Reprogrammed Cells Kept Bug-Free by SIRT1

Regenerative medicine—the promise of rejuvenating or replacing damaged or diseased tissues—will most likely rely on the use of induced pluripotent stem (iPS) cells, which are obtained when adult cells are essentially thrown into evolutionary reverse. This abrupt change can be hard on cells, which may suffer chromosomal abnormalities and DNA damage.

And so the bright vistas of regenerative medicine are shadowed by a stubborn cloud—the uncertainty that stem cells that are derived from adult cells are really safe. There is, however, a silver lining: Telomeres, the structures that protect the ends of chromosomes, increase in length during cell reprogramming. Ordinarily they shorten over time.

The increase in telomere length during reprogramming is important because it allows stem cells to acquire the immortality that characterizes them. If telomere lengthening were better understood, scientists might find ways to enhance cellular processes that preserve genome integrity and ensure the healthy functioning of stem cells. That, at least, was the reasoning behind a recent study conducted by researchers at the Spanish National Cancer Research Center (CNIO).

These researchers, who represented the CNIO’s Telomeres and Telomerase Group and Transgenic Mice Core Unit, published their findings April 17 in Stem Cell Reports, in an article entitled “SIRT1 Is Necessary for Proficient Telomere Elongation and Genomic Stability of Induced Pluripotent Stem Cells.”

As the title indicates, the researchers focused on the role of SIRT1, a protein of the sirtuin family that is involved in the maintenance of telomeres, genomic stability, and DNA damage response. SIRT1, the researchers were aware, occurs in higher amounts in embryonic stem cells. In addition, SIRT1 is downregulated upon differentiation. And so the researchers were curious to learn whether the rise in SIRT1 during cellular reprogramming and its subsequent fall, upon differentiation, were more than coincidental. That is, the researchers wanted to know how, exactly, SIRT1 was implicated in pluripotency.

Employing SIRT1-depleted mouse models and cell cultures as research tools, the CNIO research team discovered that SIRT1 is necessary for reprogramming to occur correctly and safely. “We observed cell reprogramming in the absence of SIRT1, but over time the produced iPS cells lengthen telomeres less efficiently and suffer from chromosome aberrations and DNA damage,” said María Luigia De Bonis, a postdoctoral researcher of the Telomeres and Telomerase Group. “SIRT1 helps iPS cells to remain healthy.”

In their article, the authors described the protective effect of SIRT1 as follows: “We find that SIRT1 is required for efficient postreprogramming telomere elongation, and that this effect is mediated by a c-MYC-dependent regulation of the mTert gene. We further demonstrate that SIRT1-deficient iPSCs accumulate chromosomal aberrations and show a derepression of telomeric heterochromatin. Finally, SIRT1-deficient iPSCs form larger teratomas that are poorly differentiated, highlighting a role for SIRT1 in exit from pluripotency.”

Ultimately, the researchers concluded that SIRT1 deacetylase has a role in “the maintenance of ‘good-quality’ iPSCs, with proper telomere elongation, TERRA transcription, telomeric chromatin remodeling, and genome integrity. (According to the researchers, TERRAS, or TelRNAs, are noncoding transcripts that closely associate with telomeres and negatively regulate telomerase activity in vitro.) With respect to the significance of their work, the researchers indicated that understanding the molecular mechanisms such as those evidenced by SIRT1 in established iPSC lines is “critical to the advance of iPSC technology in regenerative medicine.”