"The reprogramming process erased all nuclear and epigenetic defects and the rejuvenated pluripotent cells looked and acted like perfectly normal healthy cells," says first author Guang-Hui Liu, Ph.D., a postdoctoral researcher in the Belmonte lab.

Since lamin A is only expressed in differentiated cells but is absent from embryonic stem cells, he wondered whether iPS cells produce lamin A and/or progerin, which should follow the same expression pattern as lamin A. In his experiments, he couldn't detect either one. "The biological clock is reset in these cells because lamin A is silenced," explains Liu.

As soon as the Salk researchers differentiated Progeria-derived iPS cells, progerin expression was reactivated. "This reversible suppression of progerin expression by reprogramming and subsequent reactivation during differentiation, provides a unique model system to study human premature aging pathologies," says Izpis a Belmonte.

Progerin accumulates mainly in smooth muscle cells found within the walls of arterial blood vessels, and vascular smooth muscle cells degeneration is one of the hallmarks of Hutchinson-Gilford Progeria Syndrome-associated arteriosclerosis. In fact, vascular smooth muscle cell senescence also plays a role in advanced arteriosclerosis within the normal aging population.

Upon directed differentiation of Progeria-derived iPS cells into smooth muscle cells the premature aging phenotype, including misshapen nuclei, the loss of gene silencing marks and compromised proliferation, reappeared. Genetically modifying progeria-derived iPS cells to shut down the expression of progerin staved off the premature appearance of aging phenotypes after differentiation. "Transplantation of the progenitor cells derived from the "corrected" progeria iPS cells might hold the promise to treat these progeria children in the future." says Liu.

Source: Salk Institute