Making Safer Induced Pluripotent Stem Cells

Induced Pluripotent Stem Cells or iPSCs are made from mature, adult cells by means of genetic engineering techniques that introduce pluripotency genes into the adult cells. These introduced genes drive the adult cells to de-differentiate into an embryonic stem cell-like cells that have the ability to differentiate into almost all of the cells of the adult human body.

Despite the attractiveness of these cells for regenerative medicine, there is a dark side to iPSCs, since the production of iPSCs introduces new mutations into them. While not all iPSC lines are created equal and the methods by which they are derived also influences the degree of genetic damage to them, there are serious questions about the safety of iPSCs for clinical use.

A new paper from a Spanish group has discovered that a protein called SIRT1 is required to protect the chromosomal integrity of iPSCs during reprogramming.

Linear chromosomes are capped at their ends by special structures called telomeres. These telomeres shorten over time, but during reprogramming, the telomeres lengthen. This lengthening requires the SIRT1 protein, but SIRT1 is also required to maintain the telomeres at this elongated length. In this way, SIRT1 helps safeguard the chromosomes during reprogramming. The SIRT1 protein is also up-regulated in embryonic stem cells.

Using a mouse model system, researchers from the Spanish National Cancer Research Center’s Telomeres and Telomerase Group made cells that completely lacked any functional SIRT1 protein. Maria Luigia De Bonis, Sagrario Ortega, and Maria A. Blasco from CNIO discovered that SIRT1-deficient mouse cells could be reprogrammed, but the telomeres of these cells lengthened much less efficiently, and eventually experienced chromosome abnormalities and DNA damage. SIRT1-deficient iPSCs also formed larger, poorly differentiated tumors when transplanted into nude mice.  Thus SIRT1 seems to keep the chromosomes of iPSCs healthy.

Interestingly, the c-MYC protein, which is encoded by the c-myc gene – one of the four genes required to reprogram adult cells – is stabilized by SIRT1. Normally, the c-MYC protein has a very short half-life, but SIRT1 protects c-MYC from degradation, and c-MYC increases the production of the enzyme that replicates and elongates the telomeres; telomerase.

This work could very possibly lead to protocols that will stabilize the chromosomes of iPSCs during reprogramming. This will make iPSCs safer for possible use in the clinic.