal authors of this study, said, “Our findings demonstrate a previously unrecognized role of Jmjd3 in cellular reprogramming and provide molecular insight into the mechanisms by which the Jmjd3-PHF20 axis controls this process.’

While teasing apart the roles of Jmjd3 in reprogramming, Wang and his colleagues discovered that this protein regulates cell growth and cellular aging. These are two previously unidentified functions of Jmjd3, and Jmjd3 appears to work primarily by inactivating the protein PHF20. PHF20 is a protein that is required for adult cell reprogramming, and cells that lack PHF20 do not undergo reprogramming to iPSCs.

Rongfu Want explained it like this: “So when it comes to increasing iPSC yields, knocking down Jmjd3 is like hitting two birds with one stone.”

Jmjd3 is almost certainly not the only genetic roadblock to stem cell conversion. Wang noted, “Removal of multiple roadblacks could further enhance the reprogramming efficiency with which researchers can efficiently generate patient-specific iPSCs for clinical applications.”

While this is certainly an exciting finding, there is almost certainly a caveat that comes with it. increased reprogramming efficiency almost certainly brings the potential for increased numbers of mutations. Other studies have shown that iPSC generation is much more efficient if the protein P53 is inhibited, but P53 is the guardian of the genome. It prevents the cell from dividing if there is substantial amounts of DNA damage. Inhibiting P53 activity allows iPSC generation even if the cells have excessive amounts of DNA damage. Therefore, inhibiting those cellular processes that are meant to guard against excessive cell proliferation and growth can lead to greater numbers of mutations. Thus, before Jmjd3 inactivation is used to generate iPSCs for clinical uses, extensive animal testing must be required to ensure that this procedure does make iPSCs even less safe than they already are.

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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).

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