iPS Cells Help Provide Insights into the Premature Aging Disease Dyskeratosis Congenita

Richard Mollard MBA, PhD*

Dyskeratosis congenita is a rare but severe human disease associated with a disorder in the end of the chromosomes. This disorder results in chromosomal instability and manifests a likeness to premature aging characterised by a shortened lifespan in more severely affected patients. A recent report by Agarwal and colleagues (1) describes how reprogramming human fibroblasts taken from patients with various forms of dyskeratosis congenita produced iPS cells that overcame the limitation associated with premature aging (please read the briefing on human iPS cells).

Cells within our body are replicated under many circumstances, including: organ building during fetal development, tissue repair following injury, and normal tissue turnover as cells are lost performing their daily allocated functions. As cells replicate, the chromosomal DNA contained within these cells must also be replicated. However, such chromosomal replication poses a dilemma because the very ends of chromosomes, called telomeres, are unable to be fully replicated due to limitations of the replication process. After several rounds of replication, therefore, the ends of replicated chromosomes become shorter and shorter. Such shortening of chromosomal ends increases the risk that important genes located near the ends of the chromosomes will become damaged. As such, the cell becomes stressed and loses its ability to divide, a process known as cellular aging.

Cellular aging would pose a problem for cells that are required to divide repeatedly. Stem cells and germ cells, for example, would be limited in their ability to continually contribute to the production of new cells as the developing embryo, fetus or adult body requires. These special types of cells, however, are able to overcome this dilemma, in part by producing a molecule called telomerase that restores the length of the telomeres. These types of cells are thus equipped to avoid stress and accompanying cellular aging during extended rounds of replication because their chromosomal ends (telomeres) are protected against severe shortening.

Patients with dyskeratosis congenita bear a premature aging likeness because a genetic impairment of telomerase function results in premature cellular aging. The production of iPS cells from fibroblasts normally involves the switching on of telomerase function. An interesting question asked by Agarwal and colleagues, therefore, was whether the genetic impairment of telomerase function in patients with dyskeratosis congenita would affect the ability to produce iPS. These researchers demonstrated that despite the genetic lesion, telomerase function could be switched back on and iPS cells made.

It is believed that in the future, iPS cells will represent a valuable resource for cell replacement therapies and for testing the safety of new pharmacological products on a patient-to-patient basis. The paper by Agarwal and colleagues additionally illustrates important uses for iPS cells as tools to better understand how diseases such as dyskeratosis congenita manifest and to potentially help deliver better therapeutic strategies.

Notes:

1. Agarwal S., Loh Y.H., McLoughlin E.M., Huang J., Park I.H., Miller J.D., Huo H., Okuka M., Dos Reis R.M., Loewer S., Ng H.H., Keefe D.L., Goldman F.D., Klingelhutz A.J., Liu L., Daley G.Q. (2010) Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature 464(7286), 292-296.

*Author Affiliation
Richard Mollard, MBA, PhD
The Department of Biochemistry and Molecular Biology
Monash University
Clayton 3800
Australia

Posted July 20, 2010