Post-mitotic cells of known identity divide and make copies of themselves when brakes on cell cycle (Rb and Ink4/ARF) are transiently released

 

4. dedifferentiation.


To capitalize on natural mechanisms to induce cell plasticity, our lab set out to discover the “secret of the newt”. Newts and zebra-fish regenerate their limbs and fins by “dedifferentiation”, which entails relieving the brakes on the cell cycle by inactivating the tumor suppressor, Rb.  

As a result, the post-mitotic differentiated cells of these tissues go back one step, re-enter the cell cycle, and make numerous copies of themselves. However, this simple trick had been tried by others and did not work in mammals.

A review of the literature revealed that another cell cycle inhibitor and tumor suppressor, the product of the Ink4a locus, p19/ARF, is missing in newts and first arose in evolution in chickens. Our lab reasoned that by temporarily relieving the brakes on the cell cycle by a combined si-RNA mediated knockdown of Rb and p19/ARF, a new mammalian cell source for regeneration could be generated.

Our lab achieved proof of principle in muscle and is now exploring the extent to which this potent approach can be applied to the generation of cells from other tissues for use in regenerative medicine.

* Pajcini et al., Cell Stem Cell, 2010 (PDF)

* Blau and Pomerantz, JAMA, 2011 (PDF)